International

REVIEW OF

Neurobiology
Volume 84

SERIES EDITORS

RONALD J. BRADLEY
Department of Psychiatry, College of Medicine
The University of Tennessee Health Science Center
Memphis, Tennessee, USA

R. ADRON HARRIS
Waggoner Center for Alcohol and Drug Addiction Research
The University of Texas at Austin
Austin, Texas, USA

PETER JENNER
Division of Pharmacology and Therapeutics
GKT School of Biomedical Sciences
King’s College, London, UK

EDITORIAL BOARD

ERIC AAMODT HUDA AKIL

PHILIPPE ASCHER MATTHEW J. DURING
DONARD S. DWYER DAVID FINK
MARTIN GIURFA MICHAEL F. GLABUS
PAUL GREENGARD BARRY HALLIWELL
NOBU HATTORI JON KAAS
DARCY KELLEY LEAH KRUBITZER
BEAU LOTTO KEVIN MCNAUGHT
MICAELA MORELLI JOSÉ A. OBESO
JUDITH PRATT CATHY J. PRICE
EVAN SNYDER SOLOMON H. SNYDER
JOHN WADDINGTON STEPHEN G. WAXMAN
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 CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.
Katherine J. Bangen (81), Department of Psychiatry, School of Medicine,
University of California, San Diego 92093, USA
Yvonne Bannon (1), Department of Psychiatry and Behavioral Medicine,
University of South Florida, 3515 East Fletcher Avenue, MDC-14, Tampa,
Florida 33613, USA
Lars Bertram (167), Neuropsychiatric Genetics Group, Department of
Vertebrate Genomics, Max-Planck Institute for Molecular Genetics, Berlin
14195, Germany; and Genetics and Aging Research Unit, Department of
Neurology, Massachusetts General Hospital, Charlestown, Massachusetts,
02129, USA
Mona K. Beyer (49), The Norwegian Centre for Movement Disorders; and
Department of Radiology, Stavanger University Hospital, Stavanger, Norway
Mark W. Bondi (81), Veterans AVairs San Diego Healthcare System, San
Diego 92161, USA; and Department of Psychiatry, School of Medicine,
University of California, San Diego 92093, USA
Aimee Borazanci (245), Department of Neurology, Louisiana State University
School of Medicine-Shreveport, Shreveport, Louisiana 71103, USA
Andrea C. Bozoki (185), Department of Neurology, Michigan State University,
East Lansing, Michigan, 48824, USA
Maria T. Caserta (1), Department of Psychiatry and Behavioral Medicine,
University of South Florida, 3515 East Fletcher Avenue, MDC-14, Tampa,
Florida 33613, USA
Jody Corey-Bloom (81), Department of Neurosciences, School of Medicine,
University of California, San Diego 92093, USA; and Veterans AVairs San
Diego Healthcare System, San Diego 92161, USA
Turi O. Dalaker (49), The Norwegian Centre for Movement Disorders,
Stavanger University Hospital, Stavanger, Norway; and Department of
Neurology, BuValo Neuroimaging Analysis Center, State University of
New York at BuValo, BuValo, New York 14203, USA
Lisa Delano-Wood (81), Veterans AVairs San Diego Healthcare System,
San Diego 92161, USA; and Department of Psychiatry, School of Medicine,
University of California, San Diego 92093, USA

xi
xii CONTRIBUTORS

Jack C. de la Torre (35), Sun Health Research Institute, Center for

Alzheimer’s Research, Sun City, Arizona 85351, USA
Carol Di Perri (49), Department of Neuroradiology, IRCCS, C. Mondino,
University of Pavia, Pavia, Italy; and Department of Neurology, BuValo
Neuroimaging Analysis Center, State University of New York at BuValo,
BuValo, New York 14203, USA
Halim Fadil (245), Department of Neurology, Louisiana State University
School of Medicine-Shreveport, Shreveport, Louisiana 71103, USA
Muhammad U. Farooq (185), Department of Neurology, Michigan State
University, East Lansing, Michigan, 48824, USA
Francisco Fernandez (1), Department of Psychiatry and Behavioral Medicine,
University of South Florida, 3515 East Fletcher Avenue, MDC-14, Tampa,
Florida 33613, USA
Glen R. Finney (263, 283), Memory and Cognitive Disorders Program,
University of Florida Department of Neurology, Gainesville, Florida
32610-0236, USA
Brian Giunta (1), Department of Psychiatry and Behavioral Medicine, University
of South Florida, 3515 East Fletcher Avenue, MDC-14, Tampa, Florida
33613, USA
H. Randall GriYth (105), Department of Psychology; and Alzheimer’s Disease
Research Center; and Department of Neurology, University of Alabama at
Birmingham, Birmingham, Alabama 35233, USA
Elhachmia Ait Ben Haddou (245), Service de Neurologie B et Neurogenetique,
Hopital des Specialties, Rabat, Morocco
Jennifer C. Hanson (215), Drexel University College of Medicine, Mail Stop
423, Philadelphia, Pennsylvania 19107, USA
Jan A. den Hollander (105), Department of Medicine (Cardiology), University
of Alabama at Birmingham, Birmingham, Alabama 35233, USA
Stephen L. JaVe (151, 245), Department of Neurology, Louisiana State
University School of Medicine-Shreveport, Shreveport, Louisiana 71103,
USA
Amy J. Jak (81), Veterans AVairs San Diego Healthcare System, San Diego
92161, USA; and Department of Psychiatry, School of Medicine, University
of California, San Diego 92093, USA
Anahid Kabasakalian (283), Memory and Cognitive Disorders Program,
University of Florida Department of Neurology, Gainesville, Florida
32610-0236, USA
Roger E. Kelley (21), Department of Neurology, LSU Health Sciences Center,
Shreveport, Louisiana 71103, USA
 CONTRIBUTORS xiii

Elena Korniychuk (245), Department of Neurology, Louisiana State University

School of Medicine-Shreveport, Shreveport, Louisiana 71103, USA
Carol F. Lippa (215), Drexel University College of Medicine, Mail Stop 423,
Philadelphia, Pennsylvania 19107, USA
Francisco A. Luque (151), VA Neurology Service, Overton Brooks VAMC,
Shreveport, Louisiana 71101, USA; and Department of Neurology, Louisiana
State University School of Medicine-Shreveport, Shreveport, Louisiana
71103, USA
Uma Menon (21), Department of Neurology, LSU Health Sciences Center,
Shreveport, Louisiana 71103, USA
Alireza Minagar (245), Department of Neurology, Louisiana State University
School of Medicine-Shreveport, Shreveport, Louisiana 71103, USA
James M. Noble (133), Gertrude H. Sergievsky Center, and the Taub Institute
for Research on Alzheimer’s Disease and the Aging Brain; and Department of
Neurology, Columbia University Medical Center, New York 10032, USA; and
Department of Neurology, Harlem Hospital Center, Columbia University
College of Physicians and Surgeons, New York 10037, USA
Bradley J. Robottom (229), Department of Neurology, University of
Maryland School of Medicine, Baltimore, Maryland 21230, USA
Nikolaos Scarmeas (133), Gertrude H. Sergievsky Center, and the Taub
Institute for Research on Alzheimer’s Disease and the Aging Brain; and
Department of Neurology, Columbia University Medical Center, New York
10032, USA
Mike R. Schoenberg (1), Department of Psychiatry and Behavioral Medicine,
University of South Florida, 3515 East Fletcher Avenue, MDC-14, Tampa,
Florida 33613, USA
Christopher C. Stewart (105), Department of Psychology, University of
Alabama at Birmingham, Birmingham, Alabama 35233, USA
Jun Tan (1), Department of Psychiatry and Behavioral Medicine, University
of South Florida, 3515 East Fletcher Avenue, MDC-14, Tampa, Florida
33613, USA
William J. Weiner (229), Department of Neurology, University of Maryland
School of Medicine, Baltimore, Maryland 21230, USA
Christina E. Wierenga (81), Veterans AVairs San Diego Healthcare System,
San Diego 92161, USA; and Department of Psychiatry, School of Medicine,
University of California, San Diego 92093, USA
Mohamed Yahyaoui (245), Service de Neurologie B et Neurogenetique,
Hopital des Specialties, Rabat, Morocco
Robert Zivadinov (49), Department of Neurology, The Jacobs Neurological
Institute; and Department of Neurology, BuValo Neuroimaging Analysis
Center, State University of New York at BuValo, BuValo, New York 14203, USA
 PREFACE

The significant increase in human longevity translates into a significant increase

in the number of people with dementia around the globe. Due to its relentlessly
progressive course and lack of any effective treatments, neurodegenerative
dementing disorders pose an enormous economic and social burden on society
as well as a great emotional burden. During the last two decades, our knowledge
about molecular mechanisms of the various neurodegenerative dementias has
grown remarkably, giving us unprecedented insight into the fundamental
mechanisms of these incurable disorders.
This volume of the International Review of Neurobiology focuses on dementia and
related diseases. The volume contains various chapters on pathogenesis, clinical
features, genetics, neuroimaging and molecular pathogenesis of the neurodegen-
erative dementias. The first chapter by Caserta et al. addresses the very important
topic of normal aging and highlights its salient features. The next three chapters
discuss the role of cerebrovascular disease in cognition. First, Roger E. Kelley
provides a comprehensive update on subcortical ischemic cerebrovascular
dementia, and then J. C. de la Torre discusses the role of cerebrovascular and
cardiovascular pathology in Alzheimer’s disease. These two excellent chapters
are followed by another detailed chapter by Dalaker et al., explaining the neuro-
imaging of cognitive impairment in vascular disease. These authors provide our
readers with the latest developments on this subject, highlighting recent advances
in neuroimaging of cognitive decline caused by cerebrovascular disorders.
The focus of this volume then switches to mild cognitive impairment (MCI),
and the next three contributions cover various aspects of this significant clinical
issue. Jak et al. discuss the role of neuropsychology and neuroimaging in better
understanding of clinical subtypes of MCI. The next two chapters explore vari-
ous imaging procedures used to study MCI. Griffith et al. discuss the role of pro-
ton MR imaging in the study of dementing disorders including MCI, and then
Noble and Scarmeas provide readers with an interesting perspective on the
application of PET imaging for the diagnosis of Alzheimer’s disease and MCI.
The next section of this volume covers Alzheimer’s disease and other progressive
neurodegenerative dementias. First, Luque and Jaffe discuss the underlying molec-
ular and cellular mechanisms of dementia of the Alzheimer’s type. This interesting
chapter is followed by another superb update on the genetics of Alzheimer’s disease
by Lars Bertram. The next three chapters discuss other neurodegenerative
dementias. Bozoki and Farooq present an excellent discussion concerning the
neuropsychology and neuroimaging of frontotemporal lobar degeneration.

xv
xvi PREFACE

Next, Lippa and Hanson give an update on Lewy body dementia. This extensive
review is followed by Robottom and Weiner’s chapter on the dementia in Parkin-
son’s disease, presenting readers with the most recent findings on this subject.
The final section of this issue of the International Review of Neurobiology concen-
trates on important subjects which we as neurologists encounter on a daily
basis. First, Minagar and colleagues discuss various causes of dementia in younger
individuals and present the readers with a systematic approach for the diagnosis
of this uncommon presentation. Then, Glen Finney and Anahid Kabasakalian
discuss the pathogenesis and clinical features, as well as the diagnostic procedures
for investigating normal pressure hydrocephalus and other reversible dementias.
In summary, various contributors to this issue of the International Review of
Neurobiology have attempted to improve the readers’ knowledge concerning a
broad spectrum of dementing disorders. Each contribution provides the inquisi-
tive reader with the latest developments in our understanding of that particular
topic. The editor and the very knowledgeable contributors to this issue hope
that this volume of the International Review of Neurobiology stimulates the readers’
scientific curiosity and promotes basic and clinical research in the dementia.
Finally, I would like to acknowledge the excellent contributions of the various
authors to this issue of the International Review of Neurobiology. Without their effort
and dedication, compiling this volume would have never become a reality.
I would also like to thank Ms. Narmada Thangavelu and Mr. Charles Prem
Kumar Neelakandan from Elsevier for their time and effort expended to process
and complete on this of the journal.

ALIREZA MINAGAR
 NORMAL BRAIN AGING: CLINICAL, IMMUNOLOGICAL,
NEUROPSYCHOLOGICAL, AND NEUROIMAGING FEATURES

Maria T. Caserta, Yvonne Bannon, Francisco Fernandez, Brian Giunta,

Mike R. Schoenberg, and Jun Tan
Department of Psychiatry and Behavioral Medicine, University of South Florida,
3515 East Fletcher Avenue, MDC-14, Tampa, Florida 33613, USA

I. Introduction
II. Epidemiology of Aging: Risks and Implications
III. Normal Aging and Functional Performance
A. Quality of Life and Protective Factors
B. Centenarians
IV. T- and B-Lymphocyte Loss of Function in the Aging Immune System
V. Neuropsychology of Aging
A. Changes in Neuropsychological Function in Normal Aging
B. Staving off Cognitive Decline
VI. Imaging Studies in Aging
References

Brain aging is characterized by numerous physiological, structural, functional,

and neurocognitive changes. The interplay of these various processes is complex
and characterized by large interindividual diVerences. Although much is not
understood about how we age, there are numerous studies detailing the nature
of the changes in the brain as we age. This chapter will review some of the
functional, neuropsychological, neuroimaging, and immunological processes
known to occur in normal or ‘‘healthy’’ aging. Large epidemiological studies of
older adults have shown health status in the elderly is a function of the negative
consequences and impairment in functional performance caused by medical
co-morbidities. Immunological function declines with age, such that adaptive
immunity is reduced to previously encountered pathogens, and there is a weak-
ened adaptive immune response to novel pathogens. Structural and functional
neuroimaging studies of cognitively intact older adults have consistently shown
volume loss and loss of white matter structural integrity, particularly in prefrontal
cortex, which may be associated with cognitive decline. While data are incom-
plete, one consistent finding has been a decline in cognitive domains, such as
arithmetic/numerical ability and perceptual speed. Alternatively, other cognitive
functions such as verbal ability, word knowledge, and semantic memory remain

INTERNATIONAL REVIEW OF 1 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00401-2 0074-7742/09 $35.00
2 CASERTA et al.

quite preserved even to old age. Factors identified for healthy cognitive (brain)
aging are multifactorial, and likely incorporate biological systems as well as
cognitive reserve.

I. Introduction

The percentage of the population over age 65 is growing rapidly in the United
States. In 2000, it was 12.4% and in 2050 it is projected to be 20.6% (Health,
United States, 2005). Many people in this older age group are healthy but it is well
known that functional disability increases with age. There are many theories
of aging including ‘‘programmed aging’’ and the ‘‘wear and tear’’ theories.
The former regards aging as being regulated by an internal clock and is seen as
an extension of development, which is highly regulated and timed process. How-
ever, the interplay of disease, environment and genetics is evident not only in
epidemiological studies of aging and longevity, but also in functional assessments of
the elderly, and in such concepts as cognitive reserve and neural compensation.
Structural and functional imaging studies of intact older individuals have
delineated specific areas where there is loss of brain volume and also a reduction
in the lateralization of brain activity during cognitive performance in elderly
individuals. However, not all of these changes are detrimental to maintaining
performance levels and it is not yet clear which changes are precursors to further
cognitive decline and which may be true compensatory mechanisms.

II. Epidemiology of Aging: Risks and Implications

Through the year 2000, approximately 35 million of people living in the USA
were over 65 years. It is estimated that by 2050, this number will more than
double to 82 million with 20% of the US population age 65 years or older (see
Table I; Ferrucci et al., 2008). With the life expectancy in old age increasing, and
death rates reported to decrease, these numbers may be an underestimate of what
is to come (Minino et al., 2007). While older adults are generally healthy and
independent and are active in various roles contributing significantly to their
families and society, the increase in concurrent medical conditions causing excess
morbidity and mortality as well as disability and decline in functional per-
formance negatively impact a significant number of the elderly (Ferrucci et al.,
2008). Health status in the elderly is a function of the negative consequences
and impairment in functional performance caused by medical co-morbidities.
 CHARACTERISTICS OF NORMAL BRAIN AGING 3

TABLE I
ACTUAL AND PROJECTED GROWTH OF THE OLDER US POPULATION, 1900–2050 (MILLIONS)

>65 Years >85 Years

Year Total population (all ages) Number Percent of total Number Percent of >65 years

1900 76.1 3.1 4.1 0.1 3.2

1950 152.3 12.3 8.2 0.6 4.9
2000 276.1 34.9 12.6 4.4 12.6
2050 403.7 82.0 20.3 19.4 23.7

Note : This table from Ferrucci et al. (2008) is used with permission.

Any and all diseases occurring in the elderly cause excess disability and decre-
ments in function in a variety of domains but mostly in independent function. For
example, chronic health conditions such as hypertension, hyperglycemia, muscu-
loskeletal disorders, coronary artery disease, cancer, and mixed states of anxiety
and depression aVect a significant number of the elderly (see Table II). By race
and ethnicity these numbers vary among minority men and women when com-
pared with that in White men and women. The proportion of these with cognitive
impairment and dementing illness is also rising. Similarly, preexisting anxiety and
depression may increase the risk of developing cognitive impairment (Backman,
2008; Loebach et al., 2002).
In large epidemiologic studies such as the Canadian Study of Health and
Aging, the authors evaluated the occurrence of an adverse event (symptom, sign,
or disease), or the accumulation of a number of such co-morbid events, and
modeled the events as a logistic function of chronologic age in a population
(Graham et al., 1999). In those who were cognitively normal, a linear relation
between the log of the odds of events and chronologic age was present for the
majority of symptoms and signs. Thus, the dynamics of aging are a complex
process of accumulation of deficits (morbidity), whereby decline from some
previously healthy level of synergistically associated symptoms and signs results
in distinct patterns of disease.
But these studies are only part of the larger picture. It is a familiar epidemio-
logic concept that individuals vary not only in whether they develop a disease but
also in the ages at which disease occurs and the rates at which pre-morbid changes
progress to any specific disease. Available reports of genetic epidemiologic studies
on diseases of aging are adding a new dimension—trait genomics—to assess the
presence or absence of a disease (or occurrence of an adverse event) or evaluating
the level of a given risk factor at one point in time (NIA Aging and Genetic
Epidemiology Working Group, 2000). Moreover, two very specific types of age-
specific traits are survival traits (the age at which a specified outcome has occurred
or has not occurred) and rate-of-change traits (the rate at which individuals’
4 CASERTA et al.

TABLE II
a
AGE-ADJUSTED AND AGE-SPECIFIC MORTALITY IN THE UNITED STATES, 1950 AND 2004 AND
PERCENT CHANGE

Cause of death Age (years) 1950 2004 Change

Diseases of the heart

Males
All ages 697.0 267.9 !61.6
65–74 2292.3 723.8 !68.4
75–84 4825.0 1893.6 !60.8
85þ 9659.8 5239.3 !45.8
Females
All ages 484.7 177.3 !63.4
65–74 1419.3 388.6 !72.6
75–84 3872.0 1245.6 !67.8
85þ 8796.1 4741.5 !46.1
Cerebrovascular disease
Males
All ages 186.4 50.4 !73.0
65–74 589.6 121.1 !79.5
75–84 1543.6 402.9 !73.9
85þ 3048.6 1118.1 !63.3
Females
All ages 175.8 48.9 !72.2
65–74 522.1 96.6 !81.5
75–84 1462.2 374.9 !74.4
85þ 2949.4 1303.4 !55.8
Malignant neoplasms
Males
All ages 208.1 227.7 9.4
65–74 791.5 907.6 14.7
75–84 1332.6 1662.1 24.7
85þ 1668.3 2349.5 40.8
Females
All ages 182.3 157.4 !13.7
65–74 612.3 627.1 2.4
75–84 1007.7 1023.5 1.6
85þ 1299.7 1340.1 3.1

Note : This table from Ferrucci et al. (2008) is used with permission.
a
Data for ‘‘all ages’’ are age-adjusted using the US 2000 standard population.

characteristics change over a specified age interval). Many age-related conditions

like dementing illness are likely to be highly polygenic, posing diYculties for
identifying genes with these eVects inclusive of the survival traits associated with
longevity free of neurocognitive impairment. Moreover, there may well be a
genotype that delays or accelerates onset of several diseases could aVect disease
expression and survival significantly. Thus, many important pathologies of aging
 CHARACTERISTICS OF NORMAL BRAIN AGING 5

may be completely redefined in the era of neurogenomics. Recent neuroimaging

findings substantiate the neurogenomics data by way of pathologic finding in
age-related changes, such as vascular stiVening and loss of muscle mass that
were considered ‘‘normal’’ aging until recently. Genetic factors may also influence
not just physiologic functions at one time point but also their rates of change
with age.
Thus, with the changing health status of the elderly population, there is an
ever increasing role for epidemiology. Epidemiological studies will have a major
impact on not just informing the public health entities on the impact on future
demand for health services but also, in the era of neurogenomics, on prevention of
cognitive decline and disease states such as AD.

III. Normal Aging and Functional Performance

The biophysiological changes that occur as part of normal aging can impact
and limit functional performance in the elderly. The extent of impact to functional
performance in the elderly is dependant on numerous factors, including cognitive
status, physical disability, and medical illness (Njegovan et al., 2001), as well as,
emotional factors, quality of life, and numerous protective factors (Vaillant, 2002).
The concept of expressing functional performance in terms of a person’s ability
to carry out routine activities of daily living (ADLs) was first introduced by Katz
et al. (1963) and expanded by Lawton and Body (1969) to include more complex
functions called instrumental activities of daily living (IADLs). ADLs include
basic self-care activities such as bathing, dressing, eating, transferring, ambulation,
and toileting: IADLs include shopping, managing finances, cooking, cleaning, and
telephone use. The US Centers for Disease Control database tracks changes in
functional performance in the elderly.
The association between cognitive impairment and functional performance
has been studied extensively. A number of studies have demonstrated a relation-
ship between cognitive status and functional performance independent of social,
demographic, or medical factors (Hertzog and Wallace, 1997; Moritz et al., 1995;
Royall et al., 2005). Predicting and measuring change in ADLs and IADLs with
regards to advancing age has been the focus of many studies. Katz (1965)
hypothesized that older persons with progressive cognitive decline lost ability to
perform ADLs in the opposite order to which the skill(s) were acquired in
childhood. Additionally, functional performance of IADLs was more likely to
deteriorate prior to ADLs during the course of cognitive decline associated with
pathological process. Although many studies have looked at changes in functional
performance, and more specifically cognitive decline in the elderly with a disease
process, few studies have looked at the correlation between normal physiological
cerebral aging and cognitive decline (see below).
6 CASERTA et al.

The Freedom House Study (Royall et al., 2005) compared independence in

IADLs to executive functioning in 547 non-institutionalized people (community
dwellers) aged 70 and older. Royall’s group concluded that decline in memory
had no independent association with decline in functional performance, specifi-
cally IADLs. However, decline in executive function did correlate with a subject’s
ability to independently perform IADLs. Other studies have observed changes
in functional performance led to changes in independence, socialization,
self-perception, and quality of life (Keller et al., 1999).

A. QUALITY OF LIFE AND PROTECTIVE FACTORS

The term ‘‘successful aging’’ first appeared in medical journals in 1961 (Motta
et al., 2005). Today the term is used to describe the absence of significant disease
and disabilities, maintenance of high levels of physical and cognitive function, and
the preservation of social and productive activities (Motta et al., 2005). The
Harvard Study of Adult Development is considered the landmark study of adult
development and has provided key predictors to ‘‘successful aging.’’ This research
followed 824 individuals from three separate prospective, longitudinal studies,
selected as teenagers from various facets of mental and physical health, through-
out their lives. The three groups consisted of 268 Harvard sophomores, a sample
of 456 Inner City youths, and 90 women from Stanford—all selected as teenagers
and followed throughout their lives. The research focused on (1) adaptation to
stress, mental health, and defense mechanisms; (2) the eVects of habits—especially
alcoholism and aVective disorders upon physical health and mortality; (3) the
eVect of childhood risk factors upon adult adaptation; (4) the unfolding of adult
development; and (5) the natural history of alcohol and substance abuse (Valliant,
2002). Although the findings are numerous, key findings suggest the following
factors predictive of healthy or ‘‘successful aging’’: being a non-smokers; adaptive
coping styles, mature defense styles, and optimism; absences of alcohol abuse;
maintaining a healthy weight; stable marriage or relationships; some physical
activity; social engagement; and education. Education, including attainment and
childhood intellectual ability, is also thought to provide a cognitive reserve in later
life (Whalley et al., 2004), protecting from cognitive decline associated with normal
aging, as well as, cognitive decline associated to disease process.

B. CENTENARIANS

The number of people living beyond the age of 100 is growing throughout the
industrialized world (Motta et al., 2005). Several studies of centenarians have been
conducted to determine their level of independence, clinical condition, and
 CHARACTERISTICS OF NORMAL BRAIN AGING 7

cerebral deterioration and whether centenarians are the prototype for ‘‘successful
aging.’’ The Italian Multicenter Study on Centenarians (IMUSCE) is one such
study (Motta et al., 2008). The IMUSCE was an epidemiological study which
identified 1173 centenarians ranging in age from 100 to 109 years. A sub-sample
of 346 centenarians was studied to determine the functional performance and
cognitive status. The sub-sample was further divided into groups based on physical
health and MMSE scores. True independence in all functional performance
(IADLs) was seen in only six centenarians (1.7%): while 21 centenarians (6.1%)
presented with slight dependence in functional performance. Additionally, 68
centenarians (19.67%) had only a moderate dependency in IADLs and 251
(72.6%) were severely dependent. Of the six independent functioning centenarians
and the 21 centenarians with only slight dependence in IADLs, all have had
significant changes in their level of social and productive activities, thus they cannot
be considered prototypes of successful aging based on the current definition.

IV. T- and B-Lymphocyte Loss of Function in the Aging Immune System

With age, innate immunity progresses to a chronically active state secondary to

exhaustion of the more evolutionary recent adaptive (specific) immune system
(Franceschi et al., 2007). This is in large part due to age-associated reduction of
T-cells due to thymic involution (Aspinall 2000; Aspinall and Andrew, 2000; Linton
et al., 2005), as well as fewer bone marrow early progenitor B cells (Allman and
Miller, 2005). In early life, naı̈ve T-cells are activated by contact with antigens and
then diVerentiate into eVector or memory cells. Because the quantity of T-cells in
healthy individuals is stable over the lifespan, peripheral T-cell turnover of preex-
isting populations in the thymus is required to replace cells to the system in relatively
young individuals and to prime T-cells to new antigens (Fann et al., 2005; Pawelec,
2005; Weng, 2006). Thus in the elderly there is an increase in the number of
antigen-experienced cells and a decrease in the number of naı̈ve T-cells in the
circulation, which results in accumulation of incompetent memory lymphocytes
(Cossarizza et al., 1997). These cells likely clonally expand and became eVector
memory T-cells that were competent at one time, but then lost their antigen-specific
function due to their age. This phenomenon is believed to be owed to life-long
antigenic stress from immunosurveillance against persistent viruses (antigens),
especially cytomegalovirus (CMV) (Solana et al., 2006).
The net result of these age-associated phenomena are (1) reduced adaptive
immunity to previously encountered pathogens and (2) weakened adaptive
immune response to novel pathogens due to a reduction in the diversity of the
antigen-recognition repertoire with age by approximately 108 in young adults to
106 in the elderly (Goronzy et al., 2005). Moreover, CD8þ T-cells in the elderly
8 CASERTA et al.

display significantly decreased ability to secrete interferon-gamma (IFN-!) when

stimulated by cognate antigen in comparison to younger age groups (Ouyang
et al., 2003a,b). Also, naı̈ve CD4þ T-cells from old humans and mice show
decreased responsiveness to TCR stimulation and altered profiles of cytokine
production versus naı̈ve CD4þ T-cells from young hosts. Likewise, the helper
function of naı̈ve CD4þ T-cells for antibody production by B cells is also
decreased (Swain et al., 2005). The decline in responsiveness of naı̈ve CD4þ
T-cells is due to the chronologic age of the cells themselves, and not of the
individual host (Swain et al., 2005), suggesting that long-term maintenance of
naı̈ve CD4þ T-cells through homeostatic cytokines may not have a positive
impact on their function. Indeed, naı̈ve CD4þ T-cells that have undergone
homeostatic cell divisions proliferate less and secrete less IL-2 in response to
antigen than do naı̈ve CD4þ T-cells that have not undergone homeostatic
division as is seen in the young (Swain et al., 2005).
Unlike naı̈ve lymphocytes, memory CD4þ T lymphocytes are long lived and
relatively competent with age. These antigen-experienced T-cells, when isolated
from healthy elderly humans and healthy old mice, respond normally to antigen-
induced proliferation in vitro (Kovaiou et al., 2005) and those generated at a young
age respond well to antigens over time. Conversely, naı̈ve CD4þ T-cells derived in
old age respond poorly (Haynes et al., 2005). Together, these studies point to an
age-associated defect in memory CD4þ T-cells which may originate from defects
of aged naı̈ve CD4þ T-cells that have reduced clonal diversity and proliferation
potential. Interestingly, changes of the ratio of memory to eVector CD4þ T-cell
subsets with age have also been implicated in deficient adaptive immune
responses to viral infections and vaccines (Kang et al., 2004).
An additional important age associated defect in T-cell function is accumula-
tion of CD28!CD8þ T-cells and the loss of naı̈ve CD8þ T-cells. These T-cells are
absent in newborns while composing some 85% of circulating CD8þ T-cells in
the elderly. The accumulation of CD28!CD8þ T-cells was also shown in patients
with viral infections such as CMV (Almanzar et al., 2005). CD28!CD8þ T-cells
may signify terminal diVerentiation from the CD28þCD8þ subset after repeated
antigenic stimulation. Functionally, these cells have a reduced proliferative
response to TCR stimulation but exhibit normal or even enhanced cytotoxic
capacity and are resistant to apoptosis (Azuma et al., 1993). Furthermore, several
studies have demonstrated the virtual disappearance of naı̈ve CD8þ T-cells in the
elderly associated with a significant increase in the proportions of diVerentiated
eVector memory and eVector CD8þ T-cells in comparison to younger individuals.
Interestingly, most of these cells in the elderly do not have short telomeres. Taken
together, these data suggest that, over the course of life, these T-cell populations
have undergone a process of end-stage diVerentiation and that persistent infection
with common pathogens, such as CMV, induces chronic stimulation of specific
T-cells that leads to terminal diVerentiation to senescent cells with an altered
 CHARACTERISTICS OF NORMAL BRAIN AGING 9

functional capability (EVros et al., 2005; Fann et al., 2005; Pawelec, 2005;
Tarazona et al., 2000). Further, it seems that clonal expansion of CD28!CD8þ
T-cells seems directly responsible for increased infection rates and the common
failed response to vaccines in the elderly (Almanzar et al., 2005). Decreased
adaptive immunity also involves changes in the B-cell repertoire not unlike
those observed in the T-cell pool (Ghia et al., 2000; Szbo et al., 1999; Weksler,
2000). The quality of the humoral immune response is decreased with age owing
to low serum immunoglobulin concentrations and low numbers of antigen-
specific, immunoglobulin-secreting plasma cells. Further, antibody specificity,
isotype and aYnity changes are typical features of old age. For example, immu-
noglobulins produced in aged mice have lower aYnity and are less protective
versus those of young animals (Yang et al., 1996). This may be secondary to aging’s
adverse eVects on the germinal centre reaction in secondary lymphoid tissues
(Zheng et al., 1997) and leads to a diminished quantity of germinal centers in
response to tetanus toxoid stimulation (Kraft et al., 1987). The quantity of B
cells also decreases in the elderly (Franchesci et al., 1995). At the cellular level,
alteration in immunoglobulin generation (through class switching) in B cells is
observed in aged individuals (Frasca et al., 2005), which may contribute to the
decline of the adaptive immune response in the elderly.

V. Neuropsychology of Aging

The literature is replete with data indicating a broad spectrum of neuropsy-

chological functions decline with normal aging (e.g., Craik and Salthouse, 2000;
WoodruV-Pak, 1997). What is less clear is the line separating normal aging from
cognitive dysfunction and dementia (e.g., Morris and Cummings, 2005; Morris
et al., 2001; Petersen, 2003; Raz, 1996, 2000). Various terms and criterion have
been used to separate normal aging from abnormal, such as age associated
memory impairment (AAMI; Crook et al., 1986), aging-associated cognitive
decline (Levy, 1994), benign senescent forgetfulness (Kral, 1962), cognitive
impairment no dementia (CIND; Graham et al., 1997), mild cognitive disorder
(World Health Organization, 1978), mild cognitive impairment (MCI; Morris
et al., 2001; Petersen et al., 1999), mild neurocognitive disorder (Gutierrez et al.,
1993), and questionable dementia (Hughes et al., 1982), among others (see also
Craik and Salthouse, 2000 for a review). Further complicating the division
between normal and abnormal aging processes is the variability in neuropatho-
logical and neuropsychological functions between and within samples (e.g., see
Craik and Salthouse, 2000; WoodruV-Pak, 1997 for reviews). A summary of
neuropsychological changes associated with aging is provided below.
10 CASERTA et al.

A. CHANGES IN NEUROPSYCHOLOGICAL FUNCTION IN NORMAL AGING

It has long been recognized that some cognitive processes decline with age
while others appear less aVected, giving rise to the traditional dichotomy between
the so-called ‘‘crystallized’’ abilities (e.g., accumulated knowledge and expertise)
versus those termed ‘‘fluid’’ abilities (e.g., fluid reasoning, working memory,
visuoperceptual abilities, processing speed, etc.) (e.g., Craik and Salthouse,
2000; WoodruV-Pak, 1997 for review). Within this framework, crystallized abil-
ities have been considered generally stable with increasing age, while fluid abilities
decline with increasing age, some thought to begin declining as early as in one’s
20s (Babcock, 1930; Craik and Salthouse, 2000; Lezak, 1995; Wechsler, 1958;
WoodruV-Pak, 1997 for review). Until recently, however, much of the previous
knowledge regarding age-related cognitive decline have been criticized for lack of
longitudinal data, with most derived from cross-sectional studies or other studies
having small samples and/or short follow-up time frames (e.g., Baltes and Mayer,
1999; Hertzog et al., 2003; Schaie, 1996).
Changes in normal aging are now being understood from longitudinal data
from several sources, including the Berlin Aging Study (Baltes and Mayer, 1999),
Mayo’s Older Americans Normative Studies (MOANS; Ivnik et al., 1992), Seattle
Longitudinal Study (Schaie, 1996), and Victoria Longitudinal Study (Dixon and
de Frias, 2004; Hertzog et al., 2003). Combined, these studies provide longitudinal
data of individuals beginning in participants’ 20s up to 100 years old and beyond
(e.g., Singer et al., 2003). While data are incomplete, one consistent finding has
been a decline in select cognitive domains beginning as early as the middle to late
20s. Alternatively, other cognitive functions remain quite preserved even to very
old age (Singer et al., 2003). Schaie (1994) found the average performances of
arithmetic/numerical ability and perceptual speed beginning to decline at around
age 25 years old. Alternatively, a general decline in performance on tasks of
inductive reasoning, verbal ability, and episodic memory did not become apparent
until the fifth or sixth decade of life. While episodic memory is known to decrease
with age, some research suggesting as early as the third or fourth decade of life,
other research suggests the decline may be much less precipitous and is gradual, at
least until the seventh decade of life (Backman et al., 2000). Similarly, Singer et al.
(2003) found performance on tasks of processing speed, episodic memory, and
verbal fluency declined from 70 to 100 years old. Alternatively, word knowledge
has consistently demonstrated resilience to aging, remaining quite stable from
one’s 70s through 100þ years old (e.g., Lezak, 1995; Singer et al., 2003). Executive
functions (rapid problem solving, verbal fluency, inhibition, and flexibility) show
early and considerable age-related declines (Mittenberg et al., 1989; Parkin, 1996).
Indeed, Mittenberg et al. (1989) found performance on neuropsychological tests of
executive skills, thought to measure frontal lobe functioning, exhibited more age-
related decline than other tests in a comprehensive battery. Further complicating
 CHARACTERISTICS OF NORMAL BRAIN AGING 11

understanding age-related decline in cognitive function are data establishing

individual variability in cognitive performance can vary considerably over 1–3
year time periods, although group level change tends to be more modest, at least
to the sixth or seventh decades of life (e.g., Dixon et al., 2004; Ivnik et al., 1999).
Recent data suggest increased individual variability in cognitive function predicts
mortality (MacDonald et al., 2008).
In summary, the cognitive decline observed in normal aging reflects the com-
plex brain changes that occur with increasing age. The decline of cognitive abilities
is a complex tapestry of selective areas of preservation while other interrelated areas
decline all against a backdrop of biological and physical changes. Indeed, consider-
able research suggests two over-arching cognitive abilities that decrease with age,
processing speed, and working memory, can account for a majority of variance in
the age-related declines across a variety of cognitive skills (e.g., see Meyerson et al.,
1990; Mitchell, 1993; Salthouse, 1996). As an example, Hertzog et al. (2003) found
deficits in episodic memory could be accounted for by declines in working memory
and perceptual speed. Thus, declines in episodic memory, numerical ability/arith-
metic, verbal fluency, and problem solving are, themselves, moderated by the
decline in processing speed and working memory. It has been proposed that the
decline in processing speed may be associated with the structural integrity of
cerebral white matter, but rather than being linear, reflects a threshold phenome-
non, in which age-related declines after white matter dysfunction exceeds a critical
level (Boone et al., 1992; DeCarli et al., 1995; Raz, 2000).

B. STAVING OFF COGNITIVE DECLINE

Aerobic exercise has shown to decrease cognitive morbidity in aging, but a

more comprehensive picture including cognitive reserve and cognitive engage-
ment is likely accounting for preventing cognitive morbidity (e.g., Milgram et al.,
2006; Stern, 2006). Research has also found older adults routinely use informal
techniques to improve memory (e.g., increase use of external memory aides and
organizational skills) in compensating for daily cognitive challenges (Dixon et al.,
2001). See discussion relating cognitive reserve to structural and functional
neuroanatomy below.

VI. Imaging Studies in Aging

The changes that occur with aging in the brain are complex and are asso-
ciated with large interindividual variability. There is, however, a pattern of
selective loss and preservation delineated in numerous studies. The structural
12 CASERTA et al.

and functional deterioration in specific brain areas is thought to be responsible

for the reported cognitive decline that occurs with age while the substrates of
‘‘cognitive reserve’’ are less well defined.
Longitudinal studies using structural MRI from age 3 to 70 years old have shown
an increase in cortical gray matter until, about, age 5 followed by a gradual decline in
volume until age 70 (PfeVerbaum et al., 1994). White matter growth accelerates
during adolescence and then plateaus in the third decade. Several studies have
indicated significant gray matter tissue volume loss (Blatter et al., 1995; Brickman
et al., 2005; Sullivan et al., 2004; Thompson et al., 2003) while others have shown
greater white matter loss in aging (Guttmann et al., 1998; Jernigan et al., 2001).
In general, brain atrophy has been reported consistently in aging and it is
more pronounced in the frontal brain areas (DeCarli et al., 1994; Raz et al., 1997;
Resnick et al., 2003; Saloat et al., 1999; Tisserand et al., 2002). Other brain areas
aVected by aging are the temporal lobes with relative sparing of the parietal and
occipital lobes (Bartzokis et al., 2001; Good et al., 2001; Raz et al., 1997, 2005). The
question of whether this loss is primarily due to gray matter or white matter
volume loss remains controversial (see Sullivan and PfeVerbaum, 2007).
Although controversial, hippocampal volume is thought to remain relatively
stable with age (Shamy et al., 2006; Sullivan et al., 1995, 2001, 2005) and remains
intact in size in healthy elderly adults without concurrent hypertension (Raz et al.,
2005). There is age-related dilation of the temporal horns and this has been inter-
preted as hippocampal volume decline. It appears that volume loss and CSF expan-
sion occur in diseases such as Alzheimer’s, but not in normal aging. The relative
resilience of hippocampal volume to aging makes hippocampal deviations from
normal size a sensitive indicator of pathology, especially of the Alzheimer type.
Studies of normal aging have benefited immeasurably by the introduction of
quantitative DTI, which has successfully revealed evidence of microstructural
disruption of regional white matter even in regions appearing normal on volume
imaging. MR diVusion-weighted imaging (DWI) and DTI allow quantification of
microscopic water movement. In regions with few or no physical boundaries, such
as CSF in the ventricles, water movement is random, that is, freely diVusing, and
is therefore isotropic. By contrast, the path of a water molecule in white matter is
constrained by physical boundaries, such as the axon sheath, causing the move-
ment to be greater along the long axis of the fiber than across it and is anisotropic,
typically measured as fractional anisotropy (FA) and ranging between 0 and 1 on a
normalized scale (Pierpaoli and Basser, 1996). DTI is therefore sensitive to the
detection of tightly packed fibers in locally parallel orientation, characterizing
white matter tracts in the brain. One of the most robust findings regarding age-
related diVerences in FA has been the finding of low FA in frontal white matter
(Sullivan et al., 2001). This finding has been supported by postmortem investiga-
tions and animal models of aging (for review see Sullivan and PfeVerbaum, 2007)
and suggests that decreased brain white matter in older individuals may be a
 CHARACTERISTICS OF NORMAL BRAIN AGING 13

consequence of myelin sheath changes and/or accumulation of fluid in fiber

tracts. These types of changes may be reflected as increased white matter hyper-
intensities observed on T2-weighted MRI images in over 90% of older adults.
Beyond the structural changes summarized so far, there have been numerous
functional imaging studies that have described cognitive changes with aging.
These studies using positron emission tomography, PET, and functional magnetic
resonance imaging, fMRI, have revealed how the neural correlates of diVerent
cognitive functions change as a function of aging. Most studies show a reduction in
the lateralization of brain activity during cognitive performance in elderly indivi-
duals. For example, in a study utilizing word pair encoding, older adults showed
weaker activity in several left prefrontal cortical (PFC) areas while several PFC
regions showed increased activity (Anderson et al., 2000). During episodic memory
retrieval, age-related decreases were typically found in the right PFC and right
parietal regions, while age-related increases in activation were found in left PFC as
well as bilateral anterior cingulate and cuneus/precuneas regions (Anderson et al.,
2000; Cabeza et al., 1997, 2002). Some investigators postulated that the age-related
asymmetry reductions found in multiple studies reflect a compensatory mecha-
nism. Older adults engage both hemispheres for tasks that younger adults usually
use one hemisphere for, to compensate for neurocognitive deficits.
In a longitudinal study of 25 healthy older adults assessing changes in PET
rCBF cerebral blood flow over an 8 year period among healthy older adults found
no significant declines in verbal and figural recognition memory accuracy over an
8 year period (Beason-Held et al., 2008). There were regional increases and
decreases in brain activity were found over time in these individuals, particularly
PFC regions. These data support the cross-sectional studies described previously
where altered patterns of cerebral activity were found in old relative to young
individuals and extend these findings to show that changing brain function
continues throughout later life in cognitively stable individuals.
Although it is clear older adults demonstrate deficits relative to younger adults
in various aspects of learning and memory by neuroimaging correlates, several
studies have suggested there is diVerential susceptibility to age-related changes
and dementia related to variables like education, IQ , and engagement in leisure
activities (Gold et al., 1995; Hultcsch et al., 1999; Scarmeas et al., 2001; Stern et al.,
1994). These studies provide epidemiological evidence for the presence of cogni-
tive reserve (Stern, 2006). Cognitive reserve suggests individual diVerences in how
tasks are processed might provide some protection against age-related changes or
progressing brain pathology. Our understanding of how cognitive reserve might
be reflected by brain networks is ongoing. Stern and his colleagues (2005)
identified network activation changes which involve the right hippocampus,
posterior insula, and right and left operculum as well as the inferior parietal
lobe and association cortex, left posterior cingulated, and right and left calcarine
cortex. Young individuals activation patterns in these networks were diVerent
14 CASERTA et al.

from older individuals performing the same task at the same level (Stern et al.,
2005). These authors suggest that cognitive reserve consists of two separate
components: neural reserve and neural compensation. Neural reserve may result
from innate diVerences and/or be modulated through life events such as educa-
tional experience. The substrate for this may be neural networks that are highly
eYcient or have greater capacity in the face of higher demand. Neural compen-
sation on the other hand is defined as a change in neural network use such that
diVerent brain networks are used in a specific task, due to the physiological eVects
of aging or brain pathology. The study of the neural substrates of cognitive reserve
is in its infancy, but imaging techniques assessing both functional and structural
changes in the brains of older adults are progressing rapidly.

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 SUBCORTICAL ISCHEMIC CEREBROVASCULAR DEMENTIA

Uma Menon and Roger E. Kelley

Department of Neurology, LSU Health Sciences Center,
Shreveport, Louisiana 71103, USA

I. Terminology
II. Various Classifications of ‘‘Vascular’’ Dementia
III. Cognition and Aging
IV. Subcortical Strokes and Cognitive Impairment
V. Pathophysiology of Cognitive Impairment in Subcortical Vascular Lesions
VI. Treatment and Prevention
References

It has become increasingly apparent, especially with the advent of MRI brain
scanning, that a large number of patients develop signal intensity changes in the
subcortical white matter and periventricular region as they age. This appears to
be accelerated by risk factors for small vessel cerebrovascular disease such as
hypertension, smoking, diabetes mellitus and hyperlipidemia. The major question
becomes when such changes become clinically significant. It is obvious that
subcortical lacunar-type infarction can be identified by the clinical presentation.
For example, typical examples of so-called ‘‘lacunar syndrome’’ include pure
motor hemiparesis, pure sensory stroke, sensorimotor stroke, clumsy hand-
dysarthria, and hemiataxia-hemiparesis. The issue becomes a measure of impact
on functional ability. This is influenced by several factors. Baseline IQ and
educational level, as well as expectations of age, certainly play a role. A person
who develops cognitive impairment and long tract signs in their 50s or 60s is
certainly going to be recognized as more impaired than an 80 year old individual
who is retired and primarily is engaged in recreational activity. It would be
expected that a person born with limited intellectual capacity and/or limited
educational opportunity would be less likely to be identified as impaired than
a person who has achieved substantial economic achievement through their
innate talents.
The concept of tissue loss or lesion load becomes important when determining
how pronounced the ischemic cerebrovascular changes translate into functional
impairment. Correlative pathology may include cortical atrophy and ventricular

INTERNATIONAL REVIEW OF 21 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00402-4 0074-7742/09 $35.00
22 MENON AND KELLEY

dilatation. Loss of either cortical or subcortical tissue function is expected to be

related to functional compromise. In addition, there are potential features such as
the coexistence of small vessel cerebrovascular disease and Alzheimer’s disease.
Small vessel cerebrovascular disease might also play a contributing factor in
patients susceptible to Dementia with Lewy Bodies or patients susceptible to
fronto-temporal dementia or any other dementing process. Thus, the concept of
tissue loss or lesion burden of disease becomes increasingly important as we
recognize the potential for multifactorial issues, including genetic factors, to
contribute to the phenotypic expression.
The relationships between cognitive impairment, dementia and subcortical
vascular lesions are poorly understood. There have been several papers on the
diVerent aspects of cerebral insults and their impact on cognition, the various
kinds of dementia and diVerent methods of analyzing the impact of the various
insults to the brain. This chapter is an attempt to review all pertinent information
currently available on the poorly understood condition of ‘‘subcortical ischemic
cerebrovascular dementia.’’

I. Terminology

It is felt that the term ‘‘Subcortical Ischemic Cerebrovascular Dementia’’ better

describes the various categories of cognitive impairments related to ischemic
changes in the brain which has been identified previously as Vascular Dementia,
Vascular Cognitive Impairment or Disorder, Multi-infarct Dementia, and so on.
However, there are no clear guidelines or accepted criteria for defining the complex
category of SICD.

II. Various Classifications of ‘‘Vascular’’ Dementia

These are some of the commonly used criteria to define the dementia asso-
ciated with vascular lesions in the brain (Wetterling, et al., 1996):
1. DSM-IV Criteria for Vascular dementia
2. NINDS-AIREN criteria for the diagnosis of probable vascular dementia
(Roman et al., 1993)
3. ICD-10 research criteria (DCR-10) for dementia
4. Hachinski ischemic score
 SUBCORTICAL ISCHEMIC DEMENTIA 23

III. Cognition and Aging

Changes appear in the normal brain with aging which contribute to mental
decline. It has been estimated that after the age of 65, 6.4% of patients show
evidence of some cognitive impairment and this figure increases steadily with age
(Ankri and Poupard, 2003). With aging, vascular lesions are seen commonly in the
brain and opinions vary as to whether these lesions are clinically significant or not
with regards to cognitive changes (Fig. 1). It has also been the subject of discussion
about the location and volume of these lesions and whether that may have an
impact on cognition.
Also with aging, the risk of vascular disease increases and the prevalence has been
shown to be 0.3% during 65–69 years of age and as much as 5.2% at age 90 years
(Chabriat and Bousser, 2006). The Rotterdam study showed that the prevalence
of ‘‘vascular’’ dementia is higher in women, despite the higher incidence in men,
because of increased longevity in women by 10 years (Lobo et al., 2000).
Asymptomatic lacunar-type infarcts have been found to be present in 11–28%
of normal elderly persons in multiple studies (Longstreth et al., 1998; Price et al.,
1997; Vermeer et al., 2003). Atrial fibrillation (Ott et al., 1997) hormonal treatment
(estrogen þ progesterone) of women after age 65 (Shumaker et al., 2003), diabetes
mellitus (Leibson et al., 1997) and smoking in persons above age 60 years ( Juan
et al., 2004) have all been shown to have higher risk for ‘‘vascular’’ dementia.

FIG. 1. Subcortical white matter hyperintensities, seen on FLAIR (transaxial) MRI brain scan,
which demonstrates mild (A) and somewhat more advanced (B) periventricular findings. On noncon-
trast CT brain scan (C), there is prominent hypodensity in the periventricular region. These findings
have been referred to as Binswanger’s disease in the past, but more recently the term leukoaraiosis has
been preferred because of the nonspecific clinical correlates of such findings.
24 MENON AND KELLEY

Atrial fibrillation has also been shown to be an independent risk factor for
cognitive impairment even in the absence of a stroke (Kilander et al., 1998;
O’Connell et al., 1998). With the presence of hypertension, the greatest risk factor
for stroke, the increased risk of cognitive impairment has been shown with
diVerent studies and patient cohorts (EVA Group, 1999; Launer et al., 2000).
Stroke has been proved as a significant risk factor for cognitive impairment
and dementia with as many as 25% of patients at 3 months and up to 50% within
a year developing some degree of clinically significant cognitive impairment
(Desmond et al., 2002; Mackowiak-Cordoliani et al., 2005; Tang et al., 2004;
Tatemichi TK et al., 1994). A reported range of 25–80% of elderly subjects with
dementia has Alzheimer’s disease coexisting with the vascular lesions. This makes
the assessment of pure cerebrovascular lesions diYcult ( Jellinger, 2008).

IV. Subcortical Strokes and Cognitive Impairment

It has long been believed that the small vessel or lacunar strokes in the white
matter of the brain contribute minimally to the changes in cognition. However, a
review of the NINDS-AIREN criteria (Roman et al., 1993) demonstrates that it
includes multiple basal ganglia and white matter lacunes and extensive periven-
tricular white matter lesions on neuroimaging as causes of probable ‘‘vascular’’
dementia. Ischemic lesions in the brain can occur in various locations. However,
with the current level and techniques of neuroimaging, it is not possible to
visualize all the microinfarcts.
Areas of white matter ischemia, such as microinfarcts, often termed lacunes
have been shown to be independent predictors of development of dementia
(DeGroot et al., 2000; Kovari et al., 2004; Pasquier et al., 2000; White et al.,
2002) particularly impairments with executive functions. Lacunes, when present
in certain specific locations like the thalamus and basal ganglia, can cause
cognitive disturbances (Fig. 2). Conversely, their presence in the deep white
matter of the frontal, temporal, or parietal lobes does not seem to do so. Silbert
et al. (2008) reported that an increase in total and periventricular white matter
signal intensity changes, over time, correlates with progressive gait impairment
while the progression of the total volume hyperintensity changes in the subcortical
region is associated with memory decline in elderly subjects who are relatively
intact from a cognitive standpoint.
The hippocampus is extremely sensitive to hypoperfusion which results in
sclerosis. Both sclerosis and lacunes in the hippocampus can lead to decline in
cognition (Bastos-Leite et al., 2007; Fein et al., 2000; Kril et al., 2002) but this decline
appears to be less than that seen in patients with Alzheimer’s disease (Du et al.,
2002). Age appears to be the best and strongest predictor of the presence of white
 SUBCORTICAL ISCHEMIC DEMENTIA 25

FIG. 2. Coronal T2-weighted MRI brain scan which reveals bilateral lacunar-type infarcts (arrows)
in the thalamic region.

matter lesions in elderly subjects and whereas these white matter lesions maybe
present in the elderly persons with normal cognitive function (Breteler et al., 1994;
Carey et al., 2008; Liao et al., 1997; Lindgren et al., 1994; Longstreth et al., 1996;
Soderlund et al., 2003; Ylikoski et al., 1993), although elderly patients with demen-
tia have been noted to have an increased load of lesions. There exists conflicting
data as to whether these white matter lesions indeed contribute to cognitive decline.
Some studies (Bracco et al., 1993; Gold et al., 2007; Schmidt et al., 2002) were not
able to find any definite evidence that these white matter lesions are responsible
for the cognitive impairment in these subjects whereas some others including
the subcortical ischemic vascular dementia (SIVD) program project (Chui, 2007;
Mosley et al., 2005; Prins et al., 2005) have found that an increasing load of white
matter lesions, over time, is associated with progressive cognitive decline (Fig. 3).
Price et al. (2005) report that despite the presence of white matter abnormal-
ities, executive dysfunction is not seen until at least 25% of the white matter in the
hemisphere is involved. Furthermore, when 50% of the hemisphere is involved,
executive dysfunction exceeds the memory impairment. This forms the basis of
research criteria proposed for subcortical vascular dementia (Erkinjuntti et al.,
2000). Understandably, there is no correlation between the MMSE score and
white matter lesion load as the MMSE assesses the memory and cognitive
functions and not the executive functions.
Carey et al. (2008) found that the presence of lacunes even when not producing
any clinical deficits could cause decline in cognition and supports the view upheld
by many others that in SIVD there is a disruption in the connecting pathways of
the subcortical areas and the frontal cortex.
26 MENON AND KELLEY

FIG. 3. Pronounced subcortical hyperintensities in the subcortical white matter, specifically the
centrum semiovale, in a patient with progressive gait and cognitive impairment. This is a FLAIR
(transaxial) MRI brain scan with two adjacent sections.

V. Pathophysiology of Cognitive Impairment in Subcortical Vascular Lesions

It has been proposed that various mechanisms contribute to impaired vascu-

larity in the brain that occurs with age. Hypoperfusion related to atherosclerosis
and arteriosclerosis, hypotension related to reduction in cholinergic eVects,
changes in the autonomic regulation of blood pressure, cortical hypometabolism,
cardiac causes such as congestive heart failure with resultant systolic dysfunction
and cardiac emboli and major surgical procedures have all been cited as causes
for cognitive changes that occur in the older population (Baron et al., 1986; Carey
et al., 2008; Nagata et al., 2000; Roman, 2004).
The eVects from the above-mentioned factors occur both in the cortical and
subcortical areas. However, since the subcortical areas are mostly perfused by
penetrating and deeper branches of the primary feeding arteries, the deleterious
eVects are most noticeable with increasing involvement of these vessels (Fig. 1).
Age appears to be a significant contributing factor to the evolution of this process
along with other risk factors for occlusive cerebrovascular disease. These are most
readily detected as periventricular white matter lesions on neuroimaging, specifi-
cally MRI, in the elderly. It is also important to understand that all white matter
lesions or hyperintensities seen are not infarcts and may potentially include causes
such as astrocytic swelling as well as actual infarction (Sahlas et al., 2002).
 SUBCORTICAL ISCHEMIC DEMENTIA 27

However, in a recent neuropathological study of these white matter hyperinten-

sities (Young et al., 2008), these lesions were associated with loss of vascular
integrity which was interpreted to reflect a vascular origin.
It appears that any disruption in the limbic circuit, which has the anterior
medial thalamus as the key component, results in memory impairment mainly
involving the short term and working types (Carrera and Bogousslavsky, 2004;
Swartz and Black, 2006).
Cholinergic factors have been cited as one of the possible mechanisms respon-
sible for cognitive impairment, either causing hypotension from ineVective auto-
nomic control related to aging or from disruption of the neurotransmitter pathways
by ischemic lesions in the white matter. The treatment of Alzheimer’s disease with
cholinesterase inhibitors was based on the assumption that acetylcholine (Ach) is
involved in memory and learning processes. Cholinergic pathways hyperintensities
scale (CHIPS) developed by Bocti et al. (2005) provides a reliable rating scale based
on white matter hyper intensities in the cholinergic pathways on MRI and their
correlation to cognition in patients with Alzheimer’s disease.
Whether the CHIPS scale can also be reliably used for patients with dementia
from other causes as it relates to white matter ischemic lesions is not yet proved.
N-acetyl aspartate (NAA) is a marker of neuronal integrity as measured with MRS
and decreased levels are noted in the parietal and frontal cortices in subcortical
ischemic cerebrovascular dementia (Capizzano et al., 2000; Kattapong et al., 1996;
McKay et al., 1996). It is thought that this correlates with the subcortical white
matter lesions and supports the theory that altered metabolism plays a role in the
pathogenesis.(Baron et al., 1986; Nagata et al., 2000) Another possible mechanism
of subcortical ischemia causing cognitive deficit is interruption of the association
fibers that connect the deep white matter with areas crucial for cognition (Chui,
2007). Tullberg et al. (2004) reported that there is an inverse relation between the
glucose metabolism in the dorsolateral frontal lobe and the white matter lesion
load, which supports this concept.
Altered cortical blood flow has been demonstrated with Xe-133 inhalation
techniques and indicates that blood flow is primarily reduced in the ipsilateral
fronto-parietal cortex with the presence of subcortical ischemic areas and
reflects the subsequent changes noted in cognition and executive function
(Hojer-Pederson and Friz-Peterson, 1989). Reduced volumes of the cortical
gray matter and hippocampi have also been shown, by autopsy, in patients with
subcortical ischemic cerebrovascular dementia (Chui, 2007; SchuV et al., 2002).
Comparisons have also been drawn to the lesions of MS which also causes
cognitive impairment with subcortical white matter lesions. Reduced magnetization
transfer ratio (MTR) has been shown to correlate with myelin and axonal content in
MS and also correlates with the level of cognitive impairment (Rovaris et al., 2000,
2002; Schmierer et al., 2004). Evaluation of the MTR in subcortical ischemic
cerebrovascular dementia showed a reduction of MTR in the cortices (Leuchter
28 MENON AND KELLEY

et al., 1994), again supporting the theory that remote eVects in the cortices, resulting
from possible disruption of the connecting tracts and circuits, may be responsible
for the cognitive changes.

VI. Treatment and Prevention

Options for treatment of subcortical ischemic cerebrovascular dementia are

presently quite limited. However, the overlap in pathological mechanisms between
subcortical ischemic cerebrovascular dementia and Alzheimer’s type dementia, with
similar findings of subcortical white matter hyper intensities on MRI brain scan
(Brickman et al., 2008), suggests the potential for agents of some benefit in AD to be
of similar benefit in subcortical ischemic dementia. Such agents include the cholin-
esterase inhibitors used in AD, vasodilators like nimodipine (a calcium-channel
blocker) as well as some antioxidant agents. Results are somewhat favorable with
the drugs used in AD and include donepezil, galantamine, and rivastigmine.
Donepezil showed significant improvement in two trials with a reduction in
the cognitive decline over a period of 24 weeks (Black et al., 2003; Wilkinson et al.,
2003) and galantamine showed some improved eYcacy over placebo in another
study over 12 months (Erkinjuntti et al., 2002). Rivastigmine was also found to
have some benefit in cognition, but this was in a relatively small open-label trial.
The calcium-channel blocking agent nimodipine was tested in patients with
‘‘multi-infarct’’ dementia and, although initial observation appeared promising,
subsequent studies were not (Pantoni et al., 2000, 2005).
In view of the limited role of medications in treatment of subcortical ischemic
cerebrovascular dementia, the focus is mainly on prevention. Prevention of this
entity involves aggressive modification of the risk factors for stroke. Various
studies have proved that control of hypertension results in a decrease in incidence
of dementia up to 34% (Forette et al., 1998; PROGRESS Collaborative Group,
2001; Tzourio et al., 2003) and also a reduction in the incidence of stroke by as
much as 35–44% (Chui, 2007). However, it is sobering to know that as many
as 70% of Americans who have hypertension are unaware of their diagnosis and
up to 60% are under-treated (Chobanian et al., 2003). This places them at
enhanced risk of stroke and other complications.
Control of other risk factors for stroke, such as diabetes mellitus, hyperlipid-
emia, atrial fibrillation, and so on, is also crucial for primary prevention (AHA/
ASA Stroke Council, 2006). Evidence from various studies has shown the eYcacy
of antiplatelet agents in stroke prevention. However, there is not presently
evidence-based support that the use of such agents translates into protection
against dementia per se. However, by the same token, eVective stroke prevention
would be expected to lessen the contribution of cerebral ischemia to what might
well be a multifactorial dementing process.
 SUBCORTICAL ISCHEMIC DEMENTIA 29

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 CEREBROVASCULAR AND CARDIOVASCULAR PATHOLOGY
IN ALZHEIMER’S DISEASE

Jack C. de la Torre
Sun Health Research Institute, Center for Alzheimer’s Research, Sun City,
Arizona 85351, USA

I. Introduction
II. Risk Factors to AD
A. Cardiovascular Disease
B. Preclinical Detection of AD
C. Treatment of AD
III. Conclusions
References

Presently, compelling evidence indicates that Alzheimer’s disease (AD) is a

vascular disorder with neurodegenerative consequences and should be treated as
such. A substantial body of evidence including epidemiological, pharmacotherapeu-
tic, and neuroimaging studies support the concept of AD as a vascular disorder or
vasocognopathy that initiates as brain hypoperfusion, creating a neuronal energy
crisis. The neuronal energy crisis provokes the cellular and molecular changes that
characterize this dementia. In this brief review, the many vascular-related risk factors
to AD including some that are preventable or amenable to treatment are discussed.
Considerable human data now point in a new direction for guiding future research
into AD. This new research direction should open a window of opportunity for
decisive management and treatment of this devastating disorder.

I. Introduction

Cerebral energy supply can be interrupted after cardiac arrest or stroke, two
conditions that result in global or local brain cell death. However, brain energy
supply can dwindle slowly over long periods of time following non-fatal carotid
artery stenosis or cardiac disease, two major disorders that result in brain hypo-
perfusion. Brain hypoperfusion (not an ischemic process) does not necessarily kill
or damage nerve cells right away by significantly arresting energy nutrients
delivered via the circulation but may chronically ‘‘gnaw’’ at nerve cells over a
long period of time by destabilizing their normal function (Fig. 1).

INTERNATIONAL REVIEW OF 35 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00403-6 0074-7742/09 $35.00
36 JACK C. DE LA TORRE

Neuronal states

Metabolically
Functional neuron D dysfunctional neuron
A
Nissl bodies

Nisssl

C
Nuclear shift Nissl loss
eosinophilia
Nuclear pyknosis

Nuclear chromatosis Structurally

damaged neuron

B
Dead neuron

FIG. 1. Functional and pathological states deranging brain neurons resulting in degenerative
processes. Healthy, functional neurons (A) can either (B) die (solid arrow), (C) undergo metabolic-
structural damage (dashed arrow), (D) undergo metabolic only damage (dotted arrow). In the (C) state,
intracellular damage can be assessed histologically by noting nuclear or cytoplasmic changes in
organelles (chromatolysis, eosinophilia, nuclear shift, pyknosis, etc.). In the (D) state, bio-molecular
markers reflecting neuronal distrenss are needed to evaluate extent of metabolic dysfunction. Neuronal
metabolic dysfunction following chronic brain hypoperfusion is likely the first step in the pathologic
pathway to cytostructural damage, atrophy, and death and how such dysfunction may explain
cognitive disability, as in pre-clinical Alzheimer’s disease.

Since cerebral hypoperfusion now appears to be a major precursor of Alzhei-

mer’s disease (AD) (Aguero-Torres et al., 2006; Breteler, 2000; de la Torre, 2000,
2004a,b; de la Torre and Mussivand, 1993), the issue of glucose and oxygen
availability and delivery via the circulation becomes a key element in the puzzle to
understand the cellular-molecular cascade that leads to AD. The main reason to
focus on glucose uptake and utilization by brain cells is that this molecule is the
primary energy substrate for the brain which also consumes 20% of the total
oxygen supply used by the body (Fig. 1A).
We became interested in the role of cerebral energy metabolism on AD in the
early 1990s, when the subject was only of cursory, rare interest, following our
series of experimental brain hypoperfusion studies and a review of the clinical
dementia literature at the time (de la Torre and Mussivand, 1993). These experi-
mental studies led us to propose the vascular hypothesis of AD as the likely cause
of this disorder (de la Torre and Mussivand, 1993).
 CEREBROVASCULAR AND CARDIOVASCULAR PATHOLOGY 37

Since then, compelling evidence from a variety of clinical and basic studies has
convince us that AD should be treated as a vasocognopathy (de la Torre, 2004)
(a vascular-related, cognitive disorder) and we shall explore some of this evidence
in our review here to determine whether proof of concept is met.

II. Risk Factors to AD

The most compelling evidence for a vascular connection to AD comes from

independent epidemiological studies. Findings from the Rotterdam Study, the
Kungsholmen project, EURODEM, FINMONICA, the PROCAM study, the
Framingham study and the Honolulu-Asia study, among others, indicate that
over two dozen risk factors, all vascular related, have thus far been recognized for
AD (Table I) (Breteler, 2000; Aguero-Torres et al., 2006; de la Torre and
Mussivand, 1993). These epidemiological studies have led to the conclusion that
most of the AD cases analyzed have a vascular involvement, and that pure
dementia types (including vascular dementia) in older subjects constitute only a
minority of dementia cases (Aguero-Torres et al., 2006; Breteler, 2000). It is highly
improbable that chance alone could explain the reduction of cerebral blood flow
(CBF) induced by several dozen diVerent risk factors found linked to AD (Table I).
If indeed, a variety of vascular risk factors for AD exists and is highly important in
promoting this dementia, then the question of the role of amyloid beta (A!) needs
to be asked. Do risk factors eventually also promote the excessive production of
A! in brain or does A! promote the varied risk factors? The second possibility
seems rather unlikely due to the spectral nosology of each risk factor described
thus far (Table I), so building on the assumption that vascular-dependent risk
factors for AD do lower cerebral perfusion and eventually promote A! produc-
tion, we have introduced the role of critically attained threshold of cerebral hypoperfusion
(CATCH) (de la Torre, 2000). CATCH develops when a vascular risk factor or
factors further diminishes cerebral CBF in an individual who already has devel-
oped declining cerebral perfusion due to advanced age and a poor vascular
reserve. The reason is that CBF normally declines with age by about 21% from
age 21 to 60 (Leenders et al., 1990). Below this normal-age related CBF decline, a
‘‘CATCH brain blood flow level’’ can result from advancing age when it co-exists
with one or more vascular risk factor as listed in Table I.
The speed at which CATCH is attained depends on the person’s state of health,
lifestyle, genetics, gender, diet, environmental exposure, and other confounding
factors. Once CATCH is activated, energy hypometabolism and oxidative stress
result from continuous brain hypoperfusion and from reduced glucose and oxygen
delivery to neurons and glia (de la Torre, 2000) (Fig. 1B). The main reason for the
high glucose/O2 uptake in the normal brain is the massive amounts of ATP needed
38 JACK C. DE LA TORRE

TABLE I
SUMMARY OF FINDINGS FROM EPIDEMIOLOGICAL STUDIES (SEE TEXT) OF VASCULAR-RELATED
RISK FACTORS TO ALZHEIMER’S DISEASE

Alzheimer’s disease vascular risk factors

Brain-related risk factors

Aging
Ischemic stroke
Silent stroke
Head injury
Transient ischemic attacks
Migraine
Lower education
Hemorheologic abnormalities
Depression
Circle of Willis atherosclerosis
Heart-related risk factors
Congestive heart failure
Valvular disease
Hypertension
Hypotension
Thrombotic episodes
High serum homocysteine
Atrial fibrillation
Presence of ApoEe4 allele
Carotid atherosclerosis
Coronary artery bypass surgery
Peripheral risk factors
High serum cholesterol
High intake of saturated fat
Diabetes mellitus II
Hemorheologic abnormalities
Alcoholism
Smoking
Menopause

Highly prevalent conditions such as stroke, hypertension, atherosclerosis and heart disease are
common precursors to AD.

to maintain neuronal signaling during active ion channel flux. Ion flux is the
basis for propagation of action potentials and neurotransmission. Impaired brain
energy production also upregulates the A! rate-limiting enzyme BACE1, thus
promoting A! overproduction (Velliquette et al., 2005) (Fig. 1B). Consequently,
when mitochondrial function in neurons is disrupted by failing glucose/O2 supply
for energy production, rapid damage to brain cells occurs. Brain hypoperfusion is
the pathogenic trigger that pushes the neuronal energy crisis and the cascade of
molecular and cytopathologic changes that characterize AD (Fig. 2).
 CEREBROVASCULAR AND CARDIOVASCULAR PATHOLOGY 39

A Initial neuronal energy crisis

Trophic factors
Low glucose growth factors
Low oxygen
NGF, BDNF
ATP
Mitochondria p3
s Nerve ending
P
BA
CE
-2
AP
Nucleus UPR APP
ATP
Microtubules
TransGolgi
Nissl (rER) Reduced ATP synthesis
Oxidative stress = some free radicals
Na+ K+ ATPase pump disturbed (?)
Signal transduction impairment (?)
Non-specific protein changes Neurotransmitter dysfunction (?)
Non-Aß amyloid accumulation

B Advanced neuronal energy crisis

Trophic factors
Low glucose growth factors
Low oxygen
NGF, BDNF
ATP
Ab
Mitochondria
-1 Ab Nerve ending
CE
BA

Nucleus APP
UPR
tau
ATP Microtubules
TransGolgi
Nissl (rER) Reduced ATP synthesis
Oxidative stress = hi free radicals
+ +
Na K ATPase pump disturbed
Signal transduction impairment
Protein synthesis Neurotransmitter dysfunction
Protein assembly Increased BACE-1 increased Ab
Protein folding [UPR] Microtubule disassembly = death

Protein cleavage

FIG. 2. (A) A fundamental principle in cell biology is seen by the use of chemical energy in the form
of ATP derived from glucose/oxygen delivery to assemble, disassemble and alter protein structure.
Since proteins work to keep a neuron healthy, defects in their synthesis, assembly, folding, or cleavage
can impair the normal intracellular and extracellular secretory transport pathway and damage brain
cells. Normal neuronal energy metabolism in the brain includes optimal ATP production by mito-
chondrial oxidative phosphorylation, RNA transcription and protein synthesis, cell signaling, neuro-
transmission, axonal transport of molecules between cytoplasm and nerve ending via microtubules.
Normal brain has little or no A! accumulation. Following initial cerebral hypoperfusion, reduced ATP
synthesis can result in non-specific protein and oxidative stress changes that may lead to MCI.
Theoretically, overexpression of A! peptides and specific neurodegenerative pathology may be lacking.
40 JACK C. DE LA TORRE

Risk factors for AD are either the result of genetic susceptibility (e.g., carrying
an ApoE e4 allele) or environmental exposure of a person’s health to an event that
can introduce, accelerate, or further compromise cognitive dysfunction. At the
present time, only environmental risk factor exposure is modifiable or preventable
but in the future, genetic engineering of potential risk susceptibilities to AD could
become a realistic therapeutic target for AD.
Vascular risk factors to AD as shown in Table I have been extensively
reviewed (Aguero-Torres et al., 2006; Breteler, 2000; de la Torre and
Mussivand, 1993; Sjogren et al., 2006; Sparks et al., 2005) and only some recently
reported risk factors will be briefly discussed here.
One example of a potentially modifiable vascular risk to AD of increasing
research interest is hypercholesterolemia and dietary fat intake. A steady amount
of research has confirmed a link between high levels of cholesterol and the
development of AD (Sjogren et al., 2006).
Hypercholesterolemia acts as a precursor of atherosclerosis, cardiovascular
disease, and diabetes. For obvious reasons, high serum cholesterol levels have
generated a rapid-growing market for lipid-lowering drugs prescribed to patients
at risk of cardiovascular or cerebrovascular conditions. Statins that lower choles-
terol levels have been suggested as useful in both prevention and treatment of AD
but this conclusion needs further verification (Sparks et al., 2005). The mechanism
by which statins may provide a benefit against cerebrovascular disease including
AD remains speculative and is likely multifactorial. In 1998, it was suggested, on
the basis of murine studies, that the health benefits of statins did not merely aim at
lowering lipids (Laufs et al., 1998). Statins were shown to protect against injury by
a mechanism involving the selective upregulation of endothelial nitric oxide
synthase (Laufs et al., 1998), the enzyme that generates nitric oxide in blood
vessels and is involved with regulating vascular function. Further research along

(B) Persistent reduction of glucose and oxygen delivery to ischemic-sensitive neurons following chronic
brain hypoperfusion leads to critical ATP depletion and promotes oxidative stress, reactive oxygen
species and abnormalities in protein synthesis activating their disassembly, misfolding (generating
unfolded protein response, UPR), and abnormal cleavage. Altered protein synthesis can subsequently
form molecules that can ravage nucleic acids, protein kinases, phosphatases, lipids, and harm cell
structure. ATP cutback also hastens ionic pump dysfunction, signal transduction breakdown, neurotrans-
mitter failure, faulty cleavage of amyloid precursor protein (APP) leading to BACE-1 upregulation and
A! overproduction and microtubule damage from tau hyperphosphorylation. Retrograde axonal
transport (curved arrow) of trophic and growth factors (e.g., NGF, BDNF) essential for neuronal survival
is diminished due to energy-starved motor protein deficiency. This selective neuronal energy crisis is
caused by blood flow supply not meeting cell energy demand in highly active brain regions whose vascular
reserve capability has reached a critical threshold. About 75% of ATP energy is used on signaling
(action potentials, postsynaptic potentials, etc.). Reduced ATP synthesis is the precursor of the molecular
cascade that leads to Alzheimer’s disease (AD) and to the region-specific neurono-glial death pathway.
Key: # ¼ reduction or loss; 6 ¼ impaired reaction.
 CEREBROVASCULAR AND CARDIOVASCULAR PATHOLOGY 41

these lines has demonstrated that statins improve endothelial function, increase
nitric oxide bioavailability, provide antioxidant properties, inhibit inflammatory
responses, exert immunomodulatory actions, regulate progenitor cells, and stabi-
lize atherosclerotic plaques (Endres et al., 1998) and several studies have shown a
benefit for statins in the treatment of AD (Wolozin et al., 2000).
Another important modifiable risk factor to AD is metabolic syndrome (MeS).
MeS is a cluster of factors that can lead to the development of cardiovascular
disease. MeS is characterized by abnormal insulin, glucose, and lipoprotein
metabolism as well as by hypertension and obesity (Grundy et al., 2005). These
factors are frequently found in people with either excess abdominal body fat or a
decreased ability of the body to use insulin, which is known as insulin resistance
(Grundy et al., 2005).
MeS has been found to be associated with AD even when diabetic patients are
excluded from analysis (Vanhanen et al., 2006), suggesting that obesity associated
with cardiovascular dysfunction or hypercholesterolemia is suYcient to initiate
cognitive impairment that later can convert to AD. The number of people
with MeS increases with age and is estimated to aVect 40% of people beyond
the age of 60. People with uncontrolled diabetes mellitus type 2 and those with
heart disease or prone to stroke are most likely to develop MeS (Martins et al.,
2006).
Since obesity and lack of exercise are two conditions that can lead to MeS,
correcting these by lifestyle changes that include a healthy diet and physical
activity could help prevent or reverse MeS. The cardiovascular risk factors
associated with MeS contribute to the development of atherosclerosis that can
lead to a heart attack or a stroke. People with the MeS are also more likely to
develop type 2 diabetes mellitus (Martins et al., 2006). Insulin resistance is central
to type 2 diabetes and is also implicated in the pathogenesis of AD (Vanhanen
et al., 2006). This has prompted ongoing clinical trials in AD patients to test the
eYcacy of improving insulin-like signaling with dietary omega-3 fatty acids or
insulin-sensitizing drugs as well as by exercise regimens.
It is well established that hypertension can increase the risk of stroke and heart
problems and decrease life expectancy (de la Torre, 2006). Many studies including
the Framingham and the Honolulu-Asia Aging studies have implicated impaired
cognitive function to hypertension in geriatric patients (Elias et al., 1993). It has
also been known for some time that hypertension in the elderly is a potential risk
factor to AD (de la Torre, 2009). What is not clear is how hypertension increases
the incidence of AD, particularly in those not-treated with antihypertensives.
People with hypertension are six times more likely to have a stroke that can
lead to AD (Ivan et al., 2004). It is calculated that reducing the number of cases
aVected by stroke which are amenable to prevention or treatment, would have a
major impact in lowering the incidence and societal costs of Alzheimer’s disease
which is now estimated to aVect 25 million people worldwide.
42 JACK C. DE LA TORRE

A. CARDIOVASCULAR DISEASE

Some forms of cardiac disease that result in impairment of cardiac output or

function with consequent reduction of cerebral perfusion have been found to
increase AD risk (Alves and Busatto, 2006).
Since 20% of cardiac output goes to the brain and 80% of carotid artery flow
goes to each ipsilateral middle cerebral artery, it is no surprise that vascular lesions
of the gray and white matter are frequently associated with cardiac disease and
carotid artery stenosis, both vasculopathies that can induce cognitive impairment
and probably AD (Alves and Busatto, 2006; de Leeuw et al., 2004; Ivan et al., 2004;
Miklossy, 2003).
Moreover, cerebral hypoperfusion can result in white matter lesions and
cortical watershed microinfarcts in the absence of atherosclerosis or amyloid
angiopathy (Miklossy, 2003), and may induce microinfarcts in the hippocampus
prior to the onset of AD (de Leeuw et al., 2004).
We firmly believe that AD onset can be delayed or possibly prevented if the
heart can be kept healthy and brain hypoperfusion can be treated by restoring
normal blood flow. The upshot would be a major research breakthrough in AD
prognosis if either feat is successfully achieved. Consequently, diet, exercise, and
management of many vascular risk factors amenable to treatment may be the key
to significantly reducing the incidence of this dementia in the future.

B. PRECLINICAL DETECTION OF AD

The most important factor in developing a useful blueprint for AD treatment

is identifying such candidates at the preclinical stage before any incapacitating
cognitive damage has occurred. The reason is that once cognitive meltdown has
begun (which implies serious neuronal damage and tissue atrophy), AD pathology
may be most diYcult to reverse or arrest.
Considering AD as a vascular disorder characterized by brain hypoperfusion,
techniques that can detect regional CBF reduction during mild cognitive im-
pairment (MCI), a condition often seen prior to AD, or even before any memory
deficits are measured, will be crucial to predict AD candidates.
In our judgment, three of the most important neuroimaging tools to screen
AD candidates before major clinical symptoms have developed are single-photon
emission tomography (SPECT), injected [18F]fluorodeoxyglucose (FDG) using
positron emission tomography (PET), and transcranial Doppler (TCD) ultraso-
nography. SPECT and TCD can detect with a good degree of sensitivity and
specificy, persons showing regional brain hypoperfusion at the MCI stage, many
who later convert to AD ( Johnson et al., 1998; Ruitenberg et al., 2005).
 CEREBROVASCULAR AND CARDIOVASCULAR PATHOLOGY 43

Preclinical detection of AD as a group is now possible using FDG-PET

although the technique is considerably more expensive and labor intense than
SPECT or TCD. Individuals at risk of AD but who do not express any cognitive
deficits show local hypometabolic reductions of the cerebral metabolic rate of
glucose after FDG in brain regions that will later develop atrophy and neurode-
generation (de Leon et al., 2001). Since measures of glucose metabolic rate and
CBF are coupled (Silverman and Phelps, 2001), FDG-PET studies are proof of
concept that regional brain hypoperfusion precedes Alzheimer clinical symptoms,
A! production, and neurodegenerative changes. FDG-PET can also track AD
progression (de Leon et al., 2001).
Existing or developing coronary artery disease in the elderly patient may
worsen age-related cerebral hypoperfusion in the elderly person (de la Torre,
2006). Most patients with ischemic heart disease will present themselves in general
practice. Therefore, the community management of ischemic heart disease has
already become increasingly important and the role of the primary care physician
even more pivotal.
Inasmuch as normalization of diminished cardiac output from any cause may
prevent or reverse MCI (a high risk for prodromal AD) (de la Torre, 2006, 2008,
2009), simple, safe, and reliable diagnostic screens should be applied to older
patients in an eVort to reduce the consequences of cardiac-to-brain related AD
risk factors. We have recommended the use of cost-eVective, safe, and reliable
noninvasive tools such as echocardiography (Fig. 3) and carotid Doppler ultra-
sound to be used in the elderly individual found to complain of memory diYcul-
ties (de la Torre, 2008). Employment of noninvasive screening techniques using
carotid artery ultrasound and echocardiography (CAUSE) (de la Torre, 2008,
2009) in the detection of medically or surgically correctable conditions that reduce
heart or carotid artery blood flow to brain is anticipated to delay or prevent the
progression to Alzheimer’s or vascular dementia (VaD) in many of those aVected.
These oYce procedures involve no needles, no radiation, and no contrast agents
that may cause allergic reactions.
Carotid artery ultrasound is a safe, cost-eVective, and reasonably reliable
way to determine the clinical action that may prevent potential or continuing
cognitive decline. Such clinical action could significantly impact on the preva-
lence of incident dementia rate. Echocardiographic measurements can provide a
relatively simple, safe, reliable, and cost-eVective evaluation of impaired cardiac
function that may indicate a dangerously reduced level of cerebral perfusion that
can lead to AD.
Echocardiography is also useful in guiding therapy over time. This is possible
by measuring the eVect of therapy on multiple parameters of cardiac function,
including diastolic filling and ventricular performance, two major determinants of
preload and therefore of cardiac output (Ahmed et al., 2007). These measurements
have demonstrated considerable prognostic value in symptomatic and
44 JACK C. DE LA TORRE

RVOT Aorta
Septum
AV Aortic valve
LVOT
LV
LA
MV

Inferior wall
RVOT
Septum

Apex Left atrium

Papillary muscles Mitral valve

Myocardium Left ventricle

FIG. 3. Echocardiography image (top) is obtained by placing the ultrasound probe on the surface of
the chest over the heart. Image shows all four chambers of the heart, useful for detecting chamber
enlargement. Valvular disease, hypertension, arrhythmias, left ventricular function, ejection fraction,
and cardiac output can be determined and measured. These cardiac measurements oVer a noninva-
sive, cost-eVective and reliable approach that can identify often correctable or treatable early lesions of
the heart which may contribute to chronic brain hypoperfusion and possibly AD in the elderly patient
with mild memory complaints. Key: RVOT ¼ right ventricular outlet tract; LVOT ¼ left ventricular
outlet tract; LV ¼ left ventricle; MV ¼ mitral valve; LA ¼ left atrium.

asymptomatic patients with either preserved or abnormal cardiac function

(Ahmed et al., 2007). Such techniques can generally rule out cardiac pathology
and extracranial vessel disease. Cardiac pathology and extracranial vessel disease
have been shown to be major contributors to cerebral hypoperfusion and stroke
(Alves and Busatto, 2006) and their attrition may result in a significant impact on
lowering the prevalence of Alzheimer’s and VaD.

C. TREATMENT OF AD

There is presently no eVective treatment for AD. Five drugs are available in
the US market for prescriptive use in AD: Cognex (tacrine), Aricept (donepezil),
Excelon (rivastigmine tartrate), Reminyl (galantamine hydrobromide), and
 CEREBROVASCULAR AND CARDIOVASCULAR PATHOLOGY 45

Namenda (memantine). The first four above act to slow the synaptic breakdown
of acetylcholine, one of the neurotransmitters important in memory and learning.
Reminyl also targets both AD and ‘‘mixed’’ dementia, that is, AD complicated by
cerebrovascular pathology.
A fifth drug, memantine, is a relatively newer medication for the treatment of
Alzheimer’s disease that works ostensibly by antagonizing the N-methyl-D-
aspartate receptors. Nonprescriptive treatments for AD in present use are nonste-
roidal anti-inflammatory agents (NSAIDs), ginkgo biloba, estrogen, vitamin E,
and prescriptive statins. All these treatments, whether prescriptive or over-the-
counter, at best, provide only very modest control of symptoms generally at the
early stages of AD and oVer little to no cost-benefit ratio at the later stages of the
disease (Loveman et al., 2006). Their modest benefit to AD patients must be
weighed against their frequent side-eVects, particularly the anti-cholinergic agents
which include nausea, vomiting, dizziness, headaches, and depression. Moreover,
since most clinical trials on the eVectiveness of these medicines were sponsored by
industry or industry-paid researchers, a prominent shadow for positive bias has to
be considered (Sismondo, 2008).
It should be noted that the common link binding practically all the medicines
and therapies available or tested experimentally for AD so far is their ability to
mildly increase cerebral perfusion (de la Torre, 2004b). However, since cerebral
perfusion is only slightly improved, the beneficial eVect of medicines such as those
listed above is transient and limited. Interestingly, most of the products that
improve AD symptoms also improve the symptoms of VaD. This activity by
medicaments with diVering pharmacokinetics and pharmacodynamics, lend
additional support to the concept of brain hypoperfusion in AD and VaD and
reinforce potential therapeutic targets aimed at patients who initially present with
mild cognitive dysfunction and who display declining perfusion to the brain.
New technologies, whose primary goal is to significantly increase cerebral perfu-
sion in such patients, could delay, reverse, or prevent the neuropathological
process that can lead to dementia.

III. Conclusions

There is now compelling evidence that Alzheimer’s disease is a vascular

disorder with neurodegenerative consequences and should be treated as such.
A large body of evidence including epidemiological, pharmacotherapeutic,
and neuroimaging studies support the concept of AD as a vascular disorder
(a vasocognopathy; de la Torre, 2004a) that results in brain hypoperfusion and
consequent neuronal energy crisis that provokes the cellular and molecular
changes that characterize this dementia. Cerebrovascular and cardiovascular
46 JACK C. DE LA TORRE

conditions responsible for reducing carotid artery and cardiac blood flow to the
brain may be crucial clues in better understanding the physiopathology of AD.
This shift in thinking acknowledges the notion that current complacency on the
state of the art has created the gridlock which ignores that something is wrong in
our ability to clinically manage AD after a century of research. In this brief review,
the many vascular-related risk factors to AD including some that are preventable
or amenable to treatment are discussed. Considerable human data now point in
a new direction for guiding future research into AD. A more data driven new
research direction should open a window of opportunity that can lead to new
technologies, create new subfields by revolutionizing the field of dementia and
provide decisive management of this devastating disorder.

Acknowledgment

This research was supported by an Investigator-Initiated Research Grant from the Alzheimer’s
Association.

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 NEUROIMAGING OF COGNITIVE IMPAIRMENTS
IN VASCULAR DISEASE

Carol Di Perri,*,y Turi O. Dalaker,*,} Mona K. Beyer,z,} and Robert Zivadinov*,¶

*Department of Neurology, Buffalo Neuroimaging Analysis Center, State University
of New York at Buffalo, Buffalo, New York 14203, USA
y
Department of Neuroradiology, IRCCS, C. Mondino, University of Pavia, Pavia, Italy
z
Department of Radiology, Stavanger University Hospital, Stavanger, Norway
}
The Norwegian Centre for Movement Disorders, Stavanger University
Hospital, Stavanger, Norway
¶
Department of Neurology, The Jacobs Neurological Institute, State University of
New York at Buffalo, Buffalo, New York 14203, USA

I. Introduction
A. Structural Brain Imaging
B. Functional Imaging
C. Metabolic Imaging
II. Vascular Cognitive Impairment
A. Terminology
B. Classification
C. Histopathology of VCI
D. Diagnostic Neuroimaging Criteria in VCI
E. Therapeutic Strategies
III. Updates on Neuroimaging Techniques in VCI
A. Conventional Structural MRI
B. Nonconventional Techniques
C. Metabolic Imaging
D. Functional Imaging
E. Correlations Between Imaging Findings and Pathology
IV. Conclusions
References

Cerebrovascular disease (CVD) is increasingly recognized as a common cause

of cognitive impairment and dementia, alone or in conjunction with other neuro-
degenerative diseases, primarily Alzheimer’s disease. The term vascular cognitive
impairment (VCI) has been proposed as an umbrella term to recognize the broad
spectrum of cognitive changes associated with vascular pathology, mainly charac-
terized by executive impairment together with particular noncognitive features.

INTERNATIONAL REVIEW OF 49 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00404-8 0074-7742/09 $35.00
50 DI PERRI et al.

Magnetic resonance imaging (MRI) has become the most important neuroim-
aging methodology for assessing and monitoring the pathological changes involved
in the onset and progression of vascular neurological diseases. Conventional MRI
sequences are usually not suYcient to provide full details about the diVerent degrees
of brain damage underlying vascular disorders. However, newer and more
advanced nonconventional MRI techniques have the capacity to detect invisible
brain damage that would otherwise not be detected. This review outlines some of
the most important neuroimaging techniques commonly used in the diagnosis,
assessment, and monitoring of cognitive impairment in vascular diseases. More
detailed applications of these techniques, specifically for VCI, are discussed.

I. Introduction

A. STRUCTURAL BRAIN IMAGING

Although computed tomography (CT) is still important in many clinical

settings, magnetic resonance imaging (MRI) is becoming the imaging method of
choice, oVering better tissue specificity and sensitivity with respect to relative
pathology. Therefore, this section—which discusses structural imaging—will
refer only to MRI studies.
1. Conventional MRI Techniques
T2-weighted imaging (WI) is highly sensitive in detecting vascular lesions.
Upon gliotic transformation, that is, tissue scarring, these appear as local hyper-
intensities of T2 prolongation in the white matter (WM). There are diVerent and
various techniques for identifying T2 hyperintense lesions; among them, the most
often recommended are conventional spin echo (CSE), turbo spin echo (TSE),
and fluid-attenuated inversion recovery (FLAIR) (Zivadinov and Bakshi, 2004).
FLAIR is a MRI sequence for optimized detection of brain parenchymal patho-
logic water content. It is particularly helpful in the evaluation of periventricular
and cortical/juxtacortical lesions, where cerebrospinal fluid (CSF ) may mask the
visualization of these lesions on T2-WI (Zivadinov and Bakshi, 2004; Zivadinov
and Cox, 2007). In the last decade, continuous technical improvements in MRI
hardware and software have led to the development of new pulse sequences that
are more eYcient and sensitive. Among them, TSE or FSE, proton density (PD)
and fast-FLAIR have already demonstrated their usefulness in a wide variety
of neurologic diseases. Better lesion-to-CSF contrast is achieved with PD because
of the relatively lower signal intensity of CSF on this sequence and improved
lesion-to-tissue contrast. TSE showed greater sensitivity than CSE in detecting
areas of T2 prolongation.
 MRI AND COGNITION IN VASCULAR DISEASES 51

On noncontrast T1-WI, most ischemic lesions are iso- or hypointense in WM.

T1-hypointense lesions are an important MRI metric of neurodegeneration in
patients with diVerent neurological disorders. They represent a more advanced
pathological substrate of the lesions—mainly axonal loss, Wallerian degeneration,
and gliotic changes (Zivadinov and Bakshi, 2004; Zivadinov and Cox, 2007).
Even though these techniques are highly sensitive to tissue damage, they are
usually not capable of discerning among the possible diVerent pathological origins
of the damage (demyelinating, vascular, tumoral). Therefore, both in clinical and
research practice, they have to be supplemented with the clinical history of the
subject and, most of the time, with other newer nonconventional MRI techniques.

2. Nonconventional MRI Techniques

Magnetization transfer imaging. Magnetization transfer imaging (MTI) is an
advanced MRI technique that has been widely used to evaluate characteristics
and evolution of damaged tissue and normal appearing brain tissue (NABT).
It is based on the interactions and energy exchange between protons that are
unbound in a free water pool with those where motion is restricted due to binding
with macromolecules (Horsfield et al., 2003). MTI uses an oV-resonance radio
frequency (RF) pulse to saturate protons in macromolecules and water molecules
that are bound to macromolecules and are normally not visible due to their very
short T2* relaxation times. During pulse sequence acquisition, the saturated
protons may enter the free pool of protons, primarily water, or may transfer
their magnetization to free water protons. As a consequence, a decrease in the
MRI-visible signal is produced in areas characterized by an abundance of macro-
molecules aVected by magnetization transfer. Tissue damage is usually reflected
by a reduction in this exchange of protons and thus a decrease in the magnetiza-
tion transfer ratio (MTR). Decreases in MTR indicate a reduced capacity of
free water to exchange magnetization with the brain tissue matrix with which the
water comes into close contact. MTRs can be used to detect changes in the
structural status of brain parenchyma that may or may not be visible with
conventional MRI techniques. Therefore MTI enables semi-quantitative, repro-
ducible characterization of tissue and pathologic entities which could substantially
improve the specificity of MRI (Fig. 1).
DiVusion-weighted imaging. DiVusion-weighted imaging (DWI) and diVusion-
tensor imaging (DTI) are advanced MRI techniques that allow the measurement
of tissue water diVusion-related motion and, as a consequence, provide information
about orientation of water motion within the tissue (Rovaris et al., 2005). These
techniques take advantage of the direction-dependent mobility of protons which is
mainly due to the underlying structure of the brain tissue. The free, random
diVusion is restricted by cellular boundaries in diVerent directions to a varying
degree, for example, diVusion along a myelinated nerve fiber is much easier than
the diVusion perpendicular to it. Similarly, the apparent diVusion coeYcient (ADC)
52 DI PERRI et al.

A B C

FIG. 1. Magnetization transfer imaging: sample scan with (A) and without (B) magnetic transfer
pulse. A relative magnetization transfer ratio map (C) is generated.

is lower in highly structured tissues such as WM and gray matter (GM) than in pure
water. ADC values depend on the orientation of the tissue relative to the measure-
ment. Conventionally, the average ADC is calculated from three (DWI) or more
than three (DTI) linearly independent directions that provide information on the
overall diVusivity in the tissue. Pathological processes that modify tissue organiza-
tion can cause abnormal water motion, thereby altering ADC values. Ischemic
events can alter diVusion parameters of brain tissue in vivo, resulting in a decrease of
water diVusivity measurable with diVerent DWI and DTI indices. These measures
include mean diVusivity (MD), fractional anisotropy (FA), entropy and subsequently
tractography outcomes (Fig. 2). It is important to emphasize that, in most instances,
very acute stages of ischemic events can be detected through this technique within
the first hour of onset. On the other hand, such changes are often not recognized on
other MRI sequences. The increased sensitivity of DWI in detecting acute ischemia
is thought to be the result of the water shift restricting motion of water protons
intracellularly (cytotoxic edema), whereas conventional T2-WI shows signal
alteration mostly as a result of vasogenic edema. However, the exact origin of the
decreased ADC measurements observed in early ischemia has not been fully
established. The diminished ADC value also could be a result of decreased temper-
ature in the malperfused tissues or a combination of all these factors (Busto et al.,
1987; Crain et al., 1991).
Regardless of the cause, decreased apparent ADC is a very sensitive indicator
of an early ischemic brain event at a stage when ischemic tissue remains poten-
tially salvageable (Wolpert et al., 1993).
Atrophy measures. The measurement of brain atrophy is of growing clinical
relevance as a biomarker of the disease process, especially when correlated
with other anatomical and functional information from conventional and non-
conventional MRI. Various tools are available for semiautomatic evaluation of
brain volume, longitudinal studies and intra-/intergroup cross-sectional analysis,
 MRI AND COGNITION IN VASCULAR DISEASES 53

A B

C D

FIG. 2. DiVusion tensor imaging: Mean diVusivity (A), fractional anisotropy (B), and color-
fractional anisotropy (C) maps are presented. The maps are defined as functions of the eigenvalues
(i.e., the invariants of the diVusion tensor at each voxel); in the RGB (red-green-blue) FA map, the
corresponding eigenvectors are also displayed through color coding. A streamline tractographic
reconstruction (D) is displayed; fibers are reconstructed according to a linear algorithm following the
direction of maximum FA until a threshold value is exceeded.

such as SIENA and SIENAX of the FSL library (http://www.fmrib.ox.ac.uk/fsl/),

FreeSurfer (http://surfer.nmr.mgh.harvard.edu/), and SPM (http://www.fmrib.
ox.ac.uk/fsl/,http://www.fil.ion.ucl.ac.uk/spm/) (Fig. 3). Voxel-based analysis
methods are of growing interest, giving the opportunity to perform local atrophy
measurements and possibly displaying a stronger correlation with functional
estimates. A high resolution 3D T1-weighted scan is necessary for the analysis
and patient age, disease duration, total brain volume or any other presumably
significant parameters are typically taken into account as covariates for the
statistical analysis. A large subject cohort is indeed necessary for gaining suYcient
statistical power, especially considering the sophisticated geometric preprocessing
necessary for group analysis.
Atrophy is now proposed to be included as a secondary endpoint in longitu-
dinal trials aimed at monitoring disease progression and therapy eYcacy, as
complementary information to conventional MRI in various diseases such as
multiple sclerosis (MS) and Alzheimer’s disease (AD) (Whitwell, 2008).
54 DI PERRI et al.

A B

C D

FIG. 3. Brain segmentation with statistical parametric mapping (SPM) software: (A) 3D-T1 image,
(B) cerebrospinal fluid, (C) gray matter, and (D) white matter segmentation maps are displayed.

B. FUNCTIONAL IMAGING

1. Perfusion-Weighted Imaging
Perfusion-weighted imaging (PWI) techniques are sensitive to microscopic
levels of blood flow, defined as the amount of blood flowing into a voxel in a
certain temporal span and measured in ml blood/min/gr tissue. This index may
be altered in disease conditions and accurate monitoring is clinically relevant,
improving our understanding of the pathophysiology of the disease.
With respect to other techniques that noninvasively investigate cerebral blood
flow, such as positron emission tomography (PET), single photon emission
computed tomography (SPECT), and xenon-enhanced computed tomography
(Xe-CT), PWI shows some advantages by not using ionizing radiations, allowing a
better spatial resolution and a better signal-to-noise-ratio (SNR). In addition, PWI
is typically acquired over a short time, needing only a few extra minutes after
a conventional MRI exam.
Contrast-enhanced relative cerebral blood volume (rCBV) is the most
used perfusion imaging technique for parameter mapping. In this and other techni-
ques, both the ready availability and the T2* susceptibility eVects of gadolinium,
 MRI AND COGNITION IN VASCULAR DISEASES 55

rather than the T1 shortening eVects, make it a suitable agent for use in PWI. As long
as the bolus transit through the tissue takes only a few seconds, high temporal
resolution imaging is required to obtain sequential images during the wash-in and
wash-out of the contrast material and for processing and calculation of hemody-
namic maps (including mean transit time (MTT), time to peak (TTP), time of arrival
(T0), negative integral (N1). An important neuroradiological indication for MRI is
the evaluation of incipient or acute stroke via PWI and DWI. DWI can demonstrate
the central eVect of a stroke on the brain, whereas PWI visualizes the larger second
ring delineating blood flow and blood volume. Echo planar and, potentially, echo
volume techniques (such as PRESTO) together with appropriate computing power
oVer real time images of dynamic variations in water characteristics reflecting
perfusion, diVusion, oxygenation, and flow; qualitative and in some instances
quantitative maps of regional organ perfusion can thus be obtained (Fig. 4).

2. Nuclear Medical Imaging

The general principle behind nuclear medicine imaging is the following: a
radioactive biologically active substance is chosen in such a way that its spatial
and temporal distribution in the body reflects a particular body function or

A B

C D

FIG. 4. Perfusion-weighted imaging (PWI): Time to peak (A), mean transit time (B), relative
cerebral blood flow (C), and relative cerebral blood volume (D) maps are displayed. These and other
possible maps that characterize entity and timing of tissue perfusivity are powerful and sensitive tools
for summarizing the dynamic changes conveyed by PWI scans.
56 DI PERRI et al.

metabolism. To study the distribution without disturbing body function, only

traces of the substance are administered to the patient.
The radionucleides (radioactive tracers) are unstable nuclei that decay by
emission of gamma rays or positrons (followed by annihilation gamma rays).
Distribution of the radioactive tracer is inferred from the detected gamma rays,
trough instruments known as gamma camera, and mapped as a function of time
and/or space. The most often used radionuclides are Tc-99 m in ‘‘single photon’’
imaging and F-18 in ‘‘positron’’ imaging (Saha, 2006).
Currently used nuclear neuroimaging techniques are SPECT and PET. They
are both variations on the principle of gamma camera detection of emitted !-rays.
Tomographic reconstruction is used to construct three-dimensional images.
Metabolic activity measures, receptor-binding studies, regional blood flow, and
drug treatment response can be performed by using radiolabeled ligands.
Some applications of PET include evaluation of stroke (blood clot or bleeding
in the brain (Lovblad et al., 1997; Sobesky et al., 2005), study of dementia imaging
(Silverman, 2004) and evaluation of brain tumors (Tian et al., 2004).
The drawback of both SPECT and PET is poor spatial resolution. In some
cases, PET may be more sensitive than SPECT, but PET scanners and tracers are
much more costly than SPECT scanners and are often only available in the largest
medical centers. A way of overcoming this limit, and thereby improving diagnos-
tic accuracy, is to combine the SPECT and PET scanners with a multidetector
computer tomography (MDCT) scanner. SPECT/CT and PET/CT combine a
nuclear image with high-resolution structural CT images for accurate localization
of lesions and physiological processes (Saha, 2006). Recently, combinations with
MRI scanners have also been introduced to the radiological market.
Nuclear medicine imaging is an eVective diagnostic tool in the early diagnosis,
treatment, and prevention of numerous medical conditions. The main advantage
of these techniques is their ability to show molecular function of pathological
organs. This allows diagnosing of certain diseases and various medical conditions
much sooner than with other medical imaging methodologies which provide
mainly structural information about an organ or body part.

C. METABOLIC IMAGING

1. Magnetic Resonance Spectroscopy

In vivo magnetic resonance spectroscopy (MRS) oVers information about
the biochemistry of a selected brain tissue volume. This can represent surrogate
markers for the pathology underlying the pathological process of diVerent
neurological diseases (Narayanan et al., 2006).
 MRI AND COGNITION IN VASCULAR DISEASES 57

MRS is a quantitative method of detecting nonaqueous proton signals that

correspond to certain biological molecules in the brain. In most conventional and
nonconventional MRI techniques, the MR signal originates from water protons
and detailed images of the brain are created based on the diVerent water content
in various brain tissues. The hydrogen nuclei (protons) that are not in water
(nonaqueous protons) are distributed throughout the hundreds of biologically
significant molecules of the living brain. These molecular radio-signals are not
visible on standard MR images because they are overwhelmed by the high signal
derived from the aqueous protons. Each nonaqueous molecule has a unique
radio-frequency specific to the chemical environment itself and distinct from the
frequency of water protons. The amplitude or strength of these radio-frequencies
is dependent on the concentration of the corresponding molecule in the volume of
interest, each at its own radio-frequency position.
The most commonly used MRS technique we refer to, proton (1H) spectros-
copy, measures the relative amplitude of the corresponding peak for each of
several biological molecules by suppressing the signal from aqueous protons
(Fig. 5). The best available and most important cerebral components that have
been studied are N-acetyl aspartate (NAA), choline (Cho), creatinine(Cr)/phos-
phocreatinine (PCr), myoinositol and lactate. NAA is considered an in vivo marker
of neuronal integrity and is often measured relative to Cr (which is thought to be
unaVected by neurodegeneration). The NAA peak in an MR spectrum is
a putative marker of neuronal and axonal integrity, and the Cho peak is largely
a marker of cell-membrane turnover. Decreases in Cho usually represent inflam-
mation and demyelinating processes, while decreases in NAA are markers of
axonal and neuronal injury. On this basis, a reduction in the NAA peak is
interpreted as representing neuronal/axonal dysfunction (Narayana, 2005) and
an elevated Cho peak represents heightened cell-membrane turnover, as seen
mainly in tumors. Therefore, MRS may provide unique information regarding
metabolic changes in the CNS, evaluation of the pathogenesis, severity and
progression of the neurological disease. Other metabolic peaks of increasing
interest in the study of neurologic disorders are the glutamate/glutamine peak,
representing a mixture of amino acids and bioamines used throughout the CNS
as excitatory and inhibitory neurotransmitters (Vrenken et al., 2005), and the
myoinositol peak, representing a sugar-like molecule thought to be a marker of
glial proliferation and now recognized for its importance in osmotic regulation of
brain tissue (Narayana, 2005).
High-resolution 1H MRS is expected to improve our understanding of the
metabolic alterations that accompany ischemia, particularly those related to acid-
base balance. 1H MRS can depict an increase in lactate concentration and
concomitant decrease in intracellular pH in the hyperacute ischemic stage when
conventional MRI signal abnormalities are minimal.
58 DI PERRI et al.

A B

C D

FIG. 5. Multi-voxel sMR: a TE ¼ 25 ms (A) and TE ¼ 144 ms (B) scan are reported with the fitted
spectrum and estimated peak ratio reported for each voxel. A mixed Gaussian-Lorenztian peak shape
was chosen for the fit as the most general. Single-voxel sMR: a TE ¼ 25 ms (C) and a TE ¼ 136 ms
(D) scan are reported with the corresponding fit overlaid. The higher biochemical specificity of short TE
scans is evident at the expense of the less accurate fit due to an irregular baseline and to peak overlap.

II. Vascular Cognitive Impairment

A. TERMINOLOGY

After AD, CVD is recognized as the second most common cause of acquired
cognitive impairment and dementia, alone or in conjunction with other neurode-
generative disorders (O’Brien, 2006).
Progress in the concept of vascular cognitive impairment (VCI) has been
seriously limited by diYculties in finding agreement with respect to terminology.
O’Brien et al. (2003) have proposed using VCI as an umbrella term, including all
aspects and degrees of cognitive impairment resulting from vascular brain dam-
age. Conversely, some authors favor regarding vascular dementia (VaD) and VCI
as two diVerent entities (Roman et al., 2004). Although several definitions exist,
both DSM-IV and ICD-10 require the presence of memory impairment as an
absolute requirement, in addition to one or more other cognitive domains
being aVected. This has been largely criticized, since the presence of memory
 MRI AND COGNITION IN VASCULAR DISEASES 59

impairment is known to be more prevalent in neurodegenerative disease, such as

AD, than in CVD. The use of a term of dementia that does not require memory
impairment and instead focuses on cognitive symptoms such as executive deficits
(known to be aVected more in CVD) would possibly solve this dilemma. For the
purpose of this review, the term VCI will be considered to refer to all forms of mild
to severe cognitive impairment associated with and presumed to be caused by
CVD (O’Brien, 2006; O’Brien et al., 2003).

B. CLASSIFICATION

The proposed classification by O’Brien et al. (O’Brien, 2006; O’Brien et al.,

2003) distinguishes between sporadic and hereditary disorders that represent the
two main categories. The sporadic VCI is further divided into several clinical
subtypes: post-stroke dementia (PSD), VaD, mixed AD and VaD (mixed dementia)
and, finally, vascular mild cognitive impairment (VaMCI). The term VaD is
again subclassified into multi-infarct dementia, subcortical ischemic vascular
dementia (SIVD), strategic-infarct dementia, hypoperfusion dementia, hemorrhagic
dementia, and dementia caused by specific arteriopathies.
1. Classification of Sporadic Vascular Cognitive Impairment
Sporadic VCI is a clinical-pathological entity which includes several diVerent
sporadic vascular disorders which are not yet fully defined, whose main feature is
their contribution to cognitive impairment.
Post-stroke dementia. PSD includes all types of dementia that happen after
stroke, irrespective of their cause (Leys et al., 2005). Their prevalence is likely to
increase in the future, because of the decline in mortality after stroke (Rothwell
et al., 2004) and the aging population. Community-based studies suggest that
having a stroke doubles the risk of dementia (Leys et al., 2005). PSD might be the
result of vascular lesions, AD, WM changes or a combination of these. The causes
of PSD diVer among studies in relation to patient age, time after stroke, ethnicity
and criteria used. The risk factors are in general the same as for most vascular
disease (arterial hypertension, history of high cholesterol, diabetes, forms of heart
disease). Stroke-related variables associated with an increased risk of PSD are
stroke severity, cause, location, and recurrence (Leys et al., 2005). Most studies
have found that a more severe clinical deficit at onset is associated with a higher
risk of PDS (Tatemichi et al., 1992, 1990). The risk of PSD and its severity are not
influenced by the type of stroke (ischemic or hemorrhagic) (Barba et al., 2000;
Linden et al., 2004) (Fig. 6).
Vascular dementia. Multi-infarct dementia, also known as cortical vascular
dementia, is the traditional term used for VaD and the consequence of multiple
large cortical infarcts (Hachinski et al., 1974). It is clinically characterized by a
60 DI PERRI et al.

FIG. 6. Acute stage of left medium cerebral artery ischemic stroke: as shown on the images, the
ischemic acute stage is visible on DWI-weighted images earlier than on conventional MRI: (A) ADC
(B) eADC, and (C) conventional T2-weighted MRI scan.

relatively abrupt onset (days to weeks), a stepwise deterioration and a fluctuating

course. It is related predominantly to large vessel disease and cardiac emboli
events, being characterized by cortical-subcortical, arterial, territorial, and distal
field infarcts (watershed areas).
Subcortical ischemic vascular dementia. SIVD is attributed to small-vessel disease
and it is characterized by lacunar infarcts, ischemic WM lesions, and incom-
plete ischemic injury (Decarli, 2004; Wallin et al., 2003). The clinical onset is
variable (Babikian and Ropper, 1987) and the course is gradual, with or without
acute deficits. The early cognitive syndrome of SIVD is characterized by a
dysexecutive syndrome with slowed information processing. The dysexecutive
syndrome includes impairment in goal formulation, organizing, planning, execut-
ing, and abstraction (Cummings, 1994). Memory loss is usually milder than in
AD. In this subgroup of VaD, the onset is often more insidious and temporal
relations between cognitive syndrome, brain imaging findings and vascular dis-
ease may not be clear (O’Brien et al., 2003).
Hemorrhagic dementia. Hemorrhagic dementia is usually due to uncontrolled
hypertension or vascular malformations, subarachnoid hemorrhage and
intracerebral hemorrhage, with or without vasospasm. Due to the extent of the
hemorrhage, patients often show additional neurological impairments such as
sensorimotor changes or gait impairment. One of the most common causes of
hemorrhagic dementia is subdural hemorrhage. Although it is primarily post-
traumatic, considering it a vascular injury makes subdural hematoma a common
and insidious cause of VCI in clinical practice (Starkstein et al., 2005).
Much more common than epidural hemorrhages, subdural hemorrhages
generally result from shearing injuries due to various rotational or linear forces
(Maxeiner and WolV, 2007). The disease is commonly seen in the elderly and in
 MRI AND COGNITION IN VASCULAR DISEASES 61

alcoholics, who have evidence of brain atrophy. Cerebral atrophy increases the
length the bridging veins have to traverse between the two meningeal layers (dura
and arachnoidea), hence increasing the likelihood of shearing forces causing
a tear. It is also more common in patients on anticoagulants, who can have a
subdural hematoma with a minor injury. Chronic subdural bleeds can develop
over a period of days to weeks, often after minor head trauma, though such a
cause is not identifiable in 50% of patients. They may not be discovered until they
present clinically months or years after a head injury and they are rather common
in the elderly (Kushner, 1998) (Fig. 7).
Strategic-infarct dementia. It is characterized by focal, often small, ischemic
lesions involving specific sites critical for specific higher cortical functions.
Cortical sites more often aVected are the hippocampal formation, angular gyrus
and cingulate gyrus and thalamic infarcts (bilateral or monolateral).
Dementia caused by specific arteriopathies. Arteriopathies such as cerebral vasculitis,
that is, acute or chronic inflammatory changes of small, medium, and large
arteries or veins, can be cause of multiple ischemic lesions and lead to VCI.
They are often accompanied by systemic signs of fever, malaise, and weight loss.
Some rare arteriopathies such as inflammatory arteriopathy (e.g., polyarteritis
nodosa, temporal arteritis) and noninflammatory arteriopathy (e.g., moyamoya
disease, fibromuscular dysplasia) can cause multiple infarcts and lead to vascular
dementia as well. In cerebral amyloid angiopathy-associated vasculopathy, aneu-
rysm formation and stenosis in the leptomeningeal and cortical vessels cause
damage to the subcortical WM. In hereditary cystatin-C amyloid angiopathy,
patients have recurrent cerebral hemorrhages before the age of 40 that can lead
to dementia.

FIG. 7. Coronal and axial images of subdural hemorrhage on conventional MRI T2-weighted
sequence (A and B).
62 DI PERRI et al.

Hypoperfusion dementia. Hypoperfusion due to large vessel or cardiac disease can

aVect the watershed areas of the brain and lead to vascular dementia. A correlation
between systolic blood pressure reduction and cognitive decline in women, which was
not accounted for by other factors, has been recently demonstrated (Zhu et al., 1998).
Baseline blood pressure was not found to be significantly correlated to cognitive
decline with initial good cognition (Zhu et al., 1998). It has also been suggested (Skoog
et al., 1998) that age-related changes in brain structure may contribute to the decrease
in blood pressure in the very elderly, and that low blood pressure in dementia
disorders is mainly a secondary phenomenon. Some researchers, therefore, have
speculated that blood pressure reduction might be an early change in the dementing
process, but further studies are necessary to clarify this aspect.
Mixed AD and VaD (mixed dementia). Mixed dementia has for a long time been
underestimated as a common cause of dementia, particularly in the elderly.
In fact, its diagnosis is still mostly a challenge. It has been shown that diVerent
vascular factors, including arterial hypertension and stroke, increase the risk of
AD. Frequently, CVD coexists with AD (Decarli, 2004; de la Torre, 2004). This
overlap is increasingly important in the elderly population since CVD is a
potentially preventable and treatable cause of dementia. The actual relationship
between AD and vascular pathology is still unclear. They may represent two
independent co-occurring pathologies which happen to share risk factors (Decarli,
2004). However, accumulating evidence shows that vascular changes may actual-
ly stimulate or exacerbate the formation of AD pathology. For example, vascular
disease might determine vessel wall thickening and reduce the eYciency of the
perivascular drainage system, leading to a reduced rate of elimination of amyloid
(Nicoll et al., 2004) through the drainage system. Some of the most challenging
clinical scenarios include VaD patients with an insidious onset or slow progression
and AD patients with evidence of vascular lesions upon brain imaging. Given that
reliable biological markers for recognizing AD and discerning it from mixed
dementia do not yet exist, neuroimaging plays an important role as a potential
marker. In fact, besides early episodic memory impairment and low concentra-
tions of CSF peptides with high tau protein concentrations, early and significant
medial temporal lobe atrophy on MRI and bilateral parietal hypoperfusion on
SPECT are strongly suggestive of AD (Erkinjuntti, 2007).
Vascular mild cognitive impairment. VaMCI is a low degree of cognitive
impairment resulting from CVD which does not meet the criteria for dementia.
This entity has been relatively underestimated and understudied compared to the
nonvascular pre-Alzherimer’s (MCI) (Petersen et al., 1999). However, recent
studies have shown a higher percentage of VaMCI than VaD (Rockwood et al.,
2000) and a high tendency for converting into dementia in a relatively short time
(Wentzel et al., 2001).
 MRI AND COGNITION IN VASCULAR DISEASES 63

2. Hereditary Vascular Cognitive Impairment

Understanding of the pathogenesis of vascular disease has improved greatly in
recent years, and many molecular genetic conditions related to this symptom have
been found. Among them, there is strong interest in cerebral autosomal dominant
arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL).
CADASIL is an inherited CVD due to mutations of the Notch3 gene at the
chromosome locus 19p13. The clinical spectrum includes recurrent ischemic
episodes, cognitive deficits, migraine and psychiatric disorders. The histopatho-
logical hallmark of CADASIL is accumulation of electron dense granules (GOM)
in the media of arterioles. CADASIL was initially thought to be a rare disorder,
but increasing numbers of families have been identified; therefore, it is likely that
CADASIL is still largely underdiagnosed (Federico et al., 2005). The course of the
disease is very heterogeneous, even in the same family; some patients remain
asymptomatic until their 70s, whereas others are severely aVected from the age of
50 onward (Fig. 8).

FIG. 8. Axial FLAIR sequence displays sample images of CADASIL MRI pattern of conventional
MRI in a 32 y.o. patient.
64 DI PERRI et al.

C. HISTOPATHOLOGY OF VCI

Vascular disease produces either focal or diVuse eVects on the brain and may
cause cognitive decline. Focal CVD occurs mainly secondarily to thrombotic or
embolic vascular occlusions. Common areas of the brain associated with cognitive
decline are the WM of the cerebral hemispheres and the deep GM nuclei, especially
the striatum and the thalamus. Hypertension is the major cause of diVuse disease
and, in many patients, both focal and diVuse disease forms are observed together.
The five most common pathological findings of VaD are white matter hyperinten-
sities (WMH), macroscopic, lacunar and/or microscopic infarcts and microbleeds.

1. White Matter Hyperintensities

WMH, as revealed by MRI-histopathological studies, are associated with evi-
dence of hypoxic tissue injury (Fernando et al., 2006), with reduced capillary density
not only in the lesions but also in normal-appearing WM (Brown et al., 2007).
However, smooth periventricular lesions directly adjacent to the ventricles of high
T2 signal are considered by some researchers to be of nonischemic origin and consist
of areas of demyelination, subependymal gliosis and discontinuity of ependymal
lining (Fazekas et al., 1993).
The most important risk factor for WMH is age, but other known risk factors
are hypertension and decreased peak expiratory flow, elevated levels of glycated
hemoglobin (Murray et al., 2005), type 2 diabetes (Korf et al., 2006) and cigarette
smoking (Liao et al., 1997).

2. Macroscopic Infarcts
Infarctions involving areas of major cerebral arteries may result in large
territorial lesions with a variable amount of tissue loss. The infarcts develop in
typical stages of gliosis with increased water content. The intensity of gliotic
scarring is used in pathological studies to judge the degree and age of
the infarction ( Jellinger, 2007). Hypertension, diabetes, hypercolesterolemia,
smoking, and heart disease are the most common risk factors for infarcts.
Multiple cortical infarcts are believed to be the neuropathological cause of
multi-infarct dementia (Hachinski et al., 1974). In multi-infarct dementia, the
combined eVects of diVerent infarcts produce cognitive impairment by aVecting
neural networks. The cognitive impact of large complete infarcts depends on
localization and the extent of the ischemic lesion.
3. Lacunar Infarcts
Lacunes (small infarcts in WM and deep GM structures with diameters
ranging from 3 to 15 mm) ( Jellinger, 2007), represent diVerent stages of ischemic
injury exhibiting loss of axons and myelin together with reactive changes (Ishii
et al., 1986). In pathological studies, they have been associated with cognitive
 MRI AND COGNITION IN VASCULAR DISEASES 65

decline independent of other dementia pathology such as AD (Gold et al., 2005).

Some studies have reported that subcortical lacunes and multiple widespread
infarcts are the most common morphologic substrates of VaD ( Jellinger, 2007).
Lacunes in SIVD are typically located in the caudate, globus pallidus, thalamus,
internal capsule, corona radiata, and in frontal WM (O’Brien et al., 2003). Lacunar
state is a condition in which numerous lacunae are present, which indicates wide-
spread severe small-vessel disease. It is due to small-vessel disease aVecting all the
small vessels of the brain. The amount of lacunes has been found to be a significant
predictor of cognitive status in the elderly and of executive dysfunction in patients
3 months after an ischemic stroke (van der Flier et al., 2005; Vataja et al., 2003).

4. Microscopic Infarcts
Recently, there has been increasing focus on the contribution of cortical micro-
infarcts (not visualized by current available neuroimaging techniques) to cognitive
decline both in normal aging (Kovari et al., 2004), VaD and mixed dementia (Gold
et al., 2007a). Cortical microinfarcts might be as strong a predictor of cognitive
decline as is the presence of neurofibrillary tangles in AD (Gold et al., 2007b).

5. Microbleeds
Microbleeds (MBs), characterized histopathologically by the presence of
hemosiderin around small vessels (Fazekas et al., 1999), display themselves in
several ways, mainly as hypertensive arteriopathy or amyloid angiopathy
(Fazekas et al., 1999). MBs are often detected in demented individuals, such as
patients with AD (Hanyu et al., 2003), CADASIL (Dichgans et al., 2002), subcortical
vascular dementia (Won Seo et al., 2007) or memory loss (Cordonnier et al., 2006).
Cordonnier et al. (2006) studied the prevalence of MBs in a large cohort of patients
(772 patients) attending a memory clinic. They found that 65% of patients with
vascular dementia exhibited MBs, vs 18% of AD patients, 20% of mild cognitive
impairment patients, and 10% of patients with subjective complaints. The
presence of MBs was associated with age, WMH, lacunar infarcts, and infarcts.
This finding of a relatively high proportion of MBs in AD and mild cognitive
impairment also provides further evidence for the involvement of vascular factors
in neurodegenerative diseases such as AD.

D. DIAGNOSTIC NEUROIMAGING CRITERIA IN VCI

Conventional imaging plays a central role in the diagnostic work-up in most

vascular disorders. It is suggested that MRI should be incorporated as an essential
part of clinical trials involving VCI (O’Brien et al., 2003; Schmidt et al., 2007), but
the pulse sequences, techniques and clinical outcome to be used remain a matter
of debate (Enzinger et al., 2005; Schmidtke and Hull, 2005).
66 DI PERRI et al.

Of the available diagnostic criteria for VaD, only two of them, the NINDS-
AIREN (Roman et al., 1993) and the State of California AD Diagnostic and
Treatment Centers (ADDTC) criteria (Chui et al., 1992), require radiological
findings of CVD in the form of infarcts or WMH.

E. THERAPEUTIC STRATEGIES

Therapeutic approaches can be divided into primary prevention (preventing

the occurrence of CVD), secondary prevention (Fig. 9) (preventing the exacerba-
tion of CVD), and symptomatic treatments (O’Brien, 2006).
Much is known about primary prevention, which mainly consists of preventing
the vascular disease leading to VCI by reducing the above-mentioned risk factors
(mainly hypertension, cigarette smoking, hyperlipidemia, etc.). However, the
degree to which primary prevention can aVect nonstroke-related damage and, in
particular the development of WMH, is still mostly unclear. Secondary prevention
consists mostly of preventing recurrent vascular episodes, mainly strokes, by the use
of antiplatelet agents, carotid endarterectomy, anticoagulants for atrial fibrillation
and decreasing blood pressure (O’Brien, 2006).
Regarding symptomatic treatments, several diVerent trials have been under-
taken, although they have been largely criticized, mainly because they have
focused more on AD than VCI (the AD group is much bigger, and the eVect on
society would thus be more significant). One single study in VaD showed that
aspirin yielded better cognitive outcomes for treated as opposed to untreated
patients (Meyer et al., 1989). Many studies suggest that cholinesterase inhibitors
may prove beneficial in the treatment of VaD, both in cognitive and behavioral
symptoms, as they already have in the management of AD (Erkinjuntti et al., 2002;
Pratt and Perdomo, 2002).

FIG. 9. T2w (A) and GRE axial images (B) in a case of amyloid angiopathy.
 MRI AND COGNITION IN VASCULAR DISEASES 67

With respect to neuroimaging, such treatment eVects would be especially

interesting considering primary prevention strategies. The various neuroimaging
techniques have, as shown below, been able to detect both established CVD as
well as preclinical brain damage in healthy individuals possibly at risk. In this
respect, neuroimaging may serve as an important tool of the future in attempts to
reduce the prevalence of VCI.

III. Updates on Neuroimaging Techniques in VCI

A. CONVENTIONAL STRUCTURAL MRI

Conventional MRI techniques play an important role both for diagnosis and
prognosis in VCI patients. Our knowledge of both incidental and disease-related
findings has greatly increased during the last decades and allowed a better
understanding of the pathological basis of VCI. However, VCI shows no patho-
gnomonic imaging features. Infarct location often does not correlate with the
cognitive profile, and neuroimaging can establish the chronology of lesions only
with certain limits and cannot oVer information about the relative contribution of
neurodegenerative versus ischemic processes to the clinical presentation.

1. White Matter Hyperintensities

Apart from providing indications of ischemic lesions, MRI has, due to its
widespread availability, resulted in increased recognition that WMH on T2-WI
are common incidental findings in the brains of otherwise clinically healthy
individuals (Fig. 10) (Enzinger et al., 2006; Fazekas, 1989; Wen and Sachdev,
2004). In fact, epidemiological imaging studies show that WMH are extremely

FIG. 10. Normal findings in healthy individuals on conventional MRI: (A) axial FLAIR image,
(B) axial T2-weighted image.
68 DI PERRI et al.

common in the elderly (de Leeuw et al., 2001; Liao et al., 1997; Wen and
Sachdev, 2004). In a population-based study, de Leeuw et al. (2001) showed
that, of 1077 subjects between 60 and 90 years of age, only 5% had no WMH
detectable on MRI. Other studies have shown up to 90% prevalence of WMH
(Sachdev et al., 2005). Most studies show that women have more WMH changes
than men (de Leeuw et al., 2001; Sachdev et al., 2007; van den Heuvel et al., 2004),
while some others show contradictory findings (Wen and Sachdev, 2004).
Accumulation of WMH around the ventricles, also called leukoaraiosis,
appears as a bright signal on T2-WI, indicating pathology involving increased
water content and gliotic scarring in the WM of the brain. The FLAIR sequence
is commonly used for detection of these WMH. Typical WMH in subcortical
ischemic disease include extensive periventricular and deep WM signal abnorm-
alities, usually located in the genu and anterior limb of the internal capsule,
anterior corona radiata and anterior centrum semiovale (O’Brien et al., 2003).
In nondisabled elderly living independently, age-dependent WMH have been
recently reported as relating to both global cognitive dysfunction and various specific
cognitive performances such as executive function, attention, and speed processing
(Verdelho et al., 2007). Despite evidence that age-related WMH influence cognitive
status, some studies report that there is no such relationship, suggesting that MRI
might be oversensitive when it comes to WMH, and that higher water content in the
brain does not necessarily result in loss of function (Schmidtke and Hull, 2005). The
association between WMH (especially low grade) and cognition in nondemented
individuals is at the present time complex and not fully understood.
In subjects aVected by VaD, the NINDS-AIREN criteria (Roman et al., 1993)
require that WMH involve at least 25% of total brain WM. In order to be
significant, WMH must be diVuse and characterized by irregular periventricular
lesions extending into deep WM, sparing areas thought to be protected from
perfusion insuYciency (e.g., subcortical U-fibers and external capsule-claustrum-
extreme capsule). Studies on the relationship between WMH in VaD and cogni-
tive impairment have led to contradictory results (Cohen et al., 2002; Fernando
and Ince, 2004).This can be explained by the fact that the relationship between
WMH and dementia might be driven by a threshold eVect (Libon et al., 2008;
Wright et al., 2008), which implies that a certain amount of WMH is needed to
have clinical consequence. Once this threshold is reached, other factors might
contribute more to cognitive impairment than WMH volume (Sweet et al., 2003).
In VaMCI patients, recent studies have also found an association between WMH
volume and deficits on cognitive tests (Debette et al., 2007; Sachdev et al., 2006;
Yoshita et al., 2006), especially for executive dysfunction (Bombois et al., 2007).
Furthermore, periventricular WMH have been found to predict conversion to
VaD and mixed dementia, but not to increase the risk of developing other
dementias like AD, DLB, and fronto-temporal dementia (Bombois et al., 2008).
 MRI AND COGNITION IN VASCULAR DISEASES 69

2. Macroscopic, Lacunar, and Microscopic Infarcts

Cerebral infarction is focal brain necrosis due to complete and prolonged
ischemia that aVects all tissue elements, neurons, glia, and vessels. As previously
described, they diVer from each other with regards to their size and spatial
location. The clinical consequences vary as well, depending on the size and
location of the infarct, that is, a very small infarct in a core region such as the
rolandic area can lead to pronounced deficits with very poor outcome, whereas a
larger ischemic event in a not ‘‘eloquent’’ location can be of much less impor-
tance, that is, remain clinically silent. On conventional MRI such infarcts are seen
as hyperintensities on T2-WI regardless of their cause, and they can be detected as
soon as they enter into a subacute stage. For detecting the acute stage of an infarct
and, therefore, the therapeutical possibilities of limiting the structural damage and
neurological consequences, nonconventional techniques play a superior role.
The amount of lacunes has been found to be a significant predictor of
cognitive status in the elderly (van der Flier et al., 2005), in CADASIL disease
(Liem et al., 2007), as well as in the executive dysfunction of nondemented patients
(Carey et al., 2008) and in post-stroke patients (in the last ones in conjunction
with temporal lobe atrophy, WMH volume, education, and Mini-Mental State
Examination (MMSE)) (Vataja et al., 2003). However, an earlier study found no
association between either volume or localization of lacunes and cognition in
SIVD (Fein et al., 2000). The exact impact of lacunes on cognitive decline in SIVD is,
therefore, not yet established and fully understood.

3. Microbleeds
In patients with lobar intracranial hemorrhage, cognitive decline has been
shown to be more severe in subjects with larger numbers of MBs at baseline
(Werring et al., 2004). In a recent study, MBs appear to be primarily associated
with global cognitive impairment even in subjects with no history of neurological
disorder (Cordonnier et al., 2006; Werring et al., 2004).

4. Hereditary VCI
In hereditary VCI such as CADASIL, conventional MRI reveals extensive
cerebral WM lesions, subcortical infarcts and MBs. CADASIL is characterized by
WMH on T2-WI in the subcortical WM and basal ganglia. Two major types of
abnormalities were first observed by Skehan et al. (1995) and later confirmed by
other studies (Lesnik Oberstein et al., 2003). The most striking findings were large
confluent patches of high-signal change on T2- and proton density-weighted
images present throughout the white matter, especially in the anterior part
of the temporal lobes and the periventricular portion of the occipital lobes.
Additionally, small linear and punctuate lacunes were detected, present not only
70 DI PERRI et al.

in the periventricular white matter but also in the brain stem, basal ganglia,
thalamus, external capsule, and corpus callosum (Skehan et al., 1995).
One of the main disabling symptoms of this disease is the cognitive
impairment, providing CADASIL as a pure VCI entity. A recent study by
Viswanathan et al. (2007) showed that, among the lesions observed on conven-
tional MRI in CADASIL, the overall lacunar lesion burden seems to have the
most important impact on cognitive function and disability. These findings
suggest that preventive strategies to decrease the risk of lacunar lesions as
observed on MRI may reduce disease-related impairment in CADASIL. These
results suggest that lacunar lesions may also play a key role in disability and
cognitive impairment in more common forms of small-vessel disease.

5. Brain Atrophy
Analyses estimating brain volumes have been widely used with respect to
ischemic pathology. In normal aging, a large epidemiological study found that
high WMH volume correlated with GM atrophy (Wen et al., 2006). Medial
temporal lobe atrophy (MTA) was recently demonstrated to predict cognitive
status after stroke alone (Firbank et al., 2007) or in conjunction with brain infarct,
WMH volume, and the subject’s educational level (Pohjasvaara et al., 2000).
In CADASIL, atrophy is currently investigated as an additional important
characteristic of the disease (O’Sullivan et al., 2007; Peters et al., 2006). Cerebral
volumetric assessment might thus be an additional aspect in understanding the
pathogenesis behind neuropsychiatric and neurobehavioral changes in ischemic
brain diseases. A limitation to keep in mind is that brain atrophy might develop
rather late in the course of some diseases and for the time being serves mostly to
characterize the natural development of the pathology.

B. NONCONVENTIONAL TECHNIQUES

1. DiVusion-Weighted Imaging and DiVusion-Tensor Imaging

Data from healthy individuals and patients with MCI and dementia, inde-
pendent of their cause, converge on highlighting a positive correlation between
cognitive performance and fractional anisotropy, and a negative correlation
between cognitive performance and mean diVusivity (Kapeller et al., 2004).
Moreover, correlations between diVusional measurements and behavioral
scores (e.g., side-alternating tapping speed) have been reported for normal
individuals.
DiVusion tensor variants have also been previously shown to yield a better
correlation with cognition than conventional MRI measures in VCI. DTI indices
have been proved to correlate much more strongly with cognitive function than
 MRI AND COGNITION IN VASCULAR DISEASES 71

WMH volume in patients with ischemic lesions. The correlation was strongest for
diVusivity of normal appearing WM (NAWM), and remained significant after
controlling for conventional MRI parameters, including brain parenchymal
volume and T1 and WMH volumes. Regarding conventional measurements,
brain volume predicted cognitive impairment best. Of special interest is the
finding that DWI/DTI was able to detect specific pathology in NAWM, demon-
strating the technique as a highly sensitive and early predictor of brain damage.
This is in line with a pathological study combining postmortem MRI and
histology (Brown et al., 2007), and shows the great potential of newer imaging
techniques. DWI might thus serve as a promising imaging technique for further
knowledge about vascular changes in the brain not visible on traditional MRI
scans and for exploring the mechanisms of cognitive dysfunction in these patients.

2. Magnetization Transfer Imaging

In many previous studies, WMH were not further evaluated than assessing the
total volume of WMH based on T2-WI. As a result some studies show only
correlations, if any, between the WMH volume on one hand and measures of
cognitive function or risk factors on the other.
Recently, MTI has demonstrated that age-related WMH are quite heteroge-
neous despite their similar appearance on T2-WI, which is assumed to reflect
histological diVerences in these lesions (Spilt et al., 2006). Thus, by taking into
account the heterogeneity of age-related WMH, both in terms of etiology and in
terms of the severity of tissue destruction, a better understanding of the causes and
consequences of these lesions and other tissue structure abnormalities leading to
VCI can be obtained. This might explain previous contradictory findings on the
clinical impact of WMH, since these lesions are not uniform.

C. METABOLIC IMAGING

1. Magnetic Resonance Spectroscopy

MRS has been shown to be superior to conventional MRI measurements in
predicting cognitive decline after stroke. In a longitudinal study (Ross et al., 2006),
reduced frontal WM NAA/Cr and NAA appear to be useful predictors of
cognitive decline over 12 months and 3 years in stroke/TIA and healthy aging,
respectively. MRS may therefore play a useful role in the early investigation of
individuals at increased risk of cognitive decline after stroke/TIA. Individuals
identified to be at risk for cognitive decline may potentially benefit from early
interventions. These MRS results were better predictors than hippocampal vol-
ume, whole brain or WMH volumes. As suggested by the authors, assessment of
72 DI PERRI et al.

frontal NAA/Cr ratio might serve as a possible biomarker for identifying patients
at risk for cognitive decline after stroke/TIA.

D. FUNCTIONAL IMAGING

Contrary to the case in neurodegenerative disorders, functional imaging has

played a minor role compared to structural imaging in the investigation of
cognitive impairment in CVD. Despite this, its use has been recently growing.
It is therefore proposed by Nagata et al. (2007) that the old VaD criteria should be
revised especially due to new insight brought by nuclear imaging techniques.

1. Perfusion-Weighted Imaging
Zimny et al. (2007) studied 64 patients with dementia with diVerent degrees of
cognitive impairment to assess the relationship between cognitive impairment
according to the MMSE and values of CBF, CBV, and MTT obtained in
perfusion CT (pCT). The results of this study showed that CBF and CBV
calculated with pCT correlate with cognitive impairment in patients with demen-
tia and thus may play a role in monitoring disease progression or therapeutic
response (Zimny et al., 2007). This may be a good setting for developing new
studies using either pCT or perfusion MRI, the latter losing in spatial resolution
but gaining in tissue specificity.

2. SPECT and PET

Functional imaging studies in VCI have mainly focused on cerebral metabolism
and rCBF using techniques such as 18F-2-fluorine-2-deoxyglucose (FDG)-PET and
perfusion SPECT. The pattern of altered brain metabolism is more variable in
vascular disorders than in neurodegenerative, reflecting the heterogeneity of the
lesions involved. Still, a few studies have found that functional nuclear imaging can
distinguish VaD from diVerential diagnoses such as AD (Kerrouche et al., 2006;
Mielke et al., 1994; Nagata et al., 2000) and frontotemporal dementia (Lojkowska
et al., 2002). Functional imaging can be used to see the remote eVect of diVerent
ischemic lesions on higher cerebral functions. In the past few years, radiotracer
imaging has been used in many studies to address this issue.
For lacunar infarcts, Clarke et al. (1994) found that an isolated infarct in the left
anterior nuclei of the thalamus in a patient with clinical amnesia was associated
with reduced metabolism in the thalamus, amygdala, and posterior cingulate
cortex. These are all regions known to be involved in memory functions. Another
study found that not only symptomatic but also silent lacunes were associated with
global reduction of brain glucose metabolism (Takahashi et al., 2000).
PET and SPECT have also evaluated the eVect of WMH on cerebral metab-
olism (Clarke et al., 1994; Sultzer et al., 1995; Takahashi et al., 2000). In a
FDG-PET study of subjects with no signs of neurological disorders, Takahashi
et al. (2000) found that an increasing severity of incidental WMH, particularly
 MRI AND COGNITION IN VASCULAR DISEASES 73

periventricular lesions, was associated with reduced cerebral metabolism. Fur-

thermore, the periventicular lesions were associated with reduced performance on
tests for attention and speed. An FDG-PET study (Sultzer et al., 1995) investigated
the eVect of various ischemic subcortical lesions on cortical metabolism in patients
with VaD. This study, with relatively few subjects and heterogeneity in lesion
types, found that the type of subcortical pathology had a diVerent influence on the
amount of reduced metabolism in the cortex. In general, reduced metabolism was
associated with the presence of WMH and lacunes. In addition, the severity of
WM lesions correlated with anxiety, depression and overall severity of neuropsy-
chiatric symptoms. Reed et al. (2004) performed a PET study investigating the
impact of subcortical ischemic lesions on neuropsychological status in ischemic
VaD, taking cerebral glucose metabolism, and both hippocampal and cortical
atrophy, into consideration. The results showed that the functional impact of
subcortical lesions, both lacunes and WMH, was strongest in the dorsolateral
frontal cortex. The MRI pathology correlated with hypometabolism here
and also with reduced executive function on neuropsychological tests. Hypome-
tabolism and dysexecutive function was also associated with cortical atrophy,
suggesting that this contributed to the clinical and imaging findings.
In SIVD, Yang et al. (2002) reported that, rCBF measured by SPECT showed
a characteristic pattern with reduced metabolism in deep GM structures, superior
temporal, and ventral subcallosal gyri. This pattern correlated with cognitive
dysfunction. Taken together, the above studies suggest that vascular pathology
may aVect cerebral metabolism in a way that contributes to the cognitive
dysfunction observed in VCI.

E. CORRELATIONS BETWEEN IMAGING FINDINGS AND PATHOLOGY

Regarding ischemic changes in WM, lesion size is found to correlate with

severity of pathologically confirmed tissue damage (Fazekas et al., 1993). A recent
combined neuropathological and MRI study found that both lacunes and WMH
identified by imaging showed good correlation with CVD ( Jagust et al., 2008).
Nonconventional MRI techniques, such as DWI (O’Sullivan et al., 2004),
MRS (Ross et al., 2006), and MTI (Spilt et al., 2006), may increase both the
sensitivity and specificity of detecting histopathological changes that are not seen
by conventional MRI sequences.

IV. Conclusions

Neuroimaging plays an important role in the assessment of cognitive

impairment in vascular disease. Conventional MRI findings have been extensively
investigated and correlated with cognitive function in vascular patients.
74 DI PERRI et al.

Despite recent advances, many unsolved problems and questions remain to be

answered. In fact, conventional MRI findings of WMH are unspecific and might
not diVerentiate between various grades of histopathological damage. Higher field
strength MRI (3 T and more) and newer nonconventional techniques can provide
important contributions toward better understanding of the pathophysiology of the
disease and the relation between vascular lesions and cognitive function. Functional
imaging provides important knowledge about how the ischemic lesions aVect brain
activity and may help clarify the brain’s plasticity- and receptor-dependent com-
pensatory mechanisms in patients with a variety of neurological disorders, including
vascular diseases. Nonconventional imaging goes beyond MRI-visible pathology,
providing more information about subtle brain damage in VCI. Its results suggest
that better understanding of the pathophysiological aspects of the disease may be
obtained in the future. These techniques are unique tools for in vivo assessment of
VCI and are useful in establishing diagnosis, monitoring disease activity, measuring
therapeutic eVect, and explaining the development of disability in the short and
long term. They should be extensively taken into consideration for developing a
new and more unified classification of VCI. Further studies are warranted to clarify
the correlation between vascular brain damage and cognitive impairment.

Acknowledgments

Dr Di Perri was supported by the Dr. Larry D. Jacobs Fellowship of the BuValo Neuroimaging
Analysis Center. Dr Dalaker was supported by the Dr. Larry D. Jacobs Fellowship of the BuValo
Neuroimaging Analysis Center and a grant from the Research Council of Norway (grant# 186966).
Dr Beyer is supported by funds from the Norwegian Society of Radiology. The authors thank Eve
Salczynski for technical assistance in the preparation of this manuscript.

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 CONTRIBUTIONS OF NEUROPSYCHOLOGY AND
NEUROIMAGING TO UNDERSTANDING CLINICAL SUBTYPES OF
MILD COGNITIVE IMPAIRMENT

Amy J. Jak,*,y Katherine J. Bangen,* Christina E. Wierenga,*,y Lisa Delano-Wood,*,y

Jody Corey-Bloom,y,z and Mark W. Bondi*,y
*Department of Psychiatry, School of Medicine, University of California, San Diego
92093, USA
y
Veterans Affairs San Diego Healthcare System, San Diego 92161, USA
z
Department of Neurosciences, School of Medicine, University of California,
San Diego 92093, USA

I.Introduction
II.Neuropsychological Presentation
III.Stability of Diagnosis
IV. Conversion to Dementia
V. MCI and Health Variables
VI. Daily Functioning and MCI
VII. Neuroimaging
A. Structural MRI
B. Diffusion Tensor Imaging
C. Functional MRI
VIII. Treatment
IX. Conclusions
References

The original conceptualization of mild cognitive impairment (MCI) was

primarily as an amnestic disorder representing an intermediate stage between
normal aging and Alzheimer’s dementia (AD). More recently, broader concep-
tualizations of MCI have emerged that also encompass cognitive domains other
than memory. These characterizations delineate clinical subtypes that commonly
include amnestic and non-amnestic forms, and that involve single and multiple
cognitive domains. With the advent of these broader classifications, more specific
information is emerging regarding the neuropsychological presentation of indivi-
duals with MCI, risk for dementia associated with diVerent subtypes of MCI, and
neuropathologic substrates connected to the clinical subtypes. This review pro-
vides an overview of this burgeoning literature specific to clinical subtypes of
MCI. Focus is primarily on neuropsychological and structural neuroimaging

INTERNATIONAL REVIEW OF 81 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00405-X 0074-7742/09 $35.00
82 JAK et al.

findings specific to clinical subtypes of MCI as well as the issue of daily function-
ing. Although investigations of non-amnestic subtypes using advanced neuroim-
aging techniques and clinical trials are quite limited, we briefly review these topics
in MCI because these data provide a framework for future investigations specifi-
cally examining additional clinical subtypes of MCI. Finally, the review comments
on select methodological issues involved in studying this heterogeneous popula-
tion, and future directions to continue to improve our understanding of MCI and
its clinical subtypes are oVered.

I. Introduction

Mild cognitive impairment (MCI) is a clinical construct that describes indivi-

duals with mildly impaired performance on objective neuropsychological tests but
relatively intact global cognition and daily functioning (Petersen et al., 1999,
2001). MCI has been validated as qualitatively diVerent from both normal
aging and dementia (Petersen, 2004; Smith and Ivnik, 2003) and is a risk factor
for the development of dementia. Because of its potential importance for early
identification and intervention in those at risk for the development of dementia,
the concept of MCI has received considerable research attention. However, the
definition has evolved considerably over time. As originally proposed by Petersen
and colleagues, MCI was characterized primarily as an amnestic disorder that
represented an intermediate stage between normal aging and Alzheimer’s demen-
tia (AD) (Petersen et al., 1999). More recently, broader conceptualizations of MCI
have emerged that also encompass cognitive domains other than memory
(Petersen and Morris, 2005; Petersen et al., 2001). These characterizations delin-
eate clinical subtypes that commonly include amnestic and non-amnestic forms,
and that involve single and multiple cognitive domains (Manly et al., 2005;
Petersen and Morris, 2005; Petersen et al., 2001; Tabert et al., 2006) against the
backdrop of intact daily functioning. With the advent of these broader classifica-
tions schemes, more specific information is emerging regarding the neuropsycho-
logical presentation of individuals with MCI, risk for dementia associated with
diVerent subtypes of MCI, daily functioning, and neuropathologic substrates
connected to the clinical subtypes. The aim of this review is to provide an
overview of neuropsychological, neuroimaging, functional, and treatment find-
ings specific to clinical subtypes of MCI. In addition, methodological issues
involved in studying this heterogeneous population and future directions to
continue to improve our understanding of MCI and its clinical subtypes will
also be highlighted and discussed.
 NEUROPSYCHOLOGY AND IMAGING OF MCI SUBTYPES 83

II. Neuropsychological Presentation

It is certainly of great interest to determine factors placing individuals at

highest risk for development of dementia so as to target them for early interven-
tion. To this end, a better understanding of who is at risk for developing MCI may
be an important first step. Presently, there are limited data about risk factors that
correspond to conversion from cognitively normal to specific clinical subtypes of
MCI; although, the existing evidence suggests that advancing age and lower
education levels do place individuals at higher risk for MCI (Kryscio et al.,
2006), particularly for non-amnestic subtypes (Bickel et al., 2006; Fischer et al.,
2007). For example, individuals with less than 9 years of education have an
increased likelihood of isolated language and visuospatial deficits, as well as
multiple domain amnestic MCI, whereas higher education was associated with
increased chance of having isolated memory and executive impairments (Manly
et al., 2005). The presence of the apolipoprotein epsilon 4 allele (APOE e4)
seems to more strongly influence transitions from normal cognition to amnestic
MCI and influence conversion to multi-domain MCI to a lesser degree (Kryscio
et al., 2006).
More research attention has been paid to the neuropsychological presentation
of MCI and use of neuropsychological testing to delineate distinct clinical sub-
types (e.g., amnestic vs non-amnestic and single domain vs multiple domain).
Even when stratified into clinical subtypes, MCI is still a heterogeneous concept.
Complicating factors include widely diVering neuropsychological tests and diag-
nostic criteria used across studies in arriving at the MCI classifications as well as
inconsistency in how clinical subtypes are assigned. While Petersen advocated for
four subtypes, including single and multiple domain amnestic MCI and single and
multiple domain non-amnestic MCI, non-amnestic subtypes continue to receive
less attention in the literature and multiple domain classifications often do not
separate amnestic from non-amnestic presentations. Despite these challenges,
some converging evidence about the presentation of distinct MCI subtypes is
emerging.
Generally, multi-domain presentations seem to be more common than purely
amnestic presentations (Alexopoulos et al., 2006; Alladi et al., 2006; Lopez et al.,
2003; Manly et al., 2005; Rasquin et al., 2005); although, some studies have
identified single domains that are more common than multi-domains, and the
non-amnestic type is as frequent as the amnestic (Busse et al., 2006; Palmer et al.,
2008). Multi-domain MCI (mMCI) is the most common subtype in both stroke
and memory clinic samples (Rasquin et al., 2005). The prevalence of single
domain amnestic MCI (aMCI) ranges from 0.5 to 8% (Bickel et al., 2006; Das
et al., 2007; Di Carlo et al., 2007; Jungwirth et al., 2005; Lopez et al., 2003), mMCI
ranges from 0.5 to 16% (Bickel et al., 2006; Busse et al., 2003; Das et al., 2007;
84 JAK et al.

Di Carlo et al., 2007; Jungwirth et al., 2005; Lopez et al., 2003), and single domain
non-amnestic MCI ranges from approximately 3 to 15% (Bickel et al., 2006; Busse
et al., 2003; Di Carlo et al., 2007). There is only limited information on prevalence
rates of multi-domain non-amnestic MCI, in which one group has identified less
than a 5% prevalence rate (Bickel et al., 2006). In addition to vastly diVerent
methodological approaches to defining MCI, the prevalence rates also diVer due
to varying sample origins, with hospital samples having generally higher preva-
lence rates across subtypes than community samples (Bickel et al., 2006; Busse
et al., 2003). Presence of the APOE e4 allele may also contribute to diVering
prevalence rates. Amnestic MCI presentations have a higher proportion of
individuals with the apolipoprotein e4 allele as compared to non-amnestic groups
(Gabryelewicz et al., 2007; Manly et al., 2005; Whitwell et al., 2007). Thus, if
genetic risk is not determined, samples are likely to have diVering proportions of
individuals with the e4 allele and, therefore, diVerent prevalence rates.
Certainly the prevalence rates are impacted by the definition of MCI applied
by each study. Basing amnestic subtype diagnoses on the presence of either verbal
and/or visual memory deficits results in a larger proportion of individuals identi-
fied as amnestic MCI than just relying on verbal memory alone (Alladi et al.,
2006). Varying the cutoV score for defining impairment also alters diagnostic
outcomes by up to 12%; use of a more stringent statistical cutoV for impairment
(1.5–2.0 SD below normative expectations) increases positive predictive power
compared to lower cut points (Busse et al., 2003); although, a more liberal cutoV
for impairment has been shown to have higher sensitivity and specificity for future
development of dementia (Busse et al., 2006). These sensitivity and specificity
determinations are problematical; however, as they are based on a quite limited
neuropsychological assessment.
Aside from the use in diagnosis and determination of objective cognitive
deficits in MCI, additional neuropsychological findings may help diVerentiate
MCI subtypes. Perhaps not surprisingly, Lopez and colleagues (2006) found that,
compared to aMCI and normal cognition, mMCI was characterized by poorer
language, psychomotor speed, fine motor control, and visuoconstructional func-
tioning. What is of note is that, although the mMCI group had memory deficits,
they were to a lesser degree than the deficits noted in the aMCI group (Lopez
et al., 2006). A substantial minority of the MCI cases did not have any memory
impairment (Lopez et al., 2006), further emphasizing that examining only amnes-
tic subtypes fails to capture the full spectrum of possible cognitive declines
associated with MCI.
Spatial navigation skills of those with multi-domain amnestic MCI tend to be
more similar to spatial navigation skills of AD patients than to non-amnestic MCI
subtype groups, with both the AD and multi-domain amnestic MCI groups
impaired on virtually all portions of a spatial navigation task (Hort et al., 2007).
However, the multi-domain amnestic MCI group was generally more impaired
 NEUROPSYCHOLOGY AND IMAGING OF MCI SUBTYPES 85

than other groups across all neuropsychological tests, so it is not clear that these
spatial navigation diYculties occurred in isolation from the other impaired func-
tions. Visuospatial skills specific to facial emotional processing have also been
found to be intact in those with single domain amnestic MCI but impaired in
those with multi-domain amnestic MCI, particularly in facial aVect discrimina-
tion (Teng et al., 2007).

III. Stability of Diagnosis

Multiple studies indicate that not all individuals diagnosed with MCI will
decline and progress to a dementia diagnosis. In fact, a proportion of individuals
appear to ‘‘improve’’ over time such that, at follow up, those initially identified as
MCI are later categorized as cognitively normal. Anywhere from 20 (Fischer et al.,
2007) to 40% (Bickel et al., 2006) of those with MCI appear to revert to the normal
range upon retesting. Single domain classifications appear particularly susceptible
to this instability, with single domain non-amnestic subtype often exhibiting the
least stability over time (Bickel et al., 2006; Busse et al., 2006; Fischer et al., 2007;
Jak et al., 2007). For example, one study reported that 50% of those with single
domain MCI were normal upon later retesting whereas only 12% of those with
multi-domain MCI ‘‘recovered’’ (Bickel et al., 2006). Additional sources of insta-
bility in the MCI diagnosis can manifest via individuals changing MCI subtypes
over time. Approximately 6% of those with MCI at baseline changed subtypes at
follow up (Fischer et al., 2007; Jak et al., 2007). In contrast, over a 3-year interval,
Zanetti and colleagues (2006) identified a more anticipated trajectory of their
MCI cohort; all MCI subtypes either converted to dementia (about a quarter) or
retained their MCI status (Zanetti et al., 2006).

IV. Conversion to Dementia

Perhaps the largest amount of information exists on likelihood of conversion

to dementia from various MCI clinical subtypes. Some evidence suggests that
those with multi-domain amnestic MCI appear to be at greatest risk for future
dementia (Di Carlo et al., 2007; Palmer et al., 2008; Tabert et al., 2006), whereas
others indicate that amnestic MCI places one at highest risk for conversion to
dementia (Ravaglia et al., 2006; YaVe et al., 2006). Amnestic MCI subtypes do
seem to impart significant risk for future development of AD while multi-domain
presentations may be more common in those who eventually develop vascular
dementia (Fischer et al., 2007; Rasquin et al., 2005; YaVe et al., 2006; Zanetti et al.,
2006). YaVe and colleagues (2006) found that, of those who progressed to AD,
86 JAK et al.

76% were initially diagnosed with aMCI, 11% initially presented with single
domain non-amnestic MCI, and 13% were initially identified as mMCI (YaVe
et al., 2006). Conversely, of those who progressed to vascular dementia, 50% were
initially diagnosed with aMCI, 8% had single domain non-amnestic MCI, and
42% had mMCI (YaVe et al., 2006). Rozzini and colleagues (2007) reported that,
in a group of amnestic MCI individuals, poor global cognitive performance at
baseline and worsening executive functioning, but not worsening memory perfor-
mance, were associated with conversion to AD over a 1-year follow-up period.
Those with non-amnestic multiple domain subtype appear more likely to convert
to a non-AD dementia (Busse et al., 2006), with the single domain non-amnestic
MCI at particular risk to progress to a frontal dementia syndrome (YaVe et al.,
2006). There are reports, however, in which detailed information about MCI
subtypes does not add significant benefit in determining who may be at greatest
risk for conversion to dementia (Maioli et al., 2007; Ravaglia et al., 2006; Rountree
et al., 2007).

V. MCI and Health Variables

Understanding any additional health factors that may be more prevalent in

distinct MCI subtypes is also noteworthy as a way to further delineate risk profiles.
For example, cardiovascular risk factors, presence of the apolipoprotein e4 allele,
mood symptoms, and parkinsonian symptoms have all been investigated in MCI
subtypes. Recent research has shown that multi-domain or non-amnestic
MCI subtypes may be more likely to have cardiovascular risk factors than either
those with single domain amnestic presentations or those without MCI (Di Carlo
et al., 2007; Zanetti et al., 2006). Mariani and colleagues (2007) found that those
with single domain non-amnestic MCI had a higher frequency of ischemic heart
disease, transient ischemic attack (TIA) or stroke, a higher Hachinski ischemic
score, and more white-matter lesions on MRI compared to aMCI. Further, multi-
domain and single domain amnestic subjects exhibited similar clinical character-
istics; although, the multi-domain amnestic subtype did have a greater history of
TIA/stroke (Mariani et al., 2007). Amnestic MCI groups showed a higher preva-
lence of diabetes than controls whereas participants with non-amnestic MCI were
more likely to have hypertension than were controls (Verghese et al., 2008).
In contrast, Debette et al. (2007) found that white matter changes may play a
role in cognitive decline in MCI as a whole, but they do not appear to be specific
to either amnestic or non-amnestic clinical subtypes. Because their amnestic and
non-amnestic characterizations were multi-domain, the authors found the rate of
cognitive decline and the presence of periventricular hyperintensities was more
prominent in those with baseline executive dysfunction (Debette et al., 2007).
 NEUROPSYCHOLOGY AND IMAGING OF MCI SUBTYPES 87

Mood symptoms also appear to be more common in those with multi-domain

MCI relative to those with single domain amnestic presentations (Gabryelewicz
et al., 2007; Zanetti et al., 2006). Additionally, higher depression ratings are linked
to those whose cognitive symptoms progressed over the follow-up period (but not
to the point of dementia) and to those who converted from MCI to dementia as
compared to the stable group (Gabryelewicz et al., 2007). Hallucinations and sleep
disorders are more common in the non-amnestic than amnestic subtype (Rozzini
et al., 2008). Others have found, however, that mood symptoms are increased in
MCI cohorts as compared to cognitively normal samples, but with no significant
diVerences in mood symptoms emerging between specific MCI subtypes (Palmer
et al., 2007; Rozzini et al., 2008).
Other health factors seem to be associated with MCI in general but are not
necessarily specific to amnestic or non-amnestic presentations. For example,
lower serum folate levels (Maioli et al., 2007; Ravaglia et al., 2006), history of
atrial fibrillation (Ravaglia et al., 2006), and higher serum HDL levels (Maioli et al.,
2007) contribute to increased likelihood of conversion from MCI to dementia,
regardless of MCI subtype. Odor identification skills of MCI participants also fall
in between those of AD and healthy control groups, and MCI subtypes did not
diVer on smell identification performances (Westervelt et al., 2008).
Most conceptualizations of MCI exclude Parkinson’s disease, given that the
historical conceptualization has been of MCI as a precursor to Alzheimer’s
disease or other non-Parkinsonian dementias. In addition, the motor symptoms
associated with Parkinson’s disease often produce demonstrable changes in a
person’s activities of daily living (ADL), which confound its utility in the classifi-
cation of MCI. Recently, however, there have been eVorts to characterize the
transitional period between normal cognitive function and dementia in Parkin-
son’s disease (PD). The expanded clinical subtypes are particularly relevant to this
eVort given the diVerence in presentation between dementias of diVerent origins.
Data suggest that MCI in those with Parkinson’s is predictive of future dementia
in much the same way that it is for individuals with MCI without co-morbid PD.
Non-amnestic subtypes are particularly prevalent in Parkinson’s disease and the
presence of MCI in individuals with Parkinson’s disease does substantially raise
one’s risk of developing dementia as compared to those with PD and normal
cognition ( Janvin et al., 2006). In contrast to AD, conclusions about amnestic
subtypes of PD MCI are more diYcult to draw given the low prevalence of this
subtype. Boyle et al. (2005) found that those individuals with MCI had higher
levels of parkinsonian symptoms (though not Parkinson’s disease) than those who
were cognitively normal. Verghese et al. (2008) found greater gait abnormalities in
those with aMCI as compared to those with non-amnestic MCI or controls while
others have noted that non-amnestic subtypes have higher rates of gait dysfunc-
tion than amnestic MCI (Boyle et al., 2005). Those with mMCI may present with
more extra-pyramidal features than those with aMCI (Zanetti et al., 2006).
88 JAK et al.

VI. Daily Functioning and MCI

Embedded in the controversy surrounding the establishment of specific diag-

nostic criteria for MCI, there is much debate regarding whether impairment in
everyday activities should be included as a criterion. In its initial conceptualiza-
tion, MCI guidelines required that functional abilities remain intact (Petersen
et al., 1999) as this specific criterion helped distinguish MCI from dementia.
However, as Farias et al. (2006) note, cognitive and functional deterioration clearly
occurs over the course of MCI since such change eventually leads to conversion to
dementia for many individuals with MCI (e.g., Bruscoli and Lovestone, 2004;
Petersen et al., 1999). In light of this accumulating evidence, an international
working group proposed modified criteria for MCI, which includes ‘‘preserved
basic activities of daily living’’ and ‘‘minimal impairment in complex instrumental
functions’’ (Winblad et al., 2004, p. 243). Similarly, participants of the Interna-
tional Psychogeriatric Association Expert Conference on MCI did not require
intact ADL/instrumental activities of daily living (IADL) as a criterion but,
instead, defined MCI as ‘‘a syndrome defined as cognitive decline greater than
expected for an individual’s age and education level but that does not interfere
notably with activities of daily life’’ (Gauthier et al., 2006, p. 1262).
Emerging information about the functional status of those with distinct
clinical subtypes of MCI may shed additional light on the continuum of functional
abilities spanning normal cognition to dementia. Supporting the notion that
functional decline occurs on a continuum, several groups have reported that
IADL decrements in MCI are intermediate to the subtle declines associated
with normal aging and the frank impairments required for a dementia diagnosis
(Farias et al., 2006; Giovanetti et al., 2008; GriYth et al., 2003; Peres et al., 2006).
Published reports comparing ADL and IADL performance between MCI
individuals and their cognitively normal counterparts have demonstrated that
those with MCI show greater IADL changes in areas including shopping, man-
aging medications, and handling finances (Mariani et al., 2008). In a study
examining IADL performance across diVerent MCI subtypes, Tam et al. (2007)
reported that individuals with multiple domain MCI demonstrated impairment in
IADL relative to both amnestic MCI participants and cognitively normal older
adults. Corroborating this finding, Zanetti and colleagues (2006) demonstrated
that individuals with multi-domain MCI performed more poorly on measures of
ADL and IADL relative to amnestic MCI participants. In contrast, Farias and
colleagues (2006) demonstrated that the MCI with memory impairment group
showed somewhat more functional change relative to their MCI peers with no
memory impairment and cognitively normal older adults. Similarly, Wadley and
colleagues (2007) reported that amnestic, non-amnestic, and multiple domain
MCI subgroups all demonstrated greater diYculty with IADL performance
 NEUROPSYCHOLOGY AND IMAGING OF MCI SUBTYPES 89

compared to the cognitively normal group. However, unlike the other two MCI
groups, individuals with non-amnestic MCI did not diVer from the cognitively
normal participants in terms of IADL performance. Notably, at least one study
(Boeve et al., 2003) did not find diVerences between amnestic MCI individuals and
cognitively normal older adults in terms of functional abilities. However, it should
be noted that the MCI participants who were included in this study were
characterized as MCI based, in part, on intact ADL.
Farias and colleagues (2006) administered self-report and informant-based
versions of the Daily Function Questionnaire (DFQ) and calculated a diVerence
score by subtracting patients’ DFQ from informants’ DFQ. DFQ diVerence
scores, which indicate a lack of awareness of deficits, were greater in demented
individuals relative to their cognitively normal counterparts and MCI subtype
groups (i.e., MCI with memory impairment and MCI without memory im-
pairment). However, the diVerence scores did not diVer between MCI groups
and cognitively normal older adults. Based on these findings, Farias and
colleagues (2006) argued that individuals with MCI do not underestimate func-
tional changes as is often the case for demented individuals.
What seems clear from the above discussion is that changes in ADL and IADL
are not uncommon across the spectrum of MCI; although, it remains to be
determined whether many of these changes would be conceptualized as frank
‘‘deficits’’ or ‘‘impairments.’’ Comparing the ADL and IADL changes of MCI to
overt dementia groups would be helpful in determining cutoV criteria for im-
pairment, or administering performance-based ADL and IADL measures with
normative reference standards would also help to delineate whether such changes
represent impairment.

VII. Neuroimaging

A. STRUCTURAL MRI

In determining the clinical viability of the various clinical subtypes, many

would assert that diVerent subtypes should have distinct neuropathology or
diVerent courses of change in brain integrity. Certainly, structural neuroimaging
provides a non-invasive way to begin to examine brain changes associated with
MCI, and there is emerging evidence to support distinct neuropathological
profiles in clinical subtypes of MCI. Whitwell et al. (2007) found that those with
amnestic presentations (single or multiple domain) had greater gray matter
atrophy in medial and inferior temporal lobes compared to controls. Those
with multi-domain amnestic MCI additionally showed loss in posterior temporal
lobe, parietal association cortex, posterior cingulate, anterior insula, and the
90 JAK et al.

medial frontal lobe, a pattern of atrophy similar to that found in AD (Whitwell

et al., 2007). In support of this finding, Seo and colleagues (2007) reported that
those diagnosed with single domain amnestic MCI showed cortical thinning in left
medial temporal lobe (MTL) only, whereas those identified as multi-domain
amnestic MCI showed cortical thinning in the left MTL, precuneus, and anterior
and inferior basal temporal, insular, and temporal association cortices. The
precuneus atrophy may be responsible for additional cognitive impairments
present in the multi-domain MCI subtype and may suggest that the multi-domain
presentations are a progression from single domain presentations since the areas
of thinning noted in the multi-domain subtype encompassed all those in the single
domain subtype and the extent of MTL atrophy was greater in the multi-domain
versus the single domain subtype (Seo et al., 2007).
In contrast, Becker and colleagues (2006) did not support the multi-domain
subtype as the more advanced, transitional state between normal cognition and
AD. They found that hippocampal volumes in those with multi-domain MCI
were not statistically diVerent from those of controls, but were significantly larger
than both the amnestic MCI and AD groups (Becker et al., 2006). Bell McGinty
and colleagues (2005) found that the amnestic MCI group had greater volume loss
in left entorhinal cortex and inferior parietal lobe as compared with multi-domain
MCI. However, the multi-domain MCI group may exhibit their neuropathologi-
cal changes in other areas, namely by smaller right inferior frontal gyrus, right
middle temporal gyrus, and bilateral superior temporal gyrus as compared to
amnestic MCI (Becker et al., 2006).
Although the data are conflicting as to whether multi-domain subtypes neces-
sarily have more extensive brain changes than single domain subtypes, current
research does support the idea that diVerent clinical subtypes of MCI have distinct
neuropathology. Taken together, the available evidence suggests that those indi-
viduals with a more focal memory presentation have greater involvement of
mesial temporal structures while those with more widespread deficits had greater
involvement of association areas. Distinct MCI subtypes may represent diVerent
etiological paths to dementia, but the small sample sizes available in most of the
imaging studies to date make conclusions tentative at best.
Other advanced imaging techniques hold promise to further clarify the nature
and extent of brain changes associated with distinct clinical MCI subtypes though,
to date, use of techniques such as functional magnetic resonance imaging (FMRI)
and diVusion tensor imaging (DTI) has focused globally on MCI or on amnestic
MCI, without significant investigation of non-amnestic subtypes. An overview of
the use of these imaging techniques in MCI is provided, nonetheless, as this
preliminary work is an essential framework for future examinations of clinical
MCI subtypes.
 NEUROPSYCHOLOGY AND IMAGING OF MCI SUBTYPES 91

B. DIFFUSION TENSOR IMAGING

A growing body of research suggests that white matter pathology contributes

to age-related cognitive impairment and possibly potentiates the development of
dementia (Raz and Rodrigue, 2006; Sullivan and PfeVerbaum, 2006). Although
studies have generally shown white matter changes to be accelerated and more
severe in AD (PfeVerbaum et al., 2000; Rose et al., 2006; Takahashi et al., 2002), to
date, few studies have employed DTI to examine early white matter changes in
older adults with MCI with exceptionally limited focus on DTI-derived white
matter changes in specific MCI clinical subtypes. Several studies have shown
reduced fractional anisotropy (FA), a proxy of white matter integrity, in the
posterior cingulum fibers, and this relationship seems to be stronger in the left
versus right hemisphere (Fellgiebel et al., 2005; Medina et al., 2006; Rose et al.,
2006; Zhang et al., 2007). Rose et al. (2006) demonstrated increased diVusivity in
the entorhinal and parieto-occipital cortices, and decreased FA in the limbic
parahippocampal white matter in patients with MCI. Moreover, Kantarci et al.
(2005) was among the first to show that increased mean diVusivity of the hippo-
campus in amnestic MCI predicted future progression to dementia.
Several studies have shown decreased integrity in the posterior region of the
corpus callosum (i.e., splenium) in those with MCI (Cho et al., 2008; Delano-
Wood et al., 2007; Ukmar et al., 2008), an area which is particularly sensitive to
degenerative processes (Naggara et al., 2006; Rose et al., 2000; Takahashi et al.,
2002). Although some studies have shown changes in the frontal white matter of
MCI patients (Bozzali et al., 2002; Medina et al., 2006; Naggara et al., 2006), other
studies have not identified any diVerences (Delano-Wood et al., 2007; Head et al.,
2004; Medina et al., 2006; Ukmar et al., 2008). Although data are limited, results
suggest a pattern of retrogenesis (Bartzokis, 2004), by which microstructural
changes first occur in late-myelinating regions, spreading to early-myelinating
regions only after the disease process has progressed beyond a particular thresh-
old, which may initially manifest itself with the onset of MCI.

C. FUNCTIONAL MRI

Evidence to date indicates that functional brain decline precedes structural

decline in prodromal dementia, including adults with MCI. Therefore, functional
neuroimaging techniques may oVer the unique ability to detect early func-
tional brain changes in at-risk adults and identify the neurophysiological markers
that best predict dementia conversion.
92 JAK et al.

Given that AD neuropathology preferentially targets the MTL early in the

course of the disease, thereby resulting in the hallmark episodic memory decline,
and amnestic MCI is thought to represent prodromal AD, the majority of FMRI
studies of MCI involve memory processing (particularly encoding) in amnestic
samples. No known FMRI studies have been published focusing on other clinical
subtypes of MCI. While several studies demonstrate increased blood oxygen
level dependent (BOLD) response in the MTL (Dickerson et al., 2004, 2005;
Hamalainen et al., 2007; Kircher et al., 2007; Sperling, 2007), others report
decreased MTL activity in MCI ( Johnson et al., 2006; Machulda et al., 2003;
Mandzia et al., 2009). These discrepant findings have been interpreted as reflect-
ing bimodal functional activity whereby less impaired MCI subjects show
increased BOLD response in the hippocampus corresponding to a slight or
moderate neuronal dysfunction, and more impaired MCI subjects demonstrate
decreased BOLD response—similar to the levels observed in mild AD patients—
as the cortical neuronal networks become more severely impaired with greater
disease progression (Celone et al., 2006; Dickerson et al., 2004, 2005; Hamalainen
et al., 2007; Johnson et al., 2006; Machulda et al., 2003; Masdeu et al., 2005;
Petrella et al., 2007a). However, this interpretation is primarily derived from cross-
sectional studies and can only adequately be tested with longitudinal designs.
Few longitudinal FMRI studies of MCI have been reported. Although these
studies are often limited by small sample sizes, they demonstrate promise for the
use of FMRI to detect early AD. Those MCI patients who converted to AD
showed a stronger relationship between brain activity in the left superior parietal
lobe and the left precuneus during an angle discrimination task in the context of
comparable performance (Vannini et al., 2007). Similarly, despite equivalent
memory performance, Dickerson et al. (2004) reported that MCI patients who
subsequently declined during a 2.5-year follow-up period demonstrated increased
right parahippocampal gyrus activity during picture encoding. In a more recent
study, the same research group reported increased hippocampal activation pre-
dicted greater degree and rate of cognitive decline during a 6-year follow-up
period, even after controlling for baseline level of impairment (Miller et al., 2008).
Mandzia et al. (2009) reported that MTL activation during recognition was
positively correlated with behavioral performance. However, unlike their healthy
peers, MCI adults did not show a strong relationship between MTL activity
during picture encoding and subsequent retrieval success, highlighting the com-
plexity of the relationship between BOLD signal and eVectiveness of encoding
strategies. In contrast, Johnson et al. (2006) found reduced BOLD signal change in
the right hippocampus during picture encoding and in the posterior cingulate
during recognition of learned items in an amnestic MCI group despite compara-
ble performance to their healthy peers. However, when activation corresponding
only to successfully learned words was examined, an increase in hippocampal
activity was seen, suggesting that an increase in MTL activity may support
 NEUROPSYCHOLOGY AND IMAGING OF MCI SUBTYPES 93

successful memory encoding (Kircher et al., 2007). Similarly, a positive correlation

between extent of parahippocampal and hippocampal activation and memory
performance was found in MCI but, in a paradoxical fashion, greater clinical
impairment, was also associated with recruitment of a larger region of the right
parahippocampal gyrus during encoding (Dickerson et al., 2004). Data from
Johnson et al. (2004) provided further evidence for hippocampal dysfunction in
MCI, suggesting that adults with MCI do not habituate to increasingly familiar
items in the same manner as healthy older adults who show expected reductions
in BOLD response to repeated items over time.
Despite the prevalence of studies examining medial temporal cortex function
supporting memory, other cortical areas have also been implicated in MCI. For
example, a reduction in functional activity in the posterior cingulate cortex (PCC)
during recognition and episodic retrieval of previously learned line drawings
( Johnson et al., 2006) and object working memory (Yetkin et al., 2006), but not
during self-appraisal (Ries et al., 2007), has implicated this region in the memory
retrieval diYculty seen in amnestic MCI. The degradation of PCC functioning in
MCI is not surprising given that PET metabolic alterations in the temporoparietal
cortices and in the posterior cingulate have been reported in MCI and AD
(Desgranges et al., 1998; Matsuda, 2001; Reiman et al., 1996) as well as in
nondemented young and middle-aged adults at genetic risk for AD (Petrella
et al., 2007b; Reiman et al., 1996, 2004, 2005; Wolf et al., 2003). Similarly,
dediVerentiation in the retrosplenial cortex during the retrieval of recent versus
remote autobiographical memories and during episodic versus semantic memory
retrieval has been reported in amnestic MCI (Poettrich et al., 2009), further
implicating the medial posterior cortex in MCI. Additionally, the neural sub-
strates of visual working memory (Yetkin et al., 2006), self-appraisal (Ries et al.,
2007), and emotional working memory (Dohnel et al., 2008) in MCI have also
been examined, and generally implicate a greater number of cortical regions.
However, results are varied and highlight the need for greater attention to other
cognitive processes in MCI in order to more fully understand changes in cortical
functioning that may signal impending cognitive decline.

VIII. Treatment

One motivation to better understand the heterogeneous concept of MCI and

the risk it imparts for future development of dementia is to provide early inter-
ventions that could halt or at least slow progression of symptoms. To date,
unfortunately, there are no FDA-approved therapies for MCI. Further, aMCI
has received all the attention with regard to treatment trials with no trials
investigating other distinct clinical subtypes of MCI. Of the existing treatment
94 JAK et al.

TABLE I
CLINICAL TRIALS IN AMCI

Agent N Duration Endpoint Outcome

Donepezil 269 24 weeks Symptoms Negative

Donepezil/Vitamin E 769 3 years AD Partially positive
Rofecoxib 1200 2–3 years AD Negative
Galantamine 995 2 years CDR 1 Negative
1062 2 years CDR 1 Negative
Rivastigmine 1018 3–4 years AD Negative

AD, Alzheimer’s disease; CDR, clinical dementia rating.

trials in MCI, most have used a ‘‘progression to AD’’ design with the focus on
slowing cognitive decline and delaying conversion to AD. As a whole, the trials
have been disappointing with one possible exception, the Alzheimer’s Disease
Cooperative Study (ADCS)-sponsored trial (Petersen et al., 2005) (see Table I).
The ADCS-sponsored study of Vitamin E and donepezil for MCI involved
769 subjects at 69 centers in the US and Canada over 3 years. There were three
treatment arms: Vitamin E 2000 IU/day, donepezil 10 mg/day, and placebo.
The primary trial endpoint was conversion to AD. Although conversion to AD
favored donepezil at 1 year, there were no diVerences among groups with regard
to conversion to AD at 3 years. However, possession of the APOE e4 allele was
noted to be associated with a threefold greater risk of conversion from aMCI to
dementia and, thus, clearly an important predictor of progression. When the
authors looked at the progression to AD for APOE e4 positive participants by
treatment group, they found that the eVect of donepezil was greater in e4 positive
individuals and persisted for 2 years. While neither of the two active arms reduced
the risk of progressing to AD over the entire 36 months, donepezil reduced the
risk of progression to AD for the first 12 months in all subjects and up to 24
months in those who were positive for the APOE e4 allele. No treatment eVect
was noted for Vitamin E.
Other treatment trials have been less promising for halting conversion from
MCI to dementia over time. A large trial of rivastigmine, an acetylcholinesterase
inhibitor, was a double blind, placebo-controlled trial of 1018 patients that had
many of the same features as the ADCS trial, but was conducted in 14 countries
using multiple languages and translations of the neuropsychological instruments
(Feldman et al., 2007). At baseline, arms were not well matched with regard to
frequency of APOE e4 genotype, which was 46% in the placebo arm but only
37% in the rivastigmine arm. The study also had a lower conversion rate than
expected and had to be extended to 4 years; over that time, 21.4% of placebo
treated, but only 17.3% of rivastigmine treated, subjects progressed to AD.
 NEUROPSYCHOLOGY AND IMAGING OF MCI SUBTYPES 95

Although rivastigmine was favored, the results were not statistically significant,
and secondary assessments were also not significant. Investigation of the eYcacy
of another acetylcholinesterase inhibitor, galantamine, also failed to reveal a
significant eVect of galantamine on conversion to dementia in those with MCI
in either of two trials (Winblad et al., 2008).
Finally, another large randomized, placebo-controlled, double-blind study
examined the ability of the COX 2 inhibitor, rofecoxib, to delay disease progres-
sion in 1457 aMCI subjects (Thal et al., 2005). Once again, there was a lower than
expected annual rate of conversion to AD. Conversion to AD actually favored
placebo in this trial but the authors dismissed the significance of this finding
because the secondary cognitive measures did not corroborate the primary
outcome.
In hindsight, several important factors likely influenced the results of these
studies, including, perhaps first and foremost, the variable rate of progression
from aMCI to AD. Sources of this variability likely include subject heterogeneity,
with regard to impairment level, culture, language, and APOE e4 carrier status, in
addition to even simple diVerences in implementation of enrollment criteria. MCI
patients may show increased awareness of, or lower tolerability for, adverse
events, resulting in higher discontinuation rates. Our current outcome measures
may be insensitive; for example, the conversion design dichotomizes a continuous
variable and most of the currently used eYcacy measures follow an AD trial
model of decline. Rather than decline, however, MCI patients may show im-
provement on cognitive measures, no matter which treatment group they are
assigned to, because of at least some preservation in their ability to learn. Future
MCI trials may benefit from less heterogeneous recruitment with stricter entry
criteria and enriched populations, more sensitive cognitive and global outcome
measures that reflect subtle impairments in complex activities, novel imaging
outcomes, and longer trials.

IX. Conclusions

MCI remains a heterogeneous concept, though division of MCI into distinct

clinical subtypes serves as a promising approach to better understanding MCI as a
diagnostic entity and a risk factor for future cognitive decline. Evidence to date
suggests that multi-domain amnestic presentations are more prevalent than either
single domain amnestic or multi-domain non-amnestic presentations, though
relatively little attention has been paid to the latter subtype. Converging neuro-
psychological, daily functioning, and neuroimaging data suggest that multiple
domain presentations may place one at highest risk for future development of
dementia. The current literature also supports that knowledge of subtypes of MCI
informs the risk for future development of diVerent types of dementia.
96 JAK et al.

Though knowledge of MCI subtypes appears helpful in predicting risk of

conversion to dementia, there remains a significant minority of individuals with
MCI, particularly single domain subtype that may revert to normal cognition
when followed over time. This instability in diagnosis as well as the varying
prevalence rates, rates of conversion to dementia, and general oft-conflicting
results in the literature, are likely due to ongoing challenges in operationalizing
the diagnostic criteria for MCI. The methods for documenting objective neuro-
psychological impairment tend to be a particularly variable and ill-defined aspect
of the MCI diagnostic process across studies (Portet et al., 2006). There is little
consensus about what neuropsychological tests (or how many) should be used to
document objective cognitive impairment, what level of performance is consid-
ered cognitively impaired, how diagnostic criteria for diVerent clinical subtypes of
MCI are applied, what constitutes intact daily functioning, or about whether or
not functional abilities should be included in the diagnostic decision-making
regarding MCI. As this review highlights, the variable results in the current
MCI literature clearly illustrate the importance of (a) understanding the criteria
used to identify cognitive impairment in making the MCI diagnosis, (b) the value
of using comprehensive neuropsychological assessment when diagnosing MCI
subtypes, and (c) point to the need for further exploration of MCI subtypes,
particularly non-amnestic presentations. Investigations and interventions target-
ing only amnestic subtypes are potentially missing a sizable number of individuals
at risk.
Neuroimaging holds promise as a technique to better understand diVerences
between distinct MCI subtypes although all of the above-mentioned methodolog-
ical challenges together with small sample sizes and very limited attention paid to
non-amnestic subtypes make drawing firm conclusions from the existing imaging
literature challenging. To date, data do seem to support distinct neuropathology
in the diVerent clinical subtypes of MCI. However, there is still much overlap in
structural imaging profiles and conflicting evidence making conclusions tentative
at best. Advanced imaging techniques, such as DTI and functional MRI hold
promise for detecting microstructural white matter damage or altered activation
patterns in older adults prior to the manifestation of the full dementia syndrome.
This early identification would identify the group in whom targeted therapies will
likely have the greatest clinical impact (see Fagan et al., 2005, for discussion).
Overall, results from recent DTI studies indicate that white matter changes are
evident in at-risk older adults and further validate the use of DTI to capture
subtle, early white matter changes before significant atrophy is present. However,
to date, very few studies have employed DTI in older adults with MCI, and even
fewer have investigated the relationship between clinical subtype of MCI and
white matter integrity.
Similarly, although FMRI techniques may prove to be instrumental in the
early detection of AD, interpretation of current findings in MCI is complicated by
 NEUROPSYCHOLOGY AND IMAGING OF MCI SUBTYPES 97

various methodological diVerences between studies. In general, functional

changes in the MTL and posterior medial cortex appear to signal cognitive
decline and dementia conversion. However, discrepant results across studies
may be due to diVerences in diagnostic classification of MCI adults. Specifically,
although the majority of studies reviewed classified their patients as amnestic
MCI, it is likely that the patient sample represented a more heterogeneous group
that may reflect diVerent underlying neural pathology. This highlights the need
for future research aimed at integrating behavioral performance with measures of
functional activity that directly compare diVerent MCI subtypes with these
sophisticated neuroimaging techniques.
Finally, results of intervention trials to halt the progression of MCI have
generally been disappointing. Future trials are needed that address both amnestic
and non-amnestic presentations, employ more stringent entry criteria, use more
sensitive cognitive and global outcome measures that reflect subtle impairments in
complex activities, and include novel imaging outcomes.

Acknowledgments

This work was supported by grants from the National Institutes of Health (K24 AG026431, R01
AG012674, and P50 AG05131), by Career Development Awards from the Department of Veterans
AVairs, and by Investigator-Initiated and New Investigator Research Grants from the Alzheimer’s
Association. The authors gratefully acknowledge the assistance of staV, patients, and volunteers of the
UCSD Alzheimer’s Disease Research Center, and the UCSD Laboratory of Cognitive Imaging.

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 PROTON MAGNETIC RESONANCE SPECTROSCOPY IN
DEMENTIAS AND MILD COGNITIVE IMPAIRMENT

H. Randall Griffith,*,y,z Christopher C. Stewart,z and Jan A. den Hollander}

*Department of Neurology, University of Alabama at Birmingham, Birmingham,
Alabama 35233, USA
y
Alzheimer’s Disease Research Center, University of Alabama at Birmingham,
Birmingham, Alabama 35233, USA
z
Department of Psychology, University of Alabama at Birmingham, Birmingham,
Alabama 35233, USA
}
Department of Medicine (Cardiology), University of Alabama at Birmingham,
Birmingham, Alabama 35233, USA

I. Introduction
II. Metabolites in 1H MRS
III. 1H MRS Findings in Dementias
A. 1H MRS Findings in Alzheimer’s Disease
B. 1H MRS Findings in Amnestic Mild Cognitive Impairment
C. 1H MRS Findings in Frontotemporal Dementia
D. 1H MRS Findings in Vascular Dementia
E. 1H MRS Findings in Dementia with Lewy Bodies
F. 1H MRS Findings in Parkinson’s Disease Dementia
G. Utility of 1H MRS for Discriminating Among Dementias
H. Utility of 1H MRS for Monitoring Treatment Effects in Dementias
IV. Discussion
References

With the anticipated increase in dementias due to the aging demographic

of industrialized nations, biomarkers for neurodegenerative diseases are increas-
ingly important as new therapies are being developed for clinical trials. Proton
MR spectroscopy (1H MRS) appears poised to be a viable means of tracking brain
metabolic changes due to neurodegenerative diseases and potentially as a bio-
marker for treatment eVects in clinical therapeutic trials. This review highlights
the body of literature investigating brain metabolic abnormalities in Alzheimer’s
disease, amnestic mild cognitive impairment, frontotemporal dementia, vascular
dementia, Lewy body dementia, and Parkinson’s disease dementia. In particular,
the review addresses the viability of 1H MRS to discriminate among dementias, to
measure disease progression, and to measure the eVects of pharmacological
treatments. While findings to date are encouraging, more study is needed in
longitudinal patterns of brain metabolic changes, correspondence with changes
in clinical markers of disease progression, and sensitivity of 1H MRS measures to

INTERNATIONAL REVIEW OF 105 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00406-1 0074-7742/09 $35.00
106 GRIFFITH et al.

treatment eVects. Such developments will hopefully benefit the search for eVective
treatments of dementias in the twenty-first century.

I. Introduction

The aging demographic of persons in the United States and other industrialized
nations creates the prospect for a future major healthcare crisis from providing care
to patients with dementia worldwide. Clearly, there is a great need for better
treatments to emerge for these neurodegenerative illnesses within the next decade.
A prime issue in clinical investigation of treating neurodegenerative diseases is the
need for better markers of the disease process that can be used as measures of
treatment eYcacy (Mueller et al., 2006). The current review focuses on proton
magnetic resonance spectroscopy (1H MRS) as a marker of metabolic brain
changes in dementias and the potential for use as a biomarker in clinical trials.
Findings are discussed from studies of Alzheimer’s disease (AD), amnestic mild
cognitive impairment (MCI), frontotemporal dementia (FTD), vascular dementia
(VAD), Lewy body dementia (LBD), and Parkinson’s disease dementia (PDD).

II. Metabolites in 1H MRS

A comprehensive review of the development and technology of 1H MRS is

beyond the scope of the current review. Interested readers are referred to Ross
and Bluml (2001). Although phosphorus (31P), carbon (13C), and fluorine (19F) are
all forms of MRS (Mueller et al., 2006), 1H MRS is the most frequently encoun-
tered subtype in the dementia literature due to its superior MR signal sensitivity,
good spatial resolution, and its widespread availability ( Jones and Waldman,
2004; Ross and Bluml, 2001). This review will thus focus exclusively on
(Mueller et al., 2006) 1H MRS, and the metabolites commonly assessed in these
studies. The following metabolites are mainly of interest in dementias (see Fig. 1).
N-acetyleaspartate. N-acetyleaspartate (NAA), which resonates at 2.02 parts per
million (ppm), represents the largest proton metabolic concentration in the human
brain after H2O (Kwock, 1998; Valenzuela and Sachdev, 2001). NAA exists
primarily within neurons, axons, and their processes, and has been implicated in
several neuronal processes, including lipid and protein synthesis, mitochondrial
functioning, and osmoregulation ( Jones and Waldman, 2004). NAA is presumed to
represent neuronal density or integrity based upon comparison of in vivo and
in vitro studies (Cheng et al., 2002; Valenzuela and Sachdev, 2001) and the preva-
lence of reduced NAA levels within a number of neuropathological conditions
(Chen et al., 2000). NAA may also serve as a marker of axonal metabolic fitness
 1
H MRS IN DEMENTIAS AND MILD COGNITIVE IMPAIRMENT 107

8
NAA

7
Cr
6

Cho
5

4
mI
sI
Glu 3

4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

FIG. 1. Example spectra obtained from posterior cingulate gyrus at 3 T. mI, myo-Inositol;
sI, scyllo-Inositol; Cho, Choline; Cr, Creatine; Glu, glutamate; NAA, N-acetyleaspartate.

(Valenzuela and Sachdev, 2001), as white and gray matter have comparable NAA
levels and white matter NAA is reduced in white matter diseases (e.g., multiple
sclerosis). Normalization of NAA levels in neurological disorders has been noted
(e.g., following stroke); however, it remains unclear whether NAA ‘‘recovery’’
represents actual neuronal ‘‘recovery’’ or ‘‘regeneration’’ (Mueller et al., 2006).
Choline. The Choline (Cho) peak (3.2 ppm) represents a combination of several
choline-containing compounds, including free Cho, phosphorylcholine and gly-
cerophosphorylcholine, and to a small extent acetylcholine (Firbank et al., 2002;
Valenzuela and Sachdev, 2001). Free Cho acts as a precursor to acetylcholine,
while glycerophosphorylcholine is a product of breakdown of membrane phos-
phatidylcholine and acts as an osmoregulator (Firbank et al., 2002). Cho is slightly
more concentrated in white versus gray matter (Mueller et al., 2006) and is likely
present in glia. The Cho peak is often viewed as a marker of membrane turnover
or inflammation in 1H MRS studies (Mueller et al., 2006).
Creatine. The Creatine (Cr) peak (3.0 ppm) is composed of creatine and
phosphocreatine. Together, these metabolites buVer the energy use and energy
storage of cells (Valenzuela and Sachdev, 2001). Cr is thought to exist primarily in
glia and in neurons to a lesser extent (Firbank et al., 2002) and is found in greater
108 GRIFFITH et al.

concentrations in human gray versus white matter (Mueller et al., 2006).

Cr concentration is often used as an internal standard because it is considered
to be relatively stable, showing slow increases with age (Firbank et al., 2002;
Valenzuela and Sachdev, 2001; however see Rosen and Lenkinski, 2007).
myo-Inositol. The myo-Inositol (mI) peak (3.56 ppm) represents the presence of
myo-Inositol, a sugar alcohol that is similar in structure to glucose, and myo-
Inositol phosphate (Valenzuela and Sachdev, 2001). These metabolites are located
primarily in glia, where they are speculated to function as osmoregulators, intra-
cellular messengers, and detoxifying agents (Valenzuela and Sachdev, 2001). mI is
highly concentrated in gliosing lesions (Firbank et al., 2002) and is one of the
products of myelin breakdown (Rosen and Lenkinski, 2007). Thus, the mI peak
is thought to represent an increase in glia density or an increase in glia size and
associated brain inflammation (Brand et al., 1993; Rosen and Lenkinski, 2007;
Strange et al., 1994; Valenzuela and Sachdev, 2001).
Scyllo-Inositol. The peak resonating at 3.342 ppm is thought to represent the
presence of scyllo-Inositol (sI), a product of mI metabolism (McLaurin et al., 2000).
The neurobiological function of sI as diVerentiated from mI is unclear.
Glutamate-Glutamine. The GLX peak (2.1-2.4 ppm) represents both glutamate
(Glu) and glutamine (Gln), which cannot be individually distinguished on 1.5 T
(Mueller et al., 2006) 1H MRS but is more reliably distinguishable at 3 T (Kantarci
et al., 2003; Schubert et al., 2004). Glu acts as the major excitatory neurotransmit-
ter in the brain, and Gln is thought to play a role in the regulation and detoxifica-
tion of glutamate (Valenzuela and Sachdev, 2001). Both Glu and Gln have been
implicated in neuronal function, metabolism, and plasticity (Antuono et al., 2001).
Cycling between Glu and Gln is believed to account for approximately 80% of
cerebral metabolism (Magistretti and Pellerin, 1999). Additionally, extracellular
glutamate is excitotoxic and is now a target of treatment in neurodegenerative
dementias (Riederer and Hoyer, 2006). However, the glutamate signal in brain
(Mueller et al., 2006) 1H MRS is thought to primarily represent the intracellular
compartment (Kickler et al., 2007).

III. 1H MRS Findings in Dementias

A. 1H MRS FINDINGS IN ALZHEIMER’S DISEASE

Dementia due to AD is the most common dementia aVecting older adults

(McMurtray et al., 2006). The neuropathology of AD consists of amyloid plaques
and neurofibrillary tangles that present in a characteristic pattern with early
involvement of the medial temporal lobes and hippocampus, with subsequent
spread to paralimbic and association cortical regions (Braak and Braak, 1991).
 1
H MRS IN DEMENTIAS AND MILD COGNITIVE IMPAIRMENT 109

Definitive diagnosis of AD requires microscopic neuropathological examination

and is most commonly made postmortem (Cummings et al., 1998). Thus, the
presence and pattern of cortical metabolic abnormalities are of potential clinical
value in identifying the underlying neuropathology of AD and discriminating this
disease from other dementias (Kantarci et al., 2008).
Reduction in NAA is the most frequent 1H MRS finding in AD (Adalsteinsson
et al., 2000; Chantal et al., 2002; Christiansen et al., 1995; Ernst et al., 1997;
Heun et al., 1997; Parnetti et al., 1997; Rose et al., 1999; SchuV et al., 1997; Watanabe
et al., 2002). Single voxel 1H MRS studies of AD have consistently found reduc-
tions in NAA/Cr in the hippocampus/medial temporal lobe (Chantal et al., 2002,
2004; Dixon et al., 2002; Jessen et al., 2000; SchuV et al., 1997; Watanabe et al.,
2002) and other temporal lobe regions (Frederick et al., 1997; Herminghaus
et al., 2003; Kantarci et al., 2000; Parnetti et al., 1997), and the midline parietal
lobe/posterior cingulate (Antuono et al., 2001; GriYth et al., 2007a; Hattori et al.,
2002; Herminghaus et al., 2003; Kantarci et al., 2000, 2002b, 2003; Martinez-
Bisbal et al., 2004; Rose et al., 1999), although two studies have failed to find
abnormal NAA measures in this latter region (Waldman and Rai, 2003;
Watanabe et al., 2002). Findings of reduced NAA have also been seen in the
temporal-parietal area (Chantal et al., 2002; Ernst et al., 1997; Parnetti et al., 1996),
occipital lobes (Kantarci et al., 2000; Moats et al., 1994; Shonk et al., 1995;
Waldman et al., 2002; Watanabe et al., 2002; Weiss et al., 2003), and frontal
lobes (Chantal et al., 2002, 2004; Christiansen et al., 1995; Herminghaus et al.,
2003; Parnetti et al., 1997). In keeping with the emerging understanding of NAA
as a marker for axonal viability as well as neuronal function (Valenzuela and
Sachdev, 2001), some studies have found reduced NAA in parietal lobe white
matter (Herminghaus et al., 2003; Moats et al., 1994) and subcortical white matter
(Catani et al., 2001; Hattori et al., 2002; Heun et al., 1997; MeyerhoV et al., 1994),
while others have not demonstrated this result (Catani et al., 2002; Watanabe et al.,
2002). Studies using a whole brain spectral or multispectral approach have
generally demonstrated reduced NAA in AD (Adalsteinsson et al., 2000;
PfeVerbaum et al., 1999), which is mainly observed in posterior gray matter
(Adalsteinsson et al., 2000; MacKay et al., 1996). Taken together, reports of
widespread reductions in NAA are highly consistent with the known progression
of neurofibrillary pathology of AD, which first is prevalent limbic cortical regions
but then progresses to primary sensory-motor and visual cortices in more
advanced stages (Braak and Braak, 1991).
A few studies to date have examined the pattern of changes in NAA over the
course of one year in AD. Two such studies have pointed toward relative declines
in NAA levels in AD patients (Adalsteinsson et al., 2000; Kantarci et al., 2007),
while two others found no significant within-subjects declines (Dixon et al., 2002;
Jessen et al., 2001) despite significantly lower NAA levels compared to older
controls at both time points in one study (Dixon et al., 2002). The indication
110 GRIFFITH et al.

of these few longitudinal studies is that NAA is potentially sensitive to the

progression of AD (Doraiswamy et al., 1998; Kantarci et al., 2007), although
more studies are desirable.
Some studies in AD patients have detected abnormal measurements of Cho
(Chantal et al., 2002, 2004; Jessen et al., 2000; Kantarci et al., 2000, 2003; Lazeyras
et al., 1998; MacKay et al., 1996; MeyerhoV et al., 1994), although results have been
inconsistent, with some studies finding reduced Cho levels in AD patients com-
pared to controls (Chantal et al., 2002, 2004; Jessen et al., 2000; Kantarci et al., 2000,
2003) and other studies finding elevated Cho levels (Lazeyras et al., 1998; MacKay
et al., 1996; MeyerhoV et al., 1994). A longitudinal study found that that Cho was
elevated in AD patients versus older controls at baseline, but that the annualized
rate of change in Cho did not diVer between these groups (Kantarci et al., 2007).
The reasons for diVerences in Cho findings across studies are unclear. Cho eleva-
tions may be a consequence of increased membrane turnover secondary to neuro-
degeneration. Alternatively, Cho levels may increase secondary to increased
membrane phosphatidylcholine catabolism, which may serve as a compensatory
mechanism against chronically reduced acetylcholine levels in AD (Kantarci et al.,
2007). Abnormal Cho levels in AD may also be due to reduced choline acetyl-
transferase activity secondary to cholinergic agonist treatment (GriYth et al., 2008c;
Kantarci et al., 2007). Alternatively, discrepant findings across studies may be due to
variations in 1H MRS methods, with studies using 1H MRS sequences with longer
echo times tending to find elevated Cho levels (Lazeyras et al., 1998; MacKay et al.,
1996), while those with shorter echo times finding lowered Cho levels (Chantal
et al., 2002, 2004; Kantarci et al., 2000, 2003). The location of the voxel of interest is
also likely to account for diVerences, with decreased Cho detected in the posterior
cingulate (Kantarci et al., 2000, 2003) and medial temporal lobe (Chantal et al.,
2002, 2004; Jessen et al., 2000), while increased Cho was detected in the posterior
gray matter (Lazeyras et al., 1998; MacKay et al., 1996) and gray matter of the
centrum semiovale (MeyerhoV et al., 1994).
Studies have frequently found abnormal elevations of mI in AD patients, most
often in the temporal-parietal area (Chantal et al., 2002, 2004; Ernst et al., 1997;
Parnetti et al., 1996), posterior cingulate gyrus/mesial parietal lobe (GriYth et al.,
2007a; Herminghaus et al., 2003; Kantarci et al., 2000, 2002b, 2003; Lazeyras
et al., 1998; Martinez-Bisbal et al., 2004; Rose et al., 1999; Waldman and Rai,
2003), parietal white matter (Herminghaus et al., 2003; Moats et al., 1994), and
occipital lobes (Moats et al., 1994; Shonk et al., 1995; Waldman et al., 2002).
Abnormal mI levels are detected less often in the frontal lobes (Chantal et al.,
2002, 2004; Herminghaus et al., 2003; Parnetti et al., 1997) and subcortical regions
(Catani et al., 2001, 2002; Hattori et al., 2002; Heun et al., 1997) in AD, which is
in agreement with the known regional distribution of AD neuropathology.
One study performed at 3 T failed to detect mI diVerences in the posterior
cingulate in AD patients (Hattori et al., 2002), possibly due to higher magnetic
 1
H MRS IN DEMENTIAS AND MILD COGNITIVE IMPAIRMENT 111

field inhomogeneity and susceptibility eVects compared to 1.5 T (Kantarci et al.,

2003). A longitudinal study conducted at 1.5 T found no diVerence in annual rate
of change in mI between AD patients versus older controls, although mI levels
were elevated in AD patients at baseline (Kantarci et al., 2007). Because of the
robustness of findings involving decreased NAA and increased mI in AD patients,
and because these two metabolites appear to represent independent markers of
disease progression (Doraiswamy et al., 1998), some researchers have used the
ratio of NAA/mI to increase the sensitivity of 1H MRS to metabolite changes in
AD (Kantarci et al., 2002b, 2003; Martinez-Bisbal et al., 2004; Parnetti et al., 1997;
Rose et al., 1999; Waldman and Rai, 2003; Weiss et al., 2003). Reduced NAA/mI
in AD versus healthy controls has been observed in the posterior cingulate
(Kantarci et al., 2002b, 2003), midline parietal lobe (Rose et al., 1999), and frontal
white matter (Parnetti et al., 1997), but not frontal gray matter (Kizu et al., 2004).
The majority of (Mueller et al., 2006) 1H MRS studies in AD have used Cr in
the denominator of the metabolic ratio (Antuono et al., 2001; Bartres-Faz et al.,
2002; Block et al., 2002; Catani et al., 2001, 2002; Chantal et al., 2004;
Christiansen et al., 1995; Dixon et al., 2002; Doraiswamy et al., 1998; Ernst et al.,
1997; Frederick et al., 1997; Hattori et al., 2002; Herminghaus et al., 2003; Heun
et al., 1997; Jessen et al., 2000, 2001; Kantarci et al., 2000, 2002b, 2003; Kattapong
et al., 1996; Lazeyras et al., 1998; MacKay et al., 1996; Martinez-Bisbal et al., 2004;
MeyerhoV et al., 1994; Rose et al., 1999; SchuV et al., 1997; Shonk et al., 1995;
Waldman and Rai, 2003; Waldman et al., 2002; Weiss et al., 2003), due to its
presumed invariance in brain disease (Valenzuela and Sachdev, 2001). Findings in
AD have generally indicated no increases or decreases in Cr compared to controls
(Ernst et al., 1997; PfeVerbaum et al., 1999; SchuV et al., 1997). However, some
have documented decreased Cr levels in AD patients versus normal controls in
the left mesial temporal lobe, parieto-temporal cortex (Chantal et al., 2002), and
occipital lobe gray matter (Moats et al., 1994).
The GLX peak has been investigated in a few studies of AD (Antuono et al.,
2001; Ernst et al., 1997; Hattori et al., 2002; Herminghaus et al., 2003; Moats et al.,
1994), more recently with MRI scanners at field strengths other than 1.5 T
(Antuono et al., 2001; Hattori et al., 2002). These studies have mostly reported
reduced GLX levels in AD patients compared to controls in the posterior cingu-
late (Antuono et al., 2001; Hattori et al., 2002), occipital lobe (Moats et al., 1994),
and the dominant-hemisphere lateral temporal cortex (Herminghaus et al., 2003),
although two studies have failed to find GLX diVerences in patients with AD
(Ernst et al., 1997; GriYth et al., 2008c).
Our group has performed one of the only studies to date systematically
investigating sI in AD. We identified elevated sI/Cr in the posterior cingulate of
AD patients, with MCI patients showing a trend toward elevation (GriYth et al.,
2007a); a prior study demonstrating raised concentrations of sI has been reported
in the normal aging human brain (Kaiser et al., 2005). The mechanism by which sI
112 GRIFFITH et al.

elevations occur in AD is unclear, although given that sI is a breakdown product

of mI metabolism, this finding may reflect the same processes involved in
increased mI. sI agonist treatment has been recently shown to inhibit AD-like
brain pathology in mice (Fenili et al., 2007).
Utility of (Mueller et al., 2006) 1H MRS for discriminating Alzheimer’s disease from
normal aging: 1H MRS has been used to discriminate AD patients from cognitively
healthy older adults (Antuono et al., 2001; Dixon et al., 2002; Ernst et al., 1997;
Kantarci et al., 2002b; MacKay et al., 1996; SchuV et al., 1997; Shonk et al., 1995).
Although an early study concluded that reproducibility and inter-rater error
limited the utility of 1H MRS as a clinical tool in AD (Heun et al., 1997), several
studies have since demonstrated that NAA can provide an adequate means of
discriminating normal controls from AD patients (Antuono et al., 2001; SchuV
et al., 1997; Shonk et al., 1995) or improve discrimination of AD using structural
neuroimaging variables (Dixon et al., 2002; Ernst et al., 1997; Kantarci et al.,
2002b; MacKay et al., 1996). Among (Mueller et al., 2006) 1H MRS metabolite
ratios, the NAA/mI ratio appears to best discriminate AD patients from normal
controls (Kantarci et al., 2007). The average accuracy of detecting AD with
1
H MRS is 87.75% (range 80-100%), and the average accuracy of identifying
normal controls is 75.25 (range 73-78%) (Antuono et al., 2001; Ernst et al., 1997;
MacKay et al., 1996; SchuV et al., 1997). Estimated sensitivity of 1H MRS to AD is
83%, with a specificity of 95%, positive predictive value of 98% and a negative
predictive value of 65% (Shonk et al., 1995). Using a fixed specificity of 80%, one
study reported a sensitivity of 82% for the NAA/mI posterior cingulate (Kantarci
et al., 2002b). An early longitudinal study that reported 70% correct classification
of AD with 1H MRS at baseline and 68% after 1 year for NAA of the left
hippocampus (Dixon et al., 2002). These results are consistent with a more recent
longitudinal study examining the discriminatory value of NAA levels of
the posterior cingulate in AD patients (Kantarci et al., 2007).
1
H MRS and neurocognitive, psychological, and IADL measures in AD: Several studies
have observed significant correlations between 1H MRS and cognitive severity in
AD as measured by a common mental status measure, the Mini Mental State
Examination (MMSE) (Antuono et al., 2001; Dixon et al., 2002; Doraiswamy et al.,
1998; Ernst et al., 1997; Heun et al., 1997; Jessen et al., 2000, 2001; Parnetti et al.,
1997; Rose et al., 1999; Waldman and Rai, 2003); although, other studies have
found no association between 1H MRS and MMSE (Block et al., 2002; Hattori
et al., 2002; Watanabe et al., 2002). Fewer studies to date have investigated the
relationships between other neurocognitive measures and 1H MRS in AD.
PfeVerbaum and colleagues (PfeVerbaum et al., 1999) reported negative correla-
tions of Cr with word recognition memory and negative correlations of Cho with
face recognition memory. Chantal and colleagues (Chantal et al., 2002) observed
significant positive correlations between NAA of the left medial temporal lobe and
verbal learning and recall. Negative correlations were detected between left
 1
H MRS IN DEMENTIAS AND MILD COGNITIVE IMPAIRMENT 113

parieto-temporal cortex Cr and a confrontational naming measure, and right

parieto-temporal cortex mI and a visual construction measure (Chantal et al.,
2002). One longitudinal study observed that in AD patients the annual percent
change in NAA/Cr ratios was positively associated with annual change on a com-
monly used mental status measure, the Dementia Rating Scale (DRS), and negatively
associated with change in a dementia severity rating scale, the Clinical Dementia
Rating (CDR) (Kantarci et al., 2007). These correlations were of comparable magni-
tude with correlations observed between the rate of change in MRI ventricular
expansion and clinical progression measures (Kantarci et al., 2007).
Other studies have investigated relationships between IADLs and 1H MRS
measures in AD. In a sample of mild AD patients, our group has demonstrated
that NAA/Cr shows a positive correlation with a measure of financial abilities,
while Cho/Cr showed a negative correlation with this same financial measure
(GriYth et al., 2007c). Antuono and colleagues (Antuono et al., 2001) observed
a significant correlation between GLX ratios from the posterior cingulate and an
informant-report measure of daily activities in patients with AD, indicating more
functional impairment as the GLX ratios decreased.
Postmortem neuropathologic correlates of in vivo 1H MRS in AD: A recent study
examined postmortem neuropathological correlates of antemortem 1H MRS
of the posterior cingulate and inferior precuneate gyri in healthy controls and in
low- or high-likelihood AD, who were classified based on standard neuropatho-
logic AD criteria (Kantarci et al., 2008). The NAA/Cr, mI/Cr, and NAA/mI
ratios diVered between the low-, intermediate-, and high-likelihood AD groups
after adjusting for age, sex, and time from 1H MRS to death. Moreover, NAA/mI
showed the strongest association with Braak neurofibrillary pathology staging,
suggesting that NAA and mI provide complimentary information regarding the
extent of disease involvement in AD patients. These results are consistent with a
prior study reporting a correlation between postmortem 1H MRS brain metabo-
lite measures and neurofibrillary tangles and senile plaques in brain tissue of AD
patients (Klunk et al., 1998). Thus, antemortem 1H MRS in patients with probable
AD appears to be a sensitive marker of underlying AD neuropathology.

B. 1H MRS FINDINGS IN AMNESTIC MILD COGNITIVE IMPAIRMENT

Amnestic MCI has emerged as the diagnostic classification to denote the

transitional phase between normal cognitive aging and AD (Petersen et al.,
2001). Diagnostic criteria for amnestic MCI include (1) subjective complaints of
memory loss, preferably confirmed by an informant, (2) objective impairment on
memory testing compared to age and educationally matched normative data,
(3) otherwise normal performance on other cognitive tests, and (4) generally
preserved activities of daily living (Petersen et al., 2001). Individuals with MCI
114 GRIFFITH et al.

progress to clinically probable AD more frequently than cognitively normal peers

(Ganguli et al., 2004; Petersen et al., 2001), with a rate of 10-17% annual progres-
sion compared to a rate of 1-2% per year in the general older adult population
(Ganguli et al., 2004; GriYth et al., 2006a; Petersen et al., 1999, 2000, 2001;
Storandt et al., 2002; Tierney et al., 1996).
Several cross-sectional (Mueller et al., 2006) 1H MRS studies have been
performed to date in patients with amnestic MCI. Kantarci and colleagues
(Kantarci et al., 2000) examined metabolic ratios in the left temporal lobe, the
posterior cingulate, and the medial occipital lobe of MCI and AD patients.
Patients with MCI diVered from controls only in significant increases of mI/Cr
in the posterior cingulate; compared to AD patients, MCI patients had signifi-
cantly lower cingulate mI/Cr ratios. The authors speculated that increased mI in
MCI patients reflected very early pathological changes (possibly gliosis) preceding
neuronal dysfunction, as would be indicated by decrements in NAA. Subsequent
1
H MRS studies in MCI patients have confirmed mI increases compared to
controls in the posterior cingulate (Kantarci et al., 2003; Rami et al., 2007a), left
hippocampus (Franczak et al., 2007), and other brain regions such as the bilateral
paratrigonal white matter (Catani et al., 2001) and parieto-temporal cortex
(Chantal et al., 2004; Rami et al., 2007a). Other studies, however, have not
found diVerences between mI levels in AD and MCI (Catani et al., 2001;
Chantal et al., 2004; Garcia Santos et al., 2008; Kantarci et al., 2003).
Other (Mueller et al., 2006) 1H MRS metabolic abnormalities in MCI patients
include a significant increase of Cho in the right frontal cortex and posterior
cingulate (Chantal et al., 2004; Kantarci et al., 2003), in addition to Cho and NAA
decreases in the left medial temporal lobe (Chantal et al., 2004). NAA decreases were
also found in the right hippocampus in a small group of MCI patients (Franczak et al.,
2007) and were reduced in the posterior cingulate of MCI patients compared to
controls, but not as severe as seen in AD patients (Kantarci et al., 2003). In contrast,
Ackl et al. (2005) detected equally reduced NAA/Cr in the hippocampus of MCI
patients and AD patients, although posterior cingulate metabolic abnormalities were
observed only in the AD patients. Other studies have not detected any NAA changes
in MCI (Garcia Santos et al., 2008; Kantarci et al., 2002a). Thus, the cross-sectional
data generally indicates that metabolic brain abnormalities in MCI are transitional
between normal metabolism observed in healthy older adults and abnormalities
seen in AD. The pattern of findings generally concurs with the known early
neuropathology of AD (Braak and Braak, 1991; Markesbery et al., 2006).
To our knowledge, only two studies have investigated longitudinal metabolic
changes measured by 1H MRS in MCI patients (Bartnik Olson et al., 2008;
Kantarci et al., 2007). Kantarci and colleagues (Kantarci et al., 2007) reported
declines in NAA/Cr of the posterior cingulate in MCI and AD patients on scans
occurring approximately 1 year apart. There was a similar rate of decline in NAA
for MCI patients who converted to AD versus those patients who remained stable.
 1
H MRS IN DEMENTIAS AND MILD COGNITIVE IMPAIRMENT 115

No changes were observed in mI/Cr. Interestingly, Cho/Cr levels declined

in MCI patients who remained stable, suggesting to these authors that a compen-
satory cholinergic mechanism explained the stability of these non-converter MCI
patients. This result appears consistent with the recent finding that MCI con-
verters exhibited elevated Cho/Cr compared to non-converters at baseline (Rami
et al., 2007b). In a second longitudinal study, Bartnik Olson and colleagues
(Bartnik Olson et al., 2008) found increases of mI concentrations in the posterior
cingulate gyrus occurring over an average interval of 11 months, but non-
significant interval increases in NAA or Cho concentrations. Discrepant findings
between these two longitudinal studies may be due to the fact that Bartnik et al.
used a method to model spectral components to quantify metabolite levels, while
Kantarci and colleagues used metabolic ratios as obtained automatically following
acquisition on a General Electric (GE) scanner.
1
H MRS and neurocognitive measures in MCI: Kantarci and colleagues (Kantarci et al.,
2002a) performed correlations between a global measure of cognition (DRS) and a
measure of auditory verbal learning (AVLT) with posterior cingulate 1H MRS ratios
of NAA/Cr, NAA/mI, and mI/Cr. All three ratios were significantly correlated with
the DRS and to a lesser extent with the AVLT. Ackl and colleagues indicated that
hippocampal NAA/Cr correlated with verbal fluency and confrontation naming,
but interestingly not with memory, in a mixed MCI and AD group (Ackl et al., 2005).
Posterior cingulate 1H MRS correlated with a wider range of cognitive measures.
We very recently reported that visual executive function, as measured by clock
drawing, was negatively correlated with mI/Cr in amnestic MCI patients (GriYth
et al., 2007b). Furthermore, mI/Cr ratios accounted for 26% of the variance in clock
drawing scores after accounting for overall cognition, age, and other potential
confounding variables through stepwise multiple regression analysis.
1
H MRS predictors of dementia in MCI: Studies have indicated that baseline
NAA/Cr can predict subsequent progression, or ‘‘conversion,’’ from MCI to
AD with high sensitivity and specificity. A recent study indicated that baseline
NAA/Cr of the occipital lobe was able to discriminate amnestic MCI converters
from non-converters over a mean follow-up period of 3 years, with 100% sensi-
tivity and 75% specificity (Modrego et al., 2005). Another recent study reported
that MCI patients who converted to dementia within a 1-year follow-up showed
reduced NAA/Cr of the left paratrigonal white matter compared to stable MCI
patients (Metastasio et al., 2006). A third study concluded that NAA/Cr ratios in
both the posterior cingulate gyrus and left occipital cortex predicted conversion
with a sensitivity of about 80% and a specificity of about 70%. In general, these
studies suggest that 1H MRS may prove valuable in identifying patients with MCI
who are at risk for dementia conversion, although participant selection issues
limit the validity of the current studies, including the operational criteria for
MCI (Modrego et al., 2005) and extremely high conversion rates over 1 year
(Metastasio et al., 2006).
116 GRIFFITH et al.

C. 1H MRS FINDINGS IN FRONTOTEMPORAL DEMENTIA

FTD refers to a heterogeneous group of clinical syndromes involving progres-

sive neurodegeneration of the frontal and/or temporal lobes, including gliosis,
neuron loss, and vacuolation of surface cortical layers (Coulthard et al., 2006;
Ernst et al., 1997).
Findings of metabolic profiles in FTD patients compared to controls have
shown metabolic abnormalities in many brain cortical regions. One study inves-
tigated (Mueller et al., 2006) 1H MRS located in the temporal, frontal, and parietal
lobes and found lower ratios of NAA/Cr in the temporal and frontal lobe voxels,
in addition to an increased mI/Cr ratio in the frontal lobe voxel (Coulthard et al.,
2006). No 1H MRS abnormalities were observed in the parietal lobes (Coulthard
et al., 2006). Other 1H MRS studies suggest that the spatial distribution of brain
metabolic abnormalities of FTD patients diVers from that of AD patients.
One such study found reduced NAA and Glx and increased mI in mid-frontal
gray matter in FTD patients versus AD patients and healthy controls, whereas a
trend toward significantly increased mI in the temporoparietal gray matter was
observed in AD versus FTD patients (Ernst et al., 1997; also see Mihara et al., 2006).
Studies have reported the correspondence of 1H MRS abnormalities with
clinical and cognitive measures in patients with FTD, highlighting the clinical
importance of these metabolic abnormalities. Clinical/functional measures (i.e.,
CDR and the MMSE) have been associated with NAA and mI in the frontal
region and mI and Glx in the temporopartietal region in a group of FTD and AD
patients and healthy controls (Ernst et al., 1997). Rami et al. (2008) also reported
associations of naming ability with NAA/Cr and Cho/Cr ratios in the left
temporal pole, but not the left temporoparietal region, after controlling for
MMSE scores across a sample of FTD, MCI, and AD patients, and heathy
controls.

D. 1H MRS FINDINGS IN VASCULAR DEMENTIA

VAD results from one or a combination of cerebrovascular mechanisms that

cause degenerative changes in the brain, including infarcts, white matter lesions,
and resultant atrophy (Wiederkehr et al., 2008). Diagnosis of VAD presents a
challenge clinically due to its etiological heterogeneity, variable clinical manifes-
tation, and co-occurrence with AD pathology (only 10% of dementia cases show
pure vascular pathology on postmortem brain examination) (Holmes et al., 1999;
Jones and Waldman, 2004).
1
H MRS has revealed widespread brain metabolic abnormalities in VAD
patients. In one study, Herminghaus et al. (2003) measured spectra from voxels in
five brain regions: mid-parietal gray and white matter, mid-frontal gray and white
 1
H MRS IN DEMENTIAS AND MILD COGNITIVE IMPAIRMENT 117

matter, and the temporal gyrus mixed gray/white matter. Compared to healthy
controls, VAD patients exhibited global reductions in NAA/Cr ratios in all voxels,
along with elevations in mI/Cr ratios in parietal gray and white matter, frontal
white matter, and the temporal lobe, and elevations in Glx ratios in parietal gray
matter and the temporal lobe. In another study, Kantarci and colleagues
(Kantarci et al., 2004) reported that in the posterior cingulate VAD patients
had lower ratios of NAA/Cr, but normal ratios of mI/Cr and Cho/Cr, when
compared with healthy controls. These studies suggest that VAD involves multiple
neuropathological processes, even in regions distant from actual vascular pathol-
ogy (Kantarci et al., 2004), including neuronal dysfunction/loss, axonal damage,
myelin loss, and gliosis ( Jones and Waldman, 2004). Kantarci et al. (2004) have
speculated that reductions in NAA in distal brain areas may be secondary to
retrograde Wallerian degeneration caused from brain regions showing actual
vascular neuropathology.

E. 1H MRS FINDINGS IN DEMENTIA WITH LEWY BODIES

The cardinal features of DLB include progressive cognitive decline, along

with fluctuations in alertness and attention, persistent visual hallucinations, and
spontaneous parkinsonian motor symptoms, including rigidity and the loss of
spontaneous movement (McKeith et al., 2005). Of note, DLB patients exhibit a
striking reduction in cortical acetylcholine activity relative to AD patients
(Tiraboschi et al., 2000).
A relative paucity of 1H MRS studies has examined patients with DLB, and
their findings have been variable. Molina et al. (2002) initial study in this patient
population found decreased NAA/Cr, Cho/Cr, and Glx/Cr ratios in DLB
patients versus healthy controls in white matter from the left centrum semiovale,
but did not find significant metabolite diVerences in gray matter from the midline
parietal region. This study also found no correlations of any metabolite levels with
clinical measures (age at onset and disease duration) or measures of cognitive and
motor impairment, a result that is consistent with a prior neurochemical study
which failed to find a relationship between reductions in acetylcholine activity and
cognitive impairment in DLB (Tiraboschi et al., 2000). In contrast, a more recent
study found elevated NAA/Cr ratios in the left and right hippocampus in DLB
patients versus controls but did not find group diVerences in Cho/Cr ratios,
although their sample size was somewhat limited (n ¼ 8 in both groups) (Xuan
et al., 2008). Kantarci et al. (2004) reported elevated Cho/Cr ratios in a voxel
encompassing the posterior cingulate gyrus of DLB patients versus healthy
controls, but did not find group diVerences in NAA/Cr or mI/Cr ratios.
The data on 1H MRS findings in DLB are sparse and variable. In some
respects, these variable findings are similar to those of postmortem pathological
118 GRIFFITH et al.

studies on DLB, which have yielded inconsistent findings regard to neuronal loss
in DLB (Cordato et al., 2000; Gomez-Isla et al., 1999). Moreover, methodological
diVerences, including diVerences in symptom severity of patients, voxel place-
ment, and (Mueller et al., 2006) 1H MRS acquisition parameters (e.g., short versus
long echo time), may also account for some of the variable results across
these studies.

F. 1H MRS FINDINGS IN PARKINSON’S DISEASE DEMENTIA

Dementia observed in patients with Parkinson’s disease can manifest from a

variety of clinical and neuropathological entities, including diVuse Lewy body
pathology (Galvin et al., 2006), AD (Galvin et al., 2006), and isolated Lewy
body pathology of the substantia nigra (Galvin et al., 2006; Pletnikova et al.,
2005). A specific dementia in patients with Parkinson’s disease, termed PD with
dementia (PDD), involves the onset of a progressive dementing illness at least
1 year subsequent to the onset of the movement disorder (McKeith et al., 2005).
PDD is believed to be clinically (Benecke, 2003), cognitively (Aarsland et al., 2003),
neuropsychologically (Litvan et al., 1991), and neuropathologically (Kovari et al.,
2003) distinct from that of patients with DLB (Benecke, 2003) and patients with
AD and late motor complications (Dickson, 2000).
1
H MRS findings indicate that PDD patients exhibit abnormal brain metab-
olism as compared against healthy controls and nondemented PD patients. Initial
1
H MRS studies in PDD examined metabolite levels in the occipital cortex. These
studies found reductions in NAA levels in PDD patients versus nondemented PD
patients, but not healthy controls (Summerfield et al., 2002), and elevations in
lactate levels in PDD patients versus both nondemented PD patients and healthy
controls (Bowen et al., 1995), although similar lactate abnormalities have not been
documented subsequently (Firbank et al., 2002). More recent 1H MRS studies by
our group have investigated metabolism of the posterior cingulate gyrus, which
shows neuropathological changes in postmortem PDD studies (Braak et al., 2004)
and abnormal blood flow (Osaki et al., 2005) and dopamine transmitter alterations
(Brooks and Piccini, 2006) in antemortem PDD imaging studies. Consistent with
these post- and antemortem studies, 1H MRS of the posterior cingulate gyrus in
PDD has revealed reduced NAA/Cr ratios in PDD patients versus healthy controls
(GriYth et al., 2008a,c) and nondemented PD patients (GriYth et al., 2008a),
in addition to reduced Glu/Cr versus healthy controls (GriYth et al., 2008c).
Whereas lower NAA levels presumably reflect compromised functional integrity
of neurons in the posterior cingulate gyrus and occipital lobe in PDD, lower
Glu reductions could plausibly reflect other aspects of the PDD disease process,
such as downregulation of glutaminergic cortical eVerents from the basal ganglia to
the posterior cingulate gyrus (GriYth et al., 2008c).
 1
H MRS IN DEMENTIAS AND MILD COGNITIVE IMPAIRMENT 119

Of note, 1H MRS-derived NAA and Glu measures in the posterior cingulate

gyrus appear to be able to discriminate PDD patients from nondemented PD
patients. The NAA/Cr ratio has shown high sensitivity and reasonable specificity
in correctly discriminating individuals with PDD from PD and healthy controls
(GriYth et al., 2008a). Moreover, both NAA and Glu levels have shown modestly
strong correlations with mental status measures (MMSE and DRS scores) in PDD
(GriYth et al., 2008a,c). Future longitudinal 1H MRS studies determining whether
these brain metabolic abnormalities precede the clinical manifestation of PDD
appear warranted.

G. UTILITY OF 1H MRS FOR DISCRIMINATING AMONG DEMENTIAS

Studies have sought to compare the sensitivity and specificity of brain

metabolic profiles in discriminating among neurodegenerative dementias. Most
all of these studies have compared patients with AD to another dementia, a
question that is of clinical value given the high prevalence of AD (McMurtray
et al., 2006). Ernst and colleagues (Ernst et al., 1997) found that FTD patients
could be discriminated from AD patients and controls using a combination of
NAA and Cr values from the mid-frontal and left temporoparietal region, with
accuracy of detecting FTD of 92% and an accuracy of detecting AD of 82%.
Shonk et al. (1995) indicated that NAA/Cr of the occipital lobe detected
AD from FTD with a sensitivity of 82%, specificity of 64%, positive predictive
value of 74% and a negative predictive value of 80%. Other studies have found
no diVerences on (Mueller et al., 2006) 1H MRS between AD and FTD patients.
For example, a recent study found reduced NAA/Cr levels and increased
mI/Cr levels in the posterior cingulate gyrus in both FTD patients and AD
patients when compared with healthy controls (Mihara et al., 2006). Several
other studies have found that metabolite concentrations did not diVer signifi-
cantly between FTD and AD patients (Garrard et al., 2006; Kantarci et al., 2004;
Kizu et al., 2004).
Other studies have attempted to distinguish between VAD and AD using
1
H MRS. Patients with VAD, when compared to patients with AD, show reduced
NAA/Cr ratios in frontal gray matter and subcortical white matter, and elevated
mI/Cr in frontal white matter (Herminghaus et al., 2003; Kattapong et al., 1996;
Martinez-Bisbal et al., 2004). In comparison, patients with AD show increased
mI/Cr in the posterior cingulate gyrus (Kantarci et al., 2004; Martinez-Bisbal
et al., 2004) and occipital lobe (Rai et al., 1999; Waldman et al., 2002), as well as
increased Cho/Cr of the posterior cingulate (Martinez-Bisbal et al., 2004), when
compared with VAD patients. One study reported an 83% classification accuracy
for AD and 71% accuracy for VaD using NAA measures from whole brain gray
matter (MacKay et al., 1996), while a second study comparing patients with
120 GRIFFITH et al.

AD, VaD, MCI, and major depression reported that the NAA/mI ratio had an
81.5% sensitivity and 72.7% specificity for discriminating AD from the other
groups (Martinez-Bisbal et al., 2004).
We are aware of only two studies to date that have compared 1H MRS
across patients with Parkinson-spectrum dementias to patients with other
dementias. Kantarci and colleagues (Kantarci et al., 2004) reported that patients
with DLB had normal NAA/Cr ratios when compared to patients with AD and
patients with FTD; patients with DLB also had normal mI/Cr ratios compared
to patients with FTD. No diVerences were observed between DLB patients and
patients with VAD. GriYth and colleagues (GriYth et al., 2008c) very recently
reported that patients with PDD showed abnormally low Glu/Cr ratios when
compared with patients with AD, while patients with AD showed a trend toward
higher mI/Cr ratios when compared with patients with PDD. The Glu/Cr ratio
was able to discriminate between AD and PDD at rates greater than chance.
No studies to date that we are aware of have compared (Mueller et al., 2006)
1
H MRS between patients with DLB versus patients with PDD, although
both dementias show considerable clinical and neuropathological overlap
(Galvin et al., 2006).

H. UTILITY OF 1H MRS FOR MONITORING TREATMENT EFFECTS IN DEMENTIAS

A few studies have used 1H MRS to assess responses to pharmacological

treatment in AD patients. Krishnan et al. (2003) reported that NAA levels in
subcortical gray matter and periventricular white matter increased following
12 weeks of therapy with donepezil, a cholinesterase inhibitor. Jessen and collea-
gues ( Jessen et al., 2006) observed changes in NAA/Cr, Cho/Cr and mI/Cr ratios
associated with donepezil treatment; the 1H MRS changes were also associated
with improvement on the Alzheimer’s Disease Assessment Scale-cognitive sub-
scale (ADAS-cog), a commonly used measure of treatment eVects in AD.
In contrast, Bartha et al. (2008) found a decrease in NAA levels, along with a decrease
in mI levels, in the right hippocampus following 16 weeks of donepezil treatment.
In another study, 4 months of treatment with the cholinesterase inhibitor rivas-
tigmine was associated with an increase in NAA/Cr in the frontal lobe in AD
patients versus untreated AD patients; there was an association reported between
the metabolite changes and modest clinical improvement in the treatment
group (Modrego et al., 2006). A study investigating the eVects of treatment with
xanomeline, a cholinergic agonist, have found associations between pre- and
posttreatment changes in NAA/Cr, Cho/Cr, and mI/Cr ratios and changes in
ADAS-cog scores (Frederick et al., 2002). These studies suggest that 1H MRS has
the potential to monitor disease modifying treatment eVects that are correlated
with clinical outcome measures.
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H MRS IN DEMENTIAS AND MILD COGNITIVE IMPAIRMENT 121

The ability of 1H MRS to quantify therapeutic eVects in dementias other than

AD is unknown. One study investigated the eVect of argatroban therapy, a potent
selective thrombin inhibitor, on brain metabolite levels in peripheral arterial
occlusive disease patients, two of whom were diagnosed with VAD (Kario et al.,
1999). Prior to argatroban therapy, patients with silent cerebrovascular disease
had decreased NAA/Cr in the deep white matter. However, NAA/Cr ratios
increased significantly in patients with silent cerebrovascular disease following
argatroban therapy, accompanied by improved scores on the MMSE and
improvements in activities of daily living in the two VAD patients. While this
study highlights the potential importance of 1H MRS in the monitoring of
therapeutic eVects, continued study in larger samples of VAD and with other
therapeutic agents is clearly needed.

IV. Discussion

The use of 1H MRS as a clinical investigative tool in neurodegenerative

dementias has yielded a body of findings that could prove important for research
into the causes and treatments of dementias. While there have been some
methodological and technical advances in 1H MRS over the years, there have
been relatively consistent findings in studies of AD, providing evidence of the
stability of this technique as a potential biomarker. The emergence of studies in
other dementias, and comparative studies across dementias, has also proved
worthwhile. Nonetheless, several important issues remain to be addressed.
Across 1H MRS studies, some common findings have emerged that engender
confidence in the interpretation of brain metabolic abnormalities in dementias.
One such finding has been the nearly ubiquitous observation of reduced cortical
NAA in almost all of the major dementing illnesses (with the notable exception of
DLB in one study (Kantarci et al., 2004)). Reduction in NAA has been observed in
all major lobes of the brain as well as in the hippocampus. While NAA reduction
is primarily observed in gray matter, white matter NAA abnormalities have also
been reported. These results reify the interpretation of NAA as a marker of
neuronal and axonal integrity in dementias. NAA ratios have also shown strong
correspondence with postmortem neuropathology in AD (Kantarci et al., 2008),
presumably because higher levels of AD neuropathology correspond to greater
loss of neuronal function. However, as reduced NAA is observed in dementias
such as FTD, where there is no AD neuropathology, it is clear that NAA
abnormalities are not specific eVects of AD neuropathology alone, but are
rather sensitive to any form of neuropathology that is detrimental to neuronal
functioning. The use of NAA in combination with other 1H MRS metabolites
(such as mI) might improve the specificity of 1H MRS to detect specific forms of
122 GRIFFITH et al.

neuropathology (Kantarci et al., 2008). An advantage of 1H MRS is that data can

be collected on several metabolites simultaneously, and thus can be used to
determine metabolic profiles that could discriminate among dementias (GriYth
et al., 2008c; Kantarci et al., 2004).
The sensitivity of 1H MRS to detect dementias has been investigated in a few
studies, showing generally good ability to discriminate between dementias and
normally functioning individuals. However, 1H MRS may hold the most promise
as a means to identify earlier (preclinical) patients at risk for dementia, or
completely asymptomatic individuals, who could then be the target for early
intervention studies. The emerging body of findings in patients with amnestic
MCI, some of whom progress to have clinically probable AD, indicates that
1
H MRS might be sensitive to the metabolic eVects of neurodegenerative diseases
prior to their clinical identification. An exciting area of development has been the
identification of 1H MRS abnormalities in patients who are at genetic risk of AD
but who are otherwise completely asymptomatic, suggesting that brain metabolic
abnormalities predate identification of cognitive deficits in these patients (Godbolt
et al., 2006). Cortical 1H MRS changes that occur in patients with PD and no
dementia (GriYth et al., 2008b) resemble those reported in PDD patients (GriYth
et al., 2008c), suggesting that 1H MRS may be helpful in determining risk of
dementia in PD.
Longitudinal studies are slowly emerging to support the use of 1H MRS as a
means to track progressive brain metabolic changes. At least one study has
demonstrated that 1H MRS can be reliably obtained within the same partici-
pants at diVerent time points (Rose et al., 1999). A few longitudinal studies have
been conducted to date in AD and MCI, although other dementias have not yet
been investigated with longitudinal 1H MRS. The findings of these longitudinal
studies suggest that change in NAA corresponds well with change in clinical
status of AD, and thus possibly could be used to measure disease progression
with less error than is seen with clinical instruments such as the ADAS-cog
(Mueller et al., 2006). Some studies have employed 1H MRS to measure treat-
ment eVectiveness in AD and shown links to modest cognitive improvement with
improving metabolism. However, correspondence with clinical outcomes other
than cognitive change, such as status of daily functional activities, is desirable to
anchor 1H MRS changes to real-world outcomes. Two cross-sectional studies
have reported a correspondence between 1H MRS and daily activities in AD
(Antuono et al., 2001; GriYth et al., 2007c); these findings suggest that change in
1
H MRS would correspond to declines in complex daily activities. Clearly, a
better understanding of the longitudinal course of brain metabolic abnormalities
in dementias, and the associations of these metabolic abnormalities with cogni-
tive and daily functional changes, is essential to pursuing 1H MRS as a measure
of treatment outcomes.
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The search for viable biomarkers of dementing illnesses is critical for develop-
ment of new treatments. Mueller and colleagues outlined their six criteria for a
viable biomarker of treatment eVects in patients with dementias: (1) links between
the markers and treatment outcomes, (2) test-retest reliability; (3) sensitivity to
desired stage of treatment; (4) link to the biomarker and amyloid burden, (5) non-
invasiveness and tolerability; and (6) availability and cost (Mueller et al., 2006).
In considering 1H MRS in light of these criteria, the current state of the literature
suggests that several of the criteria are being approached. 1H MRS appears to
have some links to potential measurable outcomes, in that studies have reported
associations with cognitive functioning and instrumental daily activities, as well as
showing sensitivity to treatment eVects. Test-retest reliability has been supported
in at least one study, although interscan variability may not be at the desired level
for reliable use in individual patients. Studies in 1H MRS of preclinical dementias
have shown that early metabolic changes are observable at the stage when
treatment is most desirable (Petersen, 2004). 1H MRS is arguably among one of
the most widespread imaging modalities, in that many of the MRI scanners
commercially available have the capability of collecting 1H MRS data, although
subsequent data processing and interpretation require expertise. In our experi-
ence, 1H MRS is well tolerated in patients with mild to moderate stages of
dementia as well as individuals with movement disorders.
The link of 1H MRS with amyloid burden, one of the Mueller et al. (2006)
criteria, is questionable. While amyloid deposition is clearly correlated with NAA
and mI levels in patients with AD, abnormalities in these metabolites are also seen
in non-amyloid neuropathologies such as FTD. 1H MRS can likely play a role as
a marker of neuronal integrity with sensitivity to a number of neuropathologies
(i.e., Lewy bodies, tauopathies, cerebrovascular disease) rather than having a
specificity to amyloid. Given that questions have arisen as to the key role that
amyolid deposition plays in the dementing process in AD (Arends et al., 2000;
Dickson, 1997; Terry et al., 1991), the importance of an amyloid biomarker over a
biomarker of neuronal health is debatable.
Future directions in 1H MRS of dementias should focus on developing stable
and reliable longitudinal techniques and applying these to investigate longitudinal
changes, especially in dementias other than AD as well as longitudinal comparative
studies of AD with other dementias. Measuring correspondence of change on
clinical and functional measures with changes in 1H MRS measures is also
needed. In addition, studies are needed to further investigate whether 1H MRS
measures are sensitive to medication eVects, such as cholinesterase inhibitor use,
in patients where these treatments are considered to be beneficial. The association
of 1H MRS measures with imaging of amyloid, such as comparison with the
Pittsburgh B Compound PET procedure (Klunk et al., 2004), would be beneficial.
Lastly, as technological advances occur it would be worthwhile to expand from
124 GRIFFITH et al.

single-voxel approaches to 2D and 3D 1H MRS imaging to better understand

the extent of 1H MRS abnormalities in dementias. Such developments will
hopefully prove to benefit the search for eVective treatments of dementias in the
twenty-first century.

Acknowledgments

Funding was provided by grants from the National Institute of Aging (Alzheimer’s Disease
Research Center—1P50 AG16582-01: Harrell, PI; 1R01 AG021927-01: Marson, PI) and Alzheimer’s
of Central Alabama.

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APPLICATION OF PET IMAGING TO DIAGNOSIS OF ALZHEIMER’S
DISEASE AND MILD COGNITIVE IMPAIRMENT1

James M. Noble*,y,z and Nikolaos Scarmeasy,z

*Department of Neurology, Harlem Hospital Center, Columbia University College of Physicians
and Surgeons, New York 10037, USA
y
Department of Neurology, Columbia University Medical Center, New York 10032, USA
z
Gertrude H. Sergievsky Center, and the Taub Institute for Research on Alzheimer’s Disease
and the Aging Brain, Columbia University Medical Center, New York 10032, USA

I. Background
A. Neurobiology of Alzheimer Disease
B. Epidemiology of Alzheimer Disease
C. [18F]2-Fluoro-2-Deoxy-D-Glucose
D. Pittsburgh Compound B-PET
II. Application of PET to Primary and Specialty Care Settings
A. Diagnostic Workup of Dementia in Primary Care
B. Diagnostic Workup of Dementia in Specialty Care Settings
III. Appropriate Use of PET
A. Using Likelihood Ratio Tables
B. Using a Likelihood Ratio ‘‘Mnemonic’’
C. Using Bayesian Calculations
D. Conclusions from Using the Likelihood Ratios for PET and AD
IV. Summary
References

Alzheimer disease (AD) is the most common type of dementia and will become
increasingly prevalent with the growing elderly population. Despite established
clinical diagnostic tools, the workup for dementia among primary caregivers can
be complicated and specialist referral may not be readily available. A host of AD
diagnostic tests has been proposed to aid in diagnosis, including functional
neuroimaging such as positron emission tomography (PET). We review the
basis for FDG-PET and PiB-PET, as well as available operating statistics. From
this we advise scenarios for use of PET in primary settings and referral centers,
approach to its interpretation, and outline a clinical prediction model based on
findings.

1
Disclosures: Neither Drs. Noble nor Scarmeas have any relevant conflicts of interest.

INTERNATIONAL REVIEW OF 133 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00407-3 0074-7742/09 $35.00
134 NOBLE AND SCARMEAS

I. Background

Dementia is a common disorder among the elderly, becomes more prevalent

with advancing age, is typically medically refractory, reduces life expectancy, and
diminishes quality of life for patients and their caregivers. Worldwide 600 million
people are over the age of 60 and that number is expected to double by 2025
(UN, 2003). Of those over age 60, approximately 26 million people have dementia
of any type (Wimo et al., 2007), and as the population ages, this is projected increase
to 80 million by the year 2040 (ADI, 2006). The costs of care are staggering, with a
current annual worldwide health cost estimated at $300 billion (Wimo et al., 2007).
Despite the high prevalence of dementia among the elderly, the diagnostic
workup can be complicated, time consuming, and diYcult to interpret, particu-
larly in the primary care setting. In this manuscript, we will review the biologic
basis of positron emission technology (PET) in the diagnostic workup of Alzheimer
disease (AD) and its symptomatic prodrome, mild cognitive impairment (MCI),
as well as outline current recommendations for use PET, and identify its main
limitations to improve appropriate selection of patients.

A. NEUROBIOLOGY OF ALZHEIMER DISEASE

Abnormal accumulation of beta-amyloid (A!) peptide is widely believed to be the

underlying mechanism of pathologic and clinical changes seen in AD (Cummings,
2004). Changes typically begin in the transentorhinal and entorhinal cortex as well as
the hippocampus (Delacourte et al., 1999), and thus earliest impairments occur with
episodic memory deficits. Despite extensive neuropathologic changes, some patients
may remain asymptomatic in a prodromal state of AD (Dubois et al., 2007). Alterna-
tively, some patients develop cognitive complaints and have objective cognitive
impairment but no functional decline in level of activities of daily living, and these
are classified as MCI (Petersen et al., 2001). As disease progresses, other brain
structures become involved, initially temporal cortex and later parietal and frontal
association cortices, and finally primary motor and sensory cortices and the neocor-
tex (Delacourte et al., 1999). Symptomatically, patients progress from episodic mem-
ory loss to additional, progressive deficits in visuospatial and semantic abilities, mood
and behavioral disorders, and an eventual vegetative state.

B. EPIDEMIOLOGY OF ALZHEIMER DISEASE

Alzheimer disease (AD) is the most common type of dementia, representing

60–70% of all patients with dementia. The prevalence increases with age from
approximately 3–5% for those under 75, 15–18% for those age 75–84 years, and
 APPLICATION OF PET IMAGING IN AD AND MCI 135

45% for those older than 85 years (Alzheimer’s Association, 2008; Gurland et al.,
1999; Hebert et al., 2003; Mayeux, 2003b). In the US alone, an estimated 5.2
million have AD in 2008 and this may increase to 13.2 million by 2050
(Alzheimer’s Association, 2008). Sporadic AD represents 98% of all AD cases and
is likely due to a complex interaction of environmental, vascular, and genetic risk
factors (Mayeux, 2003a; Tang et al., 1998).
The epidemiologic data for patients at risk for late onset AD are equally
daunting. In the US alone, 25 million persons are over the age of 65 (18 million
aged 65–74 years, 12 million aged 75–84 years, and 4 million aged 85 years and
over) (He et al., 2005). Before developing AD, many patients may transition
through amnestic MCI (Petersen et al., 2001), or memory complaints with com-
mensurate objective neuropsychological test deficits, but without appreciable
impact in general cognition or daily independent function.
MCI portends to a significantly increased annual risk of conversion to AD
compared to others in their age group (Manly et al., 2008; Petersen et al., 2001).
In a multiethnic urban American population, amnestic MCI (including single or
multiple domain impairment) is prevalent in 3.8% of nondemented elderly aged
65–75 and in 6.3% of those over 75 years of age (Manly et al., 2005). Overall, most
studies suggest that MCI patients have an annual conversion rate (i.e., progres-
sion) to AD of approximately 10–15% per year (Morris et al., 2001; Petersen et al.,
1999). Recently, age-stratified data from our center have suggested that of normal
elderly individuals, the annual conversion rate from normal cognition to amnestic
MCI is 1.1% of those aged 65–69 years, 2.1% aged 70–74, 2.2% aged 75–79, and
3.4% aged 80 years and above. Moreover, among those with amnestic MCI, the
annual conversion rate to AD is 3.2% of those aged 65–69, 4.5% aged 70–74,
9.7% aged 75–79, and 11.1% aged 80 years and above (Manly et al., 2008).

C. [18F]2-FLUORO-2-DEOXY-D-GLUCOSE

Positron emission tomography (PET) enables imaging of biological activity,

and thus can identify abnormal biological activity in a host of diseases. Regional
diVerences in brain glucose metabolism using PET have been explored in demen-
tia, and [18F]2-fluoro-2-deoxy-D-glucose (FDG-PET) has become the most widely
investigated radioligand since the first descriptions of cerebral metabolism in
dementia over two decades ago (Benson et al., 1981; Farkas et al., 1982;
Friedland et al., 1983; Phelps et al., 1982). Glucose hypometabolism identified in
FDG-PET is thought to represent two findings: (1) local decreases in synaptic
activity or synaptic dysfunction in neurons aVected by Alzheimer type pathologi-
cal changes and (2) decreased synaptic activity in regions receiving projections
from these primary, diseased neurons (Friedland et al., 1985; HoVman et al.,
2000; Matsuda, 2007; McGeer et al., 1986a,b, 1990a,b; Mielke et al., 1996).
136 NOBLE AND SCARMEAS

Thus, abnormalities in regional cerebral metabolism are thought to reflect the

pattern of neuropathologic development of AD with early prominent AD changes
in the medial temporal cortex and its projections to cingulate and parieto-
temporal association cortices (Brun and Englund, 1986); although, all of these
structures may become pathologically involved with disease progression (Braak
and Braak, 1991).
Similarly, patients with MCI, with many in the earliest stages of AD change,
may only have glucose hypometabolism in the medial temporal cortex (de Leon
et al., 2001; Nestor et al., 2003). MCI patients with additional glucose hypometa-
bolism in the parietal association cortex may be at greater risk for subsequent
conversion to AD (Chetelat et al., 2003; Mosconi et al., 2004).
Despite the relatively lengthy history of FDG-PET in dementia, its clinical
utility was not fully appreciated until relatively recently. The last American
Academy of Neurology Practice Parameter for the diagnosis of dementia was
released in 2001, at a time prior to any reports of PET operating statistics from
large studies. In that report, PET was thought to ‘‘have promise for use as an
adjunct to clinical diagnosis,’’ but further studies were required ‘‘to establish the
value that it brings to diagnosis over and above a competent clinical diagnosis.’’
(Knopman et al., 2001). Since then, several studies have been reported including
one later that year, which included 284 patients undergoing dementia workup,
with 138 having neuropathological diagnosis (Silverman et al., 2001). The
authors used a typical AD pattern of parietal and temporal hypometabolism,
with or without frontal involvement, with a sensitivity of 94% (91/97; 95% CI,
89–99%) and a specificity of 73% (30/41; 95% CI, 60–87%) relative to neuro-
pathologic diagnosis (Silverman et al., 2001); other studies have found similar
values of specificity and sensitivity of PET for AD, depending on comparisons
with clinical or pathologic definitions of disease (HoVman et al., 2000;
Patwardhan et al., 2004).
In an attempt to clarify the sensitivity and specificity of PET, one meta-
analysis of articles published through 2003 found significant faults in the gener-
alizability of these studies overall (Patwardhan et al., 2004). Namely, the authors
noted that control patients may have dissimilar medical comorbidities, and that
most of the studies were performed in specialty or tertiary referral centers, and
may operate quite diVerently when used in primary care settings. Despite these
limitations their best estimate suggested the summary sensitivity of PET was
86% (95% CI: 76–93%) and summary specificity was 86% (95% CI: 72–93%)
(Patwardhan et al., 2004), and subsequent individual studies have found similar
results ( Jagust et al., 2007). Furthermore, in each of these studies, we cannot
know whether individuals with an AD PET pattern, but without either clinical
or pathologic correlate, would have eventually developed clinical AD. Thus,
these patients may underestimate the specificity of FDG-PET (fewer false
positives).
 APPLICATION OF PET IMAGING IN AD AND MCI 137

D. PITTSBURGH COMPOUND B-PET

Recent approaches to PET imaging in dementia have attempted to obviate

the examination of glucose metabolism and its inherent limitations and focus on
radioligands which bind with amyloid in the brain. One of the most promising
and well studied of these ligands used amyloid binding dye thioflavin-T derivative
[N-methyl-11C]-2-(40 -methylaminophenyl)-6-hydroxybenzothiazole, better known
as Pittsburgh Compound B (PiB)-PET, which binds to amyloid plaques and
amyloid fibrils, but not neurfibrillary tangles. The first report of PiB-PET in humans
suggested PiB aYnity is generally inversely correlated with glucose metabolism on
FDG-PET (Klunk, 2004) (e.g., regions with greater amyloid burden may be
identified in regions with relative preservation of glucose metabolism); the highest
degree of amyloid binding was associated with prefrontal cortex, and to a lesser
degree in parietal, occipital, and temporal cortex (Klunk et al., 2004; Mintun et al.,
2006). Subsequent studies have also suggested that relatively normal prefrontal
glucose metabolism on FDG-PET despite high prefrontal amyloid binding on
PiB-PET has led some to hypothesize additional mechanisms than just amyloid
underlying neuronal dysfunction in AD (Edison et al., 2007).
PiB binding has been demonstrated to be highly prevalent among larger
studies of AD patients, and to a lesser degree but with a similar pattern among
MCI patients (Kemppainen et al., 2007). PiB binding may be present in as high as
22% of elderly individuals with healthy aging, and cortical PiB is significantly
associated with episodic memory test performance among MCI and normal aged
patients (Pike et al., 2007), and facial and word recognition in all subjects (Edison
et al., 2007). One study of cognitively normal elderly and MCI subjects found no
within-group relation between learning and memory testing and PiB binding
( Jack et al., 2008). To date, the relatively limited number of studies preclude
definitive prediction of progression from MCI or a normal state to clinical AD
based on PiB-PET, but MCI patients with an AD PiB-PET pattern may be more
likely to progress to AD based on one study with relatively brief follow-up
(Forsberg et al., 2008).
Data regarding the sensitivity and specificity of PiB-PET in the diagnosis of
AD is somewhat limited. One study found increased PiB binding in 89% of
patients with clinically probable AD (Edison et al., 2007); another found 100%
sensitivity, with specificity dependent upon the age of the patient, ranging from
73 to 96% (Ng et al., 2007). As with FDG-PET, the cause for the relatively low
specificity (high false positives for AD) in some subjects is unclear, but could be
related to several reasons. First, presymptomatic individuals could lead to false
positive findings; autopsied brains of cognitively normal elderly can have patho-
logic AD changes in 25–67% of subjects (Crystal et al., 1988; Morris et al., 1996;
Mortimer et al., 2003; MRC-CFAS, 2007). Second, PiB amyloid binding is found
in other cerebral amyloidoses including cerebral amyloid angiopathy (CAA)
138 NOBLE AND SCARMEAS

(Lockhart et al., 2007). Although the data are limited, the CAA pattern of PiB-
PET signal may be distinguishable from AD; CAA may have a greater degree of
occipital amyloid identified on PiB-PET than AD patients ( Johnson et al., 2007).

II. Application of PET to Primary and Specialty Care Settings

Given the data from these studies outlined above, it is worth considering the
application and utility of PET in clinical practice. Prior to outlining the approach
to its use, the current typical sequence leading to the workup and diagnosis of
dementia bears review, to contextualize the potential role of PET within the
diagnostic workup.

A. DIAGNOSTIC WORKUP OF DEMENTIA IN PRIMARY CARE

For the workup of dementia patients, current recommendations for primary

care physicians are to provide cognitive screens to only those with reported or
suspected cognitive decline, or in the oldest old (Brodaty et al., 1998; US
Preventive Services Task Force, 2003). Without disease modifying treatment,
the current ratio of benefit to harm of screening for dementia is unclear, and
thus not recommended unless dementia is suspected (US Preventive Services Task
Force, 2003). These practices may delay recognition relative to community
screening programs (Barker et al., 2005), but expanding current screening prac-
tices may be impractical for a busy primary care physicians, already conscious of
cost concerns (Geldmacher, 2002). When concern for progressive cognitive im-
pairment is raised in the primary care setting, one of several brief cognitive
screening tests for dementia is often used. The best-studied cognitive screening
tool is the Folstein Mini-Mental Status Examination (MMSE) (Folstein et al.,
1975; US Preventive Services Task Force, 2003), but scoring and interpretation
may be somewhat dependent on education and age. If cognitive impairment is
identified, other non-cognitive screening tests are recommend for the purposes of
excluding uncommon causes non-degenerative cognitive decline (Knopman et al.,
2001). These tests include MRI (to rule out space occupying lesions, subclinical
cerebral infarcts, and other conditions) and laboratory evaluations of thyroid
function, vitamin B12 level, and syphilis serology. These tests have few limitations,
are reproducible, and are relatively simple to perform and interpret by non-
specialists.
Depending on individual practice, some primary care physicians may arrest
the workup at this point and begin treatment. Others may refer to a specialist after
screening, or even sooner—at the time of suspected cognitive impairment but
 APPLICATION OF PET IMAGING IN AD AND MCI 139

prior to screening laboratory evaluation. The current structure of diagnostic

workup is likely impractical for every patient with probable AD to be seen by a
specialist. Although data are limited, US community primary care physicians
refer 44% of their patients to specialists for diagnosis or confirmation (Fortinsky
et al., 1995). In comparison, more than 80% of community primary care physi-
cians in Germany and academic primary care physicians in Canada make
specialist referrals, most often neurologists or physicians specializing in both
psychiatry and neurology (Pimlott et al., 2006; Riedel-Heller et al., 1999). Potential
dementia specialists include neurologists (on average, 4.5 neurologists serve
100,000 US population) (World Health Organization, 2005), gerontologists (2.4
per 100,000), and geriatric psychiatrists (0.5 per 100,000) (Wimo et al., 2007);
behavioral neurologists and neuropsychiatrists comprise a small minority of
general psychiatrists and neurologists. Thus, any increase in referrals to specialists
would likely overwhelm the current system.
The statistical rigor and cost-eVectiveness of a non-selective community-based
screen using most of these diagnostic tools has not been widely reported. It has
been argued that FDG-PET can be a cost saving measure for the diagnosis of AD
in geriatric populations, in comparison to a conventional workup of clinical
evaluation and exclusion of potential mimicking diseases (Silverman et al.,
2002). However, this study considered the population of having 51% prevalent
disease (Silverman et al., 2002), which would only be applicable to a highly
selected, screened population within a primary caregiver’s oYce, or would require
an unselected population with all patients over 90 years of age, based on current
epidemiologic estimates.

B. DIAGNOSTIC WORKUP OF DEMENTIA IN SPECIALTY CARE SETTINGS

In contrast to screening tests used largely for exclusionary purposes, confir-

matory tests used in the diagnostic workup of patients with dementia are typically
used as sensitive measures to rule in a diagnosis in a patient with moderate to
highly probable disease. These tests include initial clinical evaluation, often by a
specialist, with supportive testing, decided on a case by case basis, including
neuropsychological testing, cerebrospinal fluid markers, and functional imaging
such as FDG-PET. Each of these is costly, time consuming and requires a large
amount of manpower to complete (McMahon et al., 2003). As noted elsewhere,
the additional diagnostic benefit of these diagnostic tests when done in expert
settings is unclear, and these tests may have greater potential diagnostic usefulness
when the diagnosis is less certain, as may be the case in primary care settings
(Knopman, 2001).
140 NOBLE AND SCARMEAS

III. Appropriate Use of PET

Before delving into the statistics of available studies regarding PET, the use of
sensitivity, specificity, and related statistical tools also bears brief review. From the
Table I, Sensitivity ¼ A/(A þ C) is the probability of having a positive test result
among all those with disease. The complement of sensitivity is the false negative
proportion ¼ C/(A þ C). Specificity ¼ D/(B þ D) is the probability of having a
negative test result among those without disease. Similarly, the complement of
specificity is the false positive proportion ¼ B/(B þ D). Drawn from Table I are terms
that are often cited to guide clinicians’ use for practical matters, and perhaps
incorrectly so: the predictive value terms. The positive predictive value ¼ A/(A þ B) is
the probability of having the disease given a positive test result. Similarly, the
negative predictive value ¼ D/(C þ D) is the probability of not having the disease
given a negative test result. These predictive values are often applied incorrectly;
their usefulness is dependent upon the prevalence of disease within a given
population, which may be unknown to the clinician. Furthermore, if data are
derived from case-control studies, the predictive value tools cannot be used unless
an equal sampling fraction of controls is established, and this is often diYcult.
In place of these predictive value tools, some have suggested using likelihood
ratio statistics (Grimes and Schulz, 2005), but these have not become as widely
reported, despite their relative ease of using an appropriate table or computer
program. The benefit of the likelihood ratios is that they incorporate statistics
regarding all disease states and test results, without depending on prevalence.
Instead, using Bayesian statistics these ratios allow the user to apply a likelihood
ratio to a pretest probability (either according to known disease prevalence or
clinical probability based on additional data) to derive a posttest probability.
Thus, again from Table I, the Likelihood ratio for disease if test positive ¼ sensitivity/
(1-specificity) and the Likelihood ratio for disease if test negative ¼ (1-sensitivity)/
specificity. One can also consider the likelihood ratio positive to be the ratio of
true positives to false positives, and the likelihood ratio negative as the ratio of false
negatives to true negatives. The likelihood ratios in and of themselves have little
inherent meaning but become relevant when applying them to individual
patients.

TABLE I
THE 2 # 2 TABLE

Disease No disease

Positive test result A B

Negative test result C D
 APPLICATION OF PET IMAGING IN AD AND MCI 141

Although the likelihood ratio calculations are relatively straightforward, their

application can be exacted by using Bayesian statistics, but these can be perceived
as cumbersome. An alternative strategy is the use of the likelihood ratio table
(Fig. 1), or perhaps more simply by remembering a few important numbers
(Grimes and Schulz, 2005). Here we present all three methods of practical
application of likelihood ratios.

A. USING LIKELIHOOD RATIO TABLES

When considering the FDG-PET meta-analysis outlined above (Patwardhan

et al., 2004), which identified the composite sensitivity ¼ 86% and specificity ¼ 86%
for AD, then the Likelihood ratio positive ¼ 0.86/(1–0.86) ¼ 6.1 and the
Likelihood ratio negative ¼ (1–0.86)/0.86 ¼ 0.16. Once these have been calcu-
lated, we then look to Fig. 1A, a typical likelihood ratio table. To use the likelihood
ratio table, begin with the pretest probability at the left. Using a straightedge,
tracing from the pretest probability through the likelihood ratio will derive the
posttest probability. Presumably, a posttest probability will need to be suYciently
high or low to make a clinical decision. Arguably, given that tertiary referral
centers may be correct in clinical AD diagnosis approximately 90%, then any
posttest probability at or above this would be satisfactory; a suitable threshold
value for a low likelihood posttest probability can be determined on a case by case
basis but presumably should be less than 5%.
Consider an example of a 50% pretest probability, which could be prevalence
of AD in a nonagenarian population (or alternatively a primary physician’s
clinical suspicion based on interview alone) and thus the pretest probability
without further information or diagnostic tests. In this scenario, a positive FDG-
PET with likelihood ratio positive ¼ 6.1 would increase the posttest probability to
about 90%, while a negative test result with likelihood ratio negative ¼ 0.16
would decrease the posttest probability to 10%. Alternatively, we could consider a
single, larger study of PET in AD as outlined above (Silverman et al., 2001) which
identified sensitivity ¼ 94% and specificity ¼ 73%, and thus a likelihood ratio
positive ¼ 3.5 and likelihood ratio negative ¼ 0.08. Beginning with a 50% pretest
probability, our posttest probability with a positive test increases to only about
70% while a negative test decreases the probability to about 5%.
Exploring the likelihood ratio table, one can clearly see that an uncertain
pretest probability is the best scenario for use of a diagnostic tool with suYciently
high likelihood ratio positive (ideally over 10) or low likelihood ratio negative
(ideally 0.1 or less). Very high or low pretest probabilities will not be appreciably
aVected, regardless of the likelihood ratio test characteristics (Grimes and Schulz,
2005).
 A B C D
0.1 99 0.1 99 0.1 99 0.1 99
0.2 0.2 0.2 0.2

0.5 1000 0.5 1000 0.5 1000 0.5 1000

95 95 95 95
1 90 1 90 1 90 1 90
500 500 500 500
2 200 80 2 200 80 2 200 80 2 200 80
100 100 100 100
50 70 50 70 50 70 50 70
5 20 60 5 20 60 5 20 60 5 20 60
10 50 10 50 10 50 10 50
10 10 10 10
5 40 5 40 5 40 5 40
20 2 30 20 2 30 20 2 30 20 2 30
1 1 1 1
30 20 30 20 30 20 30 20
0.5 0.5 0.5 0.5
40 0.2 40 0.2 40 0.2 40 0.2
10 10 10 10
50 0.1 50 0.1 50 0.1 50 0.1
60 0.05 60 0.05 60 0.05 60 0.05
5 5 5 5
70 0.02 70 0.02 70 0.02 70 0.02
80 0.01 80 0.01 80 0.01 80 0.01
0.005 2 0.005 2 0.005 2 0.005 2
0.002 0.002 0.002 0.002
90 1 90 1 90 1 90 1
95 0.5 95 0.5 95 0.5 95 0.5
0.001 0.001 0.001 0.001

0.2 0.2 0.2 0.2

99 0.1 99 0.1 99 0.1 99 0.1
Pretest Likelihood Post-test Pretest Likelihood Post-test Pretest Likelihood Post-test Pretest Likelihood Post-test
probability ratio probability probability ratio probability probability ratio probability probability ratio probability

FIG. 1. Likelihood ratio tables of FDG-PET in the diagnosis of Alzheimer’s disease in several age-stratified scenarios. (A) The likelihood ratio table. (B-D)
Likelihood ratio tables for age stratified elderly populations, with pretest probability using only age-based prevalence statistics (Alzheimer’s Association, 2008;
Gurland et al., 1999; Hebert et al., 2003; Mayeux, 2003b). (B) Age less than 75 years (3–5% AD prevalence). (C) Age 75–84 years (15–18% AD prevalence).
(D) Age 85 years and above (45% AD prevalence). Solid line: FDG-PET with sensitivity ¼ 86% and specificity ¼ 86% (Patwardhan et al., 2004); (LR þ ¼ 6.1
LR$ ¼ 0.16). Dotted line: FDG-PET with sensitivity ¼ 94% and specificity ¼ 73% (Silverman et al., 2001); LR þ ¼ 3.5 and LR$ ¼ 0.08. Figure (A) reprinted
with permission from Elsevier (Grimes and Schulz, 2005).
 APPLICATION OF PET IMAGING IN AD AND MCI 143

Finally, in the Fig. 1B-D, we have applied the likelihood ratios derived from
two studies of FDG-PET statistics (Patwardhan et al., 2004; Silverman et al., 2001)
to visually demonstrate the utility of applying likelihood in several diVerent
scenarios. In this figure, we derived the pretest probability in each Fig. 1B-D
from age-stratified prevalence statistics of AD (Alzheimer’s Association, 2008;
Gurland et al., 1999; Hebert et al., 2003; Mayeux et al., 2003b) in an eVort to
demonstrate the utility of FDG-PET without additional screening or further
workup. Clearly, the degree of certainty in diagnosis does not appreciably improve
from this single test until applied to those older than 85 years of age.

B. USING A LIKELIHOOD RATIO ‘‘MNEMONIC’’

Should a likelihood ratio table not be immediately available, and if one

chooses not to pursue the potentially diYcult calculation steps outlined below, a
simpler way has been suggested, requiring the user to remember a few numbers
(Grimes and Schulz, 2005). Positive likelihood ratios 2, 5, and 10, approximately
increase the posttest probability by 15% increments individually. That is, a
likelihood ratio positive of 2 increases the posttest probability by an absolute
diVerence of 15%, 5 by 30%, and 10 by 45%. Conversely, a likelihood ratio
negative of 1/2 (0.5) decreases the posttest probability by an absolute diVerence of
15%, 1/5 (0.2) by 30%, and 1/10 (0.1) by 45%. Using this method considering
one of the examples above, a likelihood ratio positive of 6.1 is similar to 5, which
would increase a pretest probability of 50% absolutely by 30% to 80%. Similarly,
a likelihood ratio negative of 0.08 is similar to 1/10 which would decrease a
pretest probability of 50% absolutely by 45%, yielding a posttest probability of
5%, as estimated by the likelihood ratio tables. Overall, comparing this simplified
methodology to the results above using the likelihood ratio tables, yields similar
but less precise results.

C. USING BAYESIAN CALCULATIONS

Aside from using likelihood ratio tables or the mnemonic as suggested above,
one can determine the exact posttest probabilities through a series of calculations,
bearing in mind that pretest probabilities may be imprecise and based on clinical
judgment. These calculations are
1. Calculate the pretest odds ¼ pretest probability /(1-pretest probability)
2. Posttest odds ¼ Pretest odds # likelihood ratio
3. Posttest probability ¼ Posttest odds/(posttest odds þ1)
144 NOBLE AND SCARMEAS

Returning to the 50% pretest example using sensitivity and specificity for PET
derived from the meta-analysis (Patwardhan et al., 2004), for a positive test
Pretest odds ¼ 0.50/(1$0.50) ¼ 1 (‘‘1:1 odds’’)
Posttest odds ¼ 1 # 6.1 ¼ 6.1
Posttest probability ¼ 6.1/(6.1 þ 1) ¼ 86%
For a negative test
Posttest odds ¼ 1 # 0.16 ¼ 0.16
Posttest probability ¼ 0.16/(1 þ 0.16) ¼ 14%
From this example we can see that the likelihood ratio table, menomnic, and
calculations yield similar results for a test with 86% sensitivity and specificity,
regarding a positive test result (posttest probability using the likelihood ratio table,
90%; mnemonic, 80%; calculation, 86%) and a negative test result (posttest proba-
bility using the likelihood ratio table, 10%; mnemonic, 5%; calculation, 14%).

D. CONCLUSIONS FROM USING THE LIKELIHOOD RATIOS FOR PET AND AD

Based on these analyses, FDG-PET should be used only in a highly selected

group of patients. Presumably, one would pursue a diagnostic workup until such a
time that there is a high degree of certainty of either dementia or normal
cognition. At this point FDG-PET should be reserved for patients having either
(a) undergone an otherwise exhaustive diagnostic workup with a specialist in
cognitive disorders or (b) partial workup with a primary care physician after
having identified a cognitive disorder, but both yielding a still-uncertain diagnosis.
This approach has been justified in expert centers attempting to distinguish
ambiguous clinical cases of AD and frontotemporal dementia; FDG-PET
changed the diagnosis in 26% of cases in which the examiner was uncertain or
not completely confident in the diagnosis, versus 5% change of clinically certain
cases after additional information provided by FDG-PET (Foster et al., 2007).
Current reimbursement practices in the United States reflect just such application
of FDG-PET, and its use is restricted to consideration of a diVerential diagnosis of
AD versus other neurodegenerative illnesses.
At this point, available data for either FDG-PET or PiB-PET in MCI are
limited and preclude accurate derivation of a likelihood ratio test statistics.
Neither study is currently indicated for suspected MCI patients, either as a
diagnostic tool or as a prediction tool for progression. Should future studies reveal
additional data regarding specificity and sensitivity of these imaging modalities, or
any other MCI/AD diagnostic tool for that matter, one can apply such data to
this formula and recapitulate this argument.
 APPLICATION OF PET IMAGING IN AD AND MCI 145

IV. Summary

Despite a relatively lengthy history of FDG-PET in the evaluation of demen-

tia, it should still be used judiciously, and only in patients with a relatively
uncertain cognitive diagnosis despite initial workup and evaluation, or if the
etiology of their dementia is unclear. The use of FDG-PET as a blind screening
tool is not recommended; although, screening in elderly at greatest risk for
dementia (age > 90) is worth considering. Newer PET radioligands such as
amyloid binding tools (PiB among them) show promise as a future diagnostic
tool, but are not commercially available at this time and cannot be recommended
for routine use based on available data. FDG-PET, PiB-PET, and other support-
ive diagnostic tests may have greater roles in diagnosis and monitoring disease
should be an era of disease-modifying therapies and prevention strategies for AD
develop.

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THE MOLECULAR AND CELLULAR PATHOGENESIS OF DEMENTIA
OF THE ALZHEIMER’S TYPE: AN OVERVIEW

Francisco A. Luque*,y and Stephen L. Jaffe*

*Department of Neurology, Louisiana State University School of Medicine-Shreveport,
Shreveport, Louisiana 71103, USA
y
VA Neurology Service, Overton Brooks VAMC, Shreveport, Louisiana 71101, USA

I. Introduction
II. Cellular Pathogenesis and Investigational Strategies
III. Molecular and Genetic Studies Resulting in Therapeutic Strategies
References

The pathogenesis of dementia of the Alzheimer’s type (DAT) remains elusive.

The neurodegeneration occurring in this disease has been traditionally believed to
be the result of toxicity caused by the accumulation of insoluble amyloid-beta 42
(AB) aggregates, however recent research questions this thesis and has suggested
other more convincing cellular and molecular mechanisms. Dysfunction of
amyloid precursor protein metabolism, AB generation/aggregation and/or
degredation/clearance, tau metabolism, protein trafficking, signal transduction,
heavy metal homeostasis, acetylcholine and cholesterol metabolism, have all been
implicated etiologically especially as to production of neurotoxic by-products
occurring as a result of a specific process derangement. In this paper, these and
other research directions are discussed as well as their implications for future
therapies. The relationship of the proposed abnormal molecular and cellular
processes to underlying genetic mutations is also scrutinized, all in an attempt
to stimulate further insight into the pathogenesis of, and thus therapeutics for this
increasingly prevalent disease.

I. Introduction

Over 100 years ago, Alzheimer described a patient with memory disturbance
and a brain pathological picture which included miliary bodies (plaques) and
dense bundles of fibrils (tangles). These observations remain the clinical
and pathological hallmarks of dementia of the Alzheimer’s type (DAT). DAT is

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NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00408-5 0074-7742/09 $35.00
152 LUQUE AND JAFFE

the most common form of dementia and accounts for 50-60% of dementia
presentations. Presently there are approximately 5.1 million patients in the
USA with DAT; and it is estimated that in the next 20 years, there will be an
additional 15 million cases. DAT incidence increases with age. Before age 60, the
incidence is about 5%; but after age 85, it increases to 50%. The annual cost
attributed to DAT in this country is $148 billion. The clinical symptoms of DAT
include alterations of abstract thinking, skilled movements, emotional expression,
executive function, and memory. The majority of DAT cases are sporadic, but
around 10% are inherited. Autosomal dominant cases are related to mutations in
the amyloid precursor protein (APP) (chromosome 21), presenilin 1 (PS1) (chro-
mosome 14), and presenilin 2 (PS2) (chromosome 1) genes. Similar pathology
with a dementing process often occurs in Down syndrome (trisomy 21).
The pathogenesis of DAT remains perplexing. Dysfunction in APP metabolism,
Ab42 (Ab) degradation and clearance, signal transduction, tau metabolism, protein
traYcking, acetylcholine and cholesterol metabolism, and homeostasis of heavy
metals may be involved (Bertram and Tanzi, 2008). DAT neurodegeneration may
be linked to dysfunction of the degradation process of Ab or other proteins, or Ab
generation with production of toxic by-products may be responsible, and aggregate
formation may be a benign phenomenon. On the other hand, Ab aggregates may be
primarily toxic interfering with the degradation of various proteins by interfering
with chaperone function. Protein folding, protein-protein interaction, and protein
membrane association are all thermodynamically driven processes utilizing enzymes
known as chaperones. The importance of chaperones for proteosomal degradation
has been corroborated in the endoplasmic reticulum (ER) where newly synthesized
proteins that are abnormal or misfolded are removed by a quality control mechanism
termed ER-associated degradation (Tai and Schuman, 2008; Zhang et al., 2004).

II. Cellular Pathogenesis and Investigational Strategies

DAT histological brain changes are especially prevalent in the frontal and
temporal lobes and include neuronal loss, extracellular deposition of Ab as ‘‘senile
plaques,’’ and the intracellular accumulation of neurofibrillary tangles composed
of microtubule-associated protein tau arrayed as paired helical filaments. One
of the earliest neuropathological changes is the presence of a large number of
reactive astrocytes at the site of Ab deposition. Ab deposition also leads to
degeneration of the microvascular basement membrane and thus alteration in
blood-brain barrier permeability (Berzin et al., 2000) (Fig. 1).
As previously noted, it is unclear whether the process of formation and accu-
mulation, precursors occurring during that process, the actual accumulated Ab,
and/or abnormal degradation initiates a series of neurotoxic events including
 THE MOLECULAR AND CELLULAR PATHOGENESIS OF DAT 153

FIG. 1. Neuropathology of Alzheimer’s disease. (A) Low power amyloid plaques, (B) high power
amyloid plaque, (C) neurofibrillary tangles, silver stained, and (D) electron micrograph of neurofibrillary
tangles composed of hyperphosphorylated tau (Courtesy of Sisodia and St. George-Hyslop, 2002; with
permission from Nature Publishing Group).

hyperphosphorylation of tau that triggers neuronal dysfunction and cell apoptosis

(the ‘‘amyloid cascade’’). Although new ligands for positron emission tomographic
(PET) imaging of Ab in vivo (Pittsburgh Compound-B) are available, their diagnostic
value is questionable due to this conundrum. However, the accumulation of
amyloid plaques is the earliest feature that can be detected in presymptomatic
individuals with a PS1 mutation or with trisomy 21. Although, it is not clear how
Ab specifically induces neurodegeneration, the accumulation of intracellular tau
does appear to be neurotoxic.
It was originally thought that plaque formation occurred over long periods
of time and long before the dementia became apparent. However, Meyer-
Luehmann et al. (2008) using a DAT mouse model provided evidence that
amyloid plaques form extremely rapidly, actually within 24 h, and their size and
final characteristics stabilize within a week. In the early stages of the disease,
microplaques can damage neighboring axons and dendrites within days. Among
the features of the DAT degenerative process are damage to synaptic connections
associated with accumulation of amyloid b oligomers, and neuritic dystrophy—
the formation of tortuous neuronal elongations with eventual loss of selective
groups of neurons. These processes have been strongly linked to DAT cognitive
impairment.
Defects in axonal transport have been described in animal models of DAT
including transgenic mice overexpressing APP, and those containing mutant PS1.
However, the mechanism is not fully understood (De Vos et al., 2008). Ab appears
154 LUQUE AND JAFFE

to disrupt the axonal transport of a variety of cargoes including mitochondria by

associating with and thus damaging the mitochondria (Hiruma et al., 2003;
Manczak et al., 2006). Mutant PS1 impairs axonal transport by causing a reduction
in kinesin-I driven motility via interaction with glycogen synthase kinase-3b to
produce phosphorylation of kinesin light chains with release of kinesin-I from
membrane-bound organelles (Pigino et al., 2003).
Disturbance of glutaminergic neurotransmission and consequent excitotoxicity
has been implicated in the progression of DAT (Matos et al., 2008). In DAT patients,
increased glutaminergic excitotoxic activity appears to occur due to Ab interference
with glutamate uptake by astrocytes, leading to increased activation of NMDA
neuronal receptors. Memantine is a noncompetitive NMDA receptor antagonist
that appears to protect neurons from glutamate mediated excitotoxicity without
interfering with the physiological NMDA receptor activation needed for cognitive
functioning. Although there is no data showing memantine has a beneficial eVect in
mild DAT, this drug is well tolerated and may be a useful adjunct in moderate to
severe disease defined as a mini-mental status exam (MMSE) score of less than 15.
Amyloid b aggregation disturbs the cellular proteosome by inducing oxidative
stress with subsequent mitochondrial and proteosomal dysfunction (Hamacher
et al., 2007). Mitochondrial dysfunction appears to be an early causative event in
neurodegeneration. Mutations of mitochondrial fusion GTPases, mitofusin 2,
and optic atrophy 1, are neurotoxic and produce oxidative stress which disrupts
the cable-like morphology of functional mitochondria. This causes impairment
of bioenergetics, interfering with mitochondrial migration and triggering
neurodegeneration (Knott et al., 2008).
Sortilin related receptor (SorLA) belongs to a family of sorting receptors that
mediate various intracellular processing and traYcking functions (Yamazaki et al.,
1996). SorLA/LR11 mediates re-internalization of APP, during which APP is
transported from the cell surface to an endocytic compartment where it is cleaved
into Ab by b secretase and ! secretase. SorLA/LR11 is highly expressed in the brain
and binds to ApoE and APP, sequestering APP in the Golgi apparatus and thus
preventing APP generation into Ab (Andersen et al., 2006). In all studies to date,
there is no consistent evidence of a SorLA association with DAT, possibly due to
allelic heterogeneity. Studies in vitro suggest that SorLA expression is reduced in the
brains of DAT patients, even in the preclinical state. SorL1-knockout mice show
increase in brain Ab level. Although there is convergence of data from genetic and
biochemical studies, more data are needed to better evaluate this association.
Transferrin (TF) is a major circulating glycoprotein involved in the metabolism
of iron and is highly expressed in the brain. Iron misregulation promotes neurode-
generation via generation of reactive oxygen species (ROS) (Brewer, 2007). Iron is
increased in the brains of DAT patients where it is associated with plaques and
tangles. Iron may play a role in the aggregation of hyperphosphorylated tau into
insoluble paired helical filaments (Yamamoto et al., 2002), and iron may also regulate
 THE MOLECULAR AND CELLULAR PATHOGENESIS OF DAT 155

the translation of APP. Thus iron levels could modulate the generation of both
plaques and tangles. Besides the binding of metals to Ab, TF has been shown to
modulate several physiochemical properties of Ab including the rate of aggregation.
The ability of neurons to regulate the influx, eZux, and subcellular compart-
mentalization of calcium is compromised in DAT. This appears due to age-related
oxidative stress, and impaired metabolism/accumulation of Ab oligomers. Ab can
promote cellular calcium overload via oxidative stress and by forming pores in the
membrane, rendering neurons vulnerable to excitotoxicity and apoptosis
(Bezprozvanny et al., 2008). Mutations of presenilin genes that cause early onset
DAT also cause ER (endoplasmic reticulum) calcium overload by impairing the
normal ER calcium leak-channel function of the presenilins. A perturbation in
calcium homeostasis may be involved in early DAT by altering APP processing
and thus Ab production. Calcium activated neural proteinases (CANPs or cal-
pains) are key enzymes in the intracellular signaling cascade and thus may mediate
calcium dependent neural degeneration. Pharmacological modulation of the
CANP system could be a potential therapeutic strategy in Alzheimer’s disease
(Saito et al., 1993).
De Luigi et al. (2002) studied the presence of circulating cytokines and the
ability of blood cells to release them in response to inflammatory stimuli in
patients with diVerent forms of dementia. A significant increase in circulating
interleukin-1b was found in moderate DAT. Chronic inflammation as found in
head trauma is an important risk factor for DAT, and the inflammatory process
aVects glial-neuronal interactions. The activation of the glial inflammatory pro-
cess, either caused by genetic or environmental insults to neurons, produces glial
derived cytokines and other proteins that results in neurodegeneration. Interleu-
kin 1 is key in initiating and coordinating neuronal synthesis and in the processing
of APP, resulting in the continuous deposition of Ab. It also promotes astrocytic
synthesis and release of inflammatory and neuroactive molecules such as S100b,
which is a neurite growth promoting cytokine. This cytokine can stress neurons
fostering neuronal cell dysfunction, causing apoptosis by increasing intraneuronal
free calcium concentrations. This neuronal injury eVect activates microglial cells
which then overexpress inteleukin 1, thereby producing feedback amplification
and self-propagation of this cytokine cycle (GriYn et al., 1998).

III. Molecular and Genetic Studies Resulting in Therapeutic Strategies

Amyloid b is generated by endoproteolysis of the APP. This is achieved by

cleavage of APP by a group of enzyme complexes: ", b, and ! secretases. Three
enzymes with " secretase activity belong to the ADAM enzyme family (desinte-
grin and methaloproteinase enzymes): ADAM9, ADAM10, and ADAM17
156 LUQUE AND JAFFE

(i.e., tumor necrosis factor converting enzyme). The b site APP cleaving enzyme-1
(BACE1), b secretase, is a type I integral membrane protein from the pepsin
family of aspartyl proteases. Gamma secretase is an intramembranous complex of
enzymes composed of presenilin 1 or 2, nicastrin, anterior pharynx defective-1,
and presenilin enhancer 2, with the presenilin being the active site (Wolfe et al.,
1999; Yu et al., 2000).
There are two pathways in the cleavage and processing of APP. One is non-
amyloidogenic. APP is cleaved by " secretase at amino acid position 83, the
carboxy terminus, producing a large amino terminal ectodomain (sAPP"). This is
secreted into the extracellular medium where it is in turn cleaved by ! secretase
producing a short peptide, p3. The cleavage by " secretase is in the middle of the
APP region, and therefore there is no Ab production. The amyloidogenic pathway
leads to Ab generation. Initially the b secretase cleaves at amino acid position 99,
releasing sAPP b into the extracellular space. Meanwhile the C99 fragment stays in
the membrane where it is cleaved by ! secretase between residues 38 and 43,
liberating a peptide which is 40 amino acids in length (Ab40). Only a small
proportion (10%) composes the 42 residue, the Ab peptide (Ab42). Ab is more
hydrophobic and thus prone to form fibrils, and is abundant in senile plaques
( Jarrett et al., 1993; Martin, 1999; Suh and Checler, 2002; Younkin, 1998). Muta-
tions in the APP gene linked to early-onset DAT produce a product that is preferen-
tially cleaved to release Ab 42 (Selkoe, 2001; Sisodia and St. George-Hyslop, 2002)
(see Fig. 2).

Non-amyloidogenic Amyloidogenic

sAPPa
sAPPb

Presenilin 1or 2
Nicastrin
ADAM9, PEN2
10 or 17 BACE1 APH-1 Ab

C83 APP APP C99 AICD

FIG. 2. Pathways in the cleavage and processing of APP (Courtesy of LaFerla et al., 2007; with
permission from Nature Publishing Group).
 THE MOLECULAR AND CELLULAR PATHOGENESIS OF DAT 157

Presently, the major investigational therapeutic strategies are focused on inhi-

biting brain Ab production, aggregation, and/or increasing Ab brain clearance.
Secretase modulators are being studied as Ab production inhibitors based on the
observation that Ab production is abolished in BACE1 knockout mice and the
DAT phenotype does not develop. BACE1 inhibitors have been developed to
reduce brain Ab accumulation in DAT transgenic mice. Rajendra et al. (2008)
focused not only on inhibition of b secretase active site binding, but also on
inhibiting the localized active enzyme at the subcellular level. He synthesized a
membrane-anchored version of b secretase transition-state inhibitor by linking it to
a sterol moiety. This targeted the inhibition of active b secretase found in endo-
somes, reducing the enzyme activity more readily than free inhibitor alone. Simi-
larly ! secretase inhibitors specific to the APP cleavage site have been developed
because of the concern of blocking ! secretase activity on other substrates such as
the notch protein. Testing in transgenic mice is underway and appears successful in
blocking the DAT phenotype, while inhibitors of Ab accumulation show no eVect
on phenotype development again suggesting that eVects of the process or the actual
precursors may be the etiologic factors of DAT neurotoxicity (Schilling et al., 2008).
Drugs that stimulate " secretase thus shifting the APP cleavage to a non-
amyloidogenic pathway also reduce Ab production. Among these, Bryostatin, a
protein kinase C activator used for cancer treatment, increases " secretase activity
and reduces Ab accumulation in DAT transgenic mice models. Removal of Ab by
immunization is based on the observation that active immunization with fibrillar
Ab reduces Ab deposition in DAT transgenic mice. In similar fashion, using a
passive antibody technique against Ab also reduces Ab deposition. It is postulated
that Ab antibodies bind to Ab plaques and induce Ab clearance by microglia.
However, a vaccine trial in humans was halted when 6% of patients developed
encephalitis apparently due to T cell response to the C-terminus of the vaccine
peptide. Presently monoclonal antibodies are being studied as well as nanobodies
in attempts to increase Ab clearance.
Inhibitors of Ab fibrillization are among peptides that interfere with the
assembly of Ab into oligomers which eventually form protofibrils and fibrils.
Two peptides have been shown to prevent the interaction Ab-Ab and Ab-ApoE
without inducing an immune response (Permanne et al., 2002; Sadowski et al.,
2004). Glycosaminoglycans bind Ab and can promote aggregation of Ab. The
drug NC-531 (Tramiprosate or Alzhemed) is a glycosaminoglycan mimetic
designed to do the opposite and block Ab aggregation. However, phase III clinical
trials did not demonstrate a therapeutic eVect for this compound. Scyllo-
cyclohexanediol inhibits Ab 42 fibril assembly, and tetracyclines as well as
rifampin inhibit amyloid formation in vitro. Terenflurbil (Flurizan) is an allosteric
modulator of ! secretase, inhibiting its activity. It is a stereoisomer of a nonsteroidal
anti-inflammatory that does not have cyclo-oxygenase (COX) activity. Again
however, a phase III trial failed to show clinical benefit.
158 LUQUE AND JAFFE

Copper and Zinc ions can induce Ab aggregation. The chelator, clioquinol
(PBT-1), reduces brain deposition of Ab in DAT transgenic mice. Clinical trials
were stopped when compound impurities produced toxicity. However, PBT-2
(a second generation metal protein attenuating compound which does not contain
iodine) is now undergoing clinical trial. In a DAT transgenic mouse model,
preliminary results suggested improvement in a subset of cognitive measures, as
well as reduction in cerebrospinal fluid and brain Ab. Apomorphine and its
derivatives promote the oligomerization of Ab but inhibit the fibrillization.
Structural activity demonstrated that 10, 11-dihydroxy substitutions in the D
ring of apomorphine are required for the inhibitory eVects. Methylation of
these hydroxyl groups reduces the inhibitory potency. The ability of these
molecules to inhibit Ab formation appears to be linked to their tendency to
undergo rapid auto-oxidation, suggesting that auto-oxidation products act
directly or indirectly on Ab and inhibit fibrillization. This paradigm oVers the
potential for designing more eYcient inhibitors of Ab amyloidogenesis in vivo
(Lashuel et al., 2002).
Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce brain Ab accumula-
tion in DAT transgenic mice. This eVect may be due to inhibition of COX or via
direct eVect on ! secretase. However, clinical trials with typical NSAIDs and
COX-2 inhibitors (celocoxib and refecoxib) as well as other anti-inflammatories
including prednisone and hydroxychloroquine, in established DAT showed no
positive eVects on cognition levels. It is postulated that this failure was due to the
lack of ability to reverse already established pathology, and that the intervention
has to be in the early stages of mild cognitive impairment (MCI). Statins also
reduce brain Ab accumulation in DAT transgenic mice. However, prospective
studies showed no association between the use of statins and the risk of DAT
development, nor were there any changes in CSF Ab levels. Large, extended,
randomized clinical trials are needed to determine if any benefit can be obtained
with this drug class.
Nitric oxide may be involved in DAT neurodegeneration. By using redox
proteomic techniques, 10 proteins have been associated with an increase of nitro-
tyrosine immunoreactivity in the brains of DAT patients. Of these proteins,
"-enolase has been shown to be oxidized in the brains of DAT patients (Calabrese
et al., 2007; Castegna et al., 2002). It is one of the subunits of enolase which catalizes
the reversible conversion of 2-phosphoglycerate to phosphoenolpyruvate in glycoly-
sis. This, in addition to the increase of nitration of the triosephosphate isomerase that
interconverts dihydroxyacetone phosphate and 3-phosphoglyceraldehyde in glycol-
ysis, may explain the altered glucose tolerance and metabolism seen in DAT
patients. Neuropeptide h3 (a phosphatidylethanolamine-binding protein), hippo-
campal cholinergic neurostimulating peptide, and raf-kinase inhibitor protein have
various functions in the brain. In vitro, they upregulate levels of choline acetyltrans-
ferase in cholinergic neurons following N-methyl D-aspartate (NMDA) receptor
 THE MOLECULAR AND CELLULAR PATHOGENESIS OF DAT 159

activation. The activity of this enzyme is reduced in DAT patients. Together with
cholinergic deficits, the nitration of neuropolypeptide h3 and the subsequent loss of
neurotrophic action on cholinergic neurons of the hippocampus and basal forebrain
may be part of the explanation of cognitive decline in DAT (Giacobini, 2003; Rossor
et al., 1982).
The polyphenolic molecule, curcumin, shows promise in reducing nitrosative
brain injury and delaying the onset of neurodegenerative disorders. It is a strong
antioxidant that inhibits lipid peroxidation intercepting and neutralizing ROS
and reactive nitrogen species (RNS) and increasing haeme-oxygenase I expression
in astrocytes and neurons. Dietary curcumin suppressed indicators of inflamma-
tion and oxidative damage in the brains of DAT transgenic mice (Butterfield et al.,
2002; Scapagnini et al., 2006). However, antioxidants including vitamin E did not
show any eVect on the rate of progression of MCI to DAT in large studies.
Drugs that reduce tau phosphorylation by inhibiting tau such as CDK5 (cyclin-
dependent kinase 5) and GSK-3b (glycogen synthase kinase 3b) are being tested.
Since tau phosphorylation results from the action of multiple kinases and
phosphatases, these drugs may not eVect normalization of tau phosphorylation.
Despite the identification of mutations in three genes associated with early-
onset DAT (i.e., the APP, PS1, and PS2 genes) and one genetic risk factor for
sporadic DAT (the gene for apolipoprotein E), our understanding of the patho-
logical genetic mechanism remains elusive. There are additionally over 500
diVerent gene candidates which may be involved in DAT pathogenesis, and at
least 20 loci with modest but significant eVects on the risk for this disease (Bertram
and Tanzi, 2008). The APP gene is located at chromosome 21q21.3. Twenty-nine
mutations in 78 aVected families have been identified. These mutations are close
to the b and ! secretase APP cleavage sites (Goate et al., 1991). The PS1 gene is
located at chromosome 14q24.3 and 166 mutations have been identified in 362
families. These mutations are associated with an increase in the Ab42/Ab40
ratio, and are located throughout the gene for the PS1 molecule where ! secretase
complexing occurs (Sherrington et al., 1995). PS2 localizes to chromosome 1q31-42.
Ten mutations have been identified in 18 aVected families. There is an increase in
the Ab42/Ab40 ratio, similar to the eVects of PS1 gene mutations. The mutations
are found throughout the gene, and thus ! secretase complexing is aVected
(Levy-Lahad et al., 1995; Rogaev et al., 1995).
Roberson et al. (2007) studied a hybrid mouse expressing mutant APP
and having the tau gene inactivated. The elimination of tau did not alter the
accumulation of senile plaques but did prevent the memory loss, behavioral
disturbances and sudden death associated with this DAT-like phenotype. The
complete elimination of tau was not necessary, a reduction of 50% producing
significant improvements. On the other hand, soluble Ab assemblies cause mem-
ory loss and bind to dendritic spines. It would appear that soluble Ab assemblies
and not the precipitated senile plaques are the cause of impaired cognition, but
160 LUQUE AND JAFFE

the exact mechanism remains ill-defined (Lacor et al., 2004). Roberson appropri-
ately sounded a note of caution in extrapolating mouse data into human patho-
physiology in which other compensatory mechanisms may be playing a role
(Avila et al., 2004).
Bertram and Tanzi (2008) discussed 10 diVerent selected genes potentially
implicated in DAT. Angiotensin converting enzyme (ACE) has been shown
in vitro to degrade naturally secreted Ab and this could explain the increased
risk of DAT in carriers of the ACE I allele; however, the relevance in vivo needs to
be demonstrated. CH25H (cholesterol 25-hydrolase) which is responsible for the
synthesis of 25-hydroxycholesterol, is a potent regulator of transcription of genes
involved in cholesterol and lipid metabolism. There seems to be an association
between variants of CH25H and DAT. One study (Papassotiropoulus et al., 2005)
suggested an increased DAT risk associated with a certain CH25H haplotype
(containing the rs13500 risk allele) leading to an increase in CSF lathosterol
(a metabolite precursor of cholesterol) as well as a higher brain Ab load with
lower levels of Ab in the CSF of non-demented elderly subjects. Both CH25H and
lipase A (LIPA) as well as APOE are involved in cholesterol metabolism, and Ab
production and clearance have been shown to be regulated by cholesterol. Drugs
that inhibit cholesterol synthesis lower Ab in cellular and animal models.
Nicotinic acetylcholine receptors are widely expressed in the brain, and the
b2 (CHRNB2) subunit is particularly abundant and forms a heteropentameric
receptor ("4b2) with the "4 subunit. The CHRNB2 gene which encodes the
nAChR b2 subunit maps to chromosome 1q21. Two independent genetic associ-
ation studies have investigated the potential involvement of this gene in DAT risk.
Wu et al. (2004) found that Ab directly inhibits the "4b2 receptor complex, and
that nicotine possibly by activating the NACHR can mitigate the toxic eVects
of Ab, as well as influencing tau phosphorylation in vitro and in vivo (Oddo
et al., 2005).
Grb-2-associated binder 2 (GAB2) is a highly conserved scaVolding/adaptor
protein involved in signaling pathways and in particular in the transduction of
cytokine and growth-receptor signaling (Liu and Rohrschneider, 2002; Sarmay
et al., 2006). GAB2 is expressed ubiquitously, although in greatest amounts in
white blood cells, the prefrontal cortex, and the hypothalamus. All 10 GAB2 gene
single nucleotide polymorphisms (SNPs) showed significant association with DAT.
A protective role is predicated for all the minor alleles. All 10 of the SNPs display a
high LOD score (log10 ratio of probability data occurring if loci linked, to
probability data occurring with unlinked loci), and therefore probably point to a
single underlying signal eVect. Of the 10 associated markers, only one,
rsl1385600, is predicted to map within the coding region for GAB2 where it
does not appear to produce a change in amino acid sequence. It has been
suggested that changes in GAB2 expression could potentially aVect glycogen
synthase kinase 3 (GSK3)-dependent phosphorylation of tau, and thus formation
 THE MOLECULAR AND CELLULAR PATHOGENESIS OF DAT 161

of neurofibrillary tangles. Moreover, growth factor receptor-bound protein

2 which binds GAB2 has been reported to bind tau, APP and PS1 and
2 (Nizzari et al., 2007).
Laminins are intermediate filament proteins that are a component of the nuclear
lamina. Alternative splicing produces two diVerent isoforms, laminin A (LMNA)
and C. Mutations in LMNA have been found to cause a number of diVerent
disorders. The LMNA gene maps 1.5 Mb distal to the CHRNB2 gene on
chromosome 1, and close to the presumed DAT linkage region at 1q22-q25.
Only one group has reported an association between variants of LMNA and DAT
(Grupe et al., 2007), the LMNA association ranked second in terms of genetic
eVect size of all non-APOE-4 related genes with an OR (odds ratio) of 1.35.
Macrotubule-associated protein tau (MAPT) is found in NFTs. The gene
that encodes MAPT has been suspected of harboring disease causing mutations,
but the search for such mutations in DAT has been unsuccessful. However, MAPT
mutations were found to cause another form of dementia, frontotemporal lobar
degeneration with parkinsonism linked to chromosome 17 (FTDP-17). Despite the
lack of MAPT mutation associations in DAT, it is likely that tau dysfunction still
contributes to an increased risk of developing DAT (Ballatore et al., 2007).
Prion protein (PRP) is a membrane tethered glycoprotein that is highly
expressed in all regions of the brain, mostly in neurons. Its physiological functions
are not clear. Mutations of prion protein gene (PRNP) are a major determinant of
familial and sporadic prion diseases such as Creutzfeldt-Jakob disease. Most prion
diseases produce a rapidly progressive neurodenegeneration with spongioform
brain changes and amyloid plaques that consist of misfolded PRP aggregates.
There are more than two dozen diVerent amino acid substitution mutations
identified, which are transmitted in an autosomal dominant fashion with 100%
penetrance. Ab positive plaques in DAT brains often contain PRP deposits.
Recent evidence from studies using APP-PRNP double transgenic mice suggests
that PRP might actually promote plaque formation in DAT by increasing Ab
aggregation (Schwarze-Eicker et al., 2005).

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 ALZHEIMER’S DISEASE GENETICS: CURRENT STATUS
AND FUTURE PERSPECTIVES

Lars Bertram
Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max-Planck
Institute for Molecular Genetics, Berlin 14195, Germany
Genetics and Aging Research Unit, Department of Neurology,
Massachusetts General Hospital, Charlestown,
Massachusetts, 02129, USA

I. Introduction: The Genetic Dichotomy of Alzheimer’s Disease

II. Genome-Wide Association Studies in AD
III. Systematic Field Synopsis and Meta-Analyses: The AlzGene Database
IV. Strengths and Limitations of the AlzGene Approach
V. Assessment of Case-Control Associations Using Family-Based Methods
VI. Conclusions
References

Alzheimer’s disease (AD) is a genetically complex disease whose pathogenesis

is largely influenced by genetic factors. Three decades of intensive research have
yielded four established AD genes (APP, PSEN1, PSEN2, APOE), and hundreds of
potential susceptibility loci, none of which has been unequivocally shown to
modify disease risk using conventional methodologies. The results of genome-
wide association studies (GWAS) are now adding to an already vast and compli-
cated body of data. To facilitate the evaluation and interpretation of these
findings, we have recently created a database for genetic association studies in
AD (‘‘AlzGene’’; available at http://www.alzgene.org). In addition to systemati-
cally screening and summarizing the scientific literature for eligible studies,
AlzGene provides the results of allele-based meta-analyses for all polymorphisms
with suYcient genotype data. Currently, these meta-analyses highlight over 20
diVerent potential AD genes, several of which were originally implicated by a
GWAS. First follow-up analyses in a large collection of over 1300 AD families
reveal that—in addition to APOE—genetic variants in ACE, CHRNB2, GAB2, and
TF show the most consistent risk eVects across a wide range of independent
samples and study designs. The chapter highlights these and other promising
findings from the recent AD genetics literature and provides an overview of the
powerful new tools aiding researchers today to unravel the genetic underpinnings
of this devastating disease.

INTERNATIONAL REVIEW OF 167 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00409-7 0074-7742/09 $35.00
168 LARS BERTRAM

I. Introduction: The Genetic Dichotomy of Alzheimer’s Disease

Similar to many other adult-onset disorders, Alzheimer’s disease (AD) shows a

genetic dichotomy of cases with Mendelian inheritance (‘‘simplex AD’’) versus
cases governed by an array of diVerent genetic and nongenetic risk factors
(‘‘complex AD’’; Bertram and Tanzi, 2005; Tanzi, 1999). Simplex AD is rare
(<5%) and usually shows an early (<65 years) or often times very early (<50
years) age of onset and, owing to its typical familial accumulation and inheritance
pattern, is also known as ‘‘early-onset familial AD’’ (EOFAD). Currently, muta-
tions in three genes are known to cause EOFAD, all leading to altered cerebral
levels of the amyloid-! peptide (A!), the main constituent of senile plaques, and
one of the neuropathological hallmarks of the disease (Tanzi and Bertram, 2005).
The mutated genes leading to EOFAD are APP (amyloid precursor protein;
Goate et al., 1991), PSEN1 (presenilin 1; Sherrington et al., 1995), and PSEN2
(presenilin 2; Levy-Lahad et al., 1995; Rogaev et al., 1995), and all three are
intimately involved in the production of A!, which is liberated from APP via
two enzymatic cleavage events, mediated by !- and "-secretase. The latter is a
protein complex consisting of various components, in which the presenilins
form the "-secretase active site. Even though EOFAD represents only a tiny
fraction of all AD cases, the knowledge gained from uncovering its genetic
underpinnings has been instrumental in our current understanding of the forces
leading to AD across all onset ages and have corroborated the ‘‘amyloid hypoth-
esis.’’ This hypothesis posits that a dysregulation of the production/function of A!
is the initiating event in the pathogenetic cascade eventually leading to neurode-
generation and dementia (Glenner and Wong, 1984; reviewed in Hardy and
Selkoe, 2002; Tanzi and Bertram, 2005). Finally, many of the currently most
promising therapeutic approaches in the AD field aim to directly intersect
or reverse the pathological build-up of A!, which for the first time would allow
a causal treatment of AD as opposed to the merely symptomatic options available
to date.
Despite its relatively high heritability (Bergem et al., 1997; Gatz et al., 2006;
Meyer and Breitner, 1998)—that is, the proportion by which phenotypic varia-
tion is determined by genetic variation—the genetic make-up of complex AD,
which, owing to its later onset age (! 65 years), is also known as ‘‘late-onset AD’’
(LOAD), has proved to be much more diYcult to decipher. This is at least in part
due to problems that generally aggravate epidemiological research in many
neuropsychiatric diseases, for example, small genetic eVect sizes and reduced
penetrance of the involved genetic factors, a considerable degree of phenotypic
variability and co-morbidity with other late-onset disorders, the lack of extended
pedigrees for LOAD cases, and the absence of disease-specific biomarkers
(Kennedy et al., 2003). The identification of susceptibility genes is further
 CURRENT STATUS OF ALZHEIMER’S GENETICS 169

complicated by gene-gene interactions that are diYcult to predict and model, and
a sizeable but diYcult to detect and measure environmental component.
Notwithstanding these challenges, several chromosomal regions thought to
harbor novel LOAD genes have been identified via whole genome linkage
analyses, some, for example, on chromosomes 9, 10, and 12, overlapping across
diVerent samples (Bertram et al., 2000; Blacker et al., 2003; Ertekin-Taner et al.,
2000; Hamshere et al., 2007; Kehoe et al., 1999; Li et al., 2002; Myers et al., 2000;
Pericak-Vance et al., 2000). Furthermore, well over 1000 ‘‘candidate gene’’
studies—that is, studies that focus on certain genes based on some prior hypothesis
regarding their potential involvement in the disease process—have been published
over the past two decades claiming or refuting genetic association between putative
AD genes and aVection status and/or certain endophenotypes (Bertram et al., 2007).
Currently, nearly 150 AD genetic association papers are published each year,
at increasing pace. However, with the exception of one genetic variant, the
e4-allele of the apolipoprotein E gene (APOE; Saunders et al., 1993; Strittmatter
et al., 1993) none of these candidates has been proved to consistently influence
disease risk or onset age in more than a handful of samples (Bertram and
Tanzi, 2008). Instead, most studies of ‘‘novel AD genes’’ have been followed by a
large number of conflicting reports, challenging prior claims that they may play an
important role in contributing to disease risk. For geneticists as well as clinicians the
growing number of (mostly conflicting) genetic association findings in AD has
become increasingly diYcult to follow, evaluate, and interpret.

II. Genome-Wide Association Studies in AD

An alternative to the traditional candidate gene approach is aVorded by

recent advances in large-scale genotyping technologies which now enable
researchers to perform comprehensive and largely hypothesis-free genome-wide
association studies (GWAS; Craddock et al., 2008; McCarthy et al., 2008). Four
groups have reported the results of AD GWAS to date (Table I; Bertram et al.,
2008a; Coon et al., 2007; Grupe et al., 2007; Li et al., 2008). The first (Grupe et al.,
2007) tested roughly 17,000 single nucleotide polymorphisms (SNPs) in or very
near genetic coding regions (‘‘cSNPs’’). The only polymorphisms found to consis-
tently associate with AD risk across the diVerent samples were located in close
proximity to APOE, and most likely reflect linkage disequilibrium (LD) with the
e4-allele. Although a number of additional loci were highlighted as potential AD
genes by the authors, none showed the same consistency of eVect or same level of
statistical significance as the e4-related variants. The second study (Coon et al.,
2007) tested "500,000 SNPs in roughly 1100 unrelated AD cases and controls.
 TABLE I
OVERVIEW OF ALL PUBLISHED GWAS IN AD

No. AD cases No. controls

GWA study Design Population No. SNPs (total)a (total)a ‘‘Featured’’ genes

Grupe et al. (2007) Case-control USA and UK 17,343 380 (1428) 396 (2062) APOE*, ACAN, BCR, CTSS,
EBF3, GALP,
GWA_14q32.13,
GWA_7p15.2, LMNA,
LOC651924, MYH13,
PCK1, PGBD1, THEM5,
TNK1, TRAK2, UBD

170
Coon et al. (2007) and Case-control USA, Netherlands 502,627 446 (861) 290 (550) APOE*, GAB2
Reiman et al. (2007)
Li et al. (2008) Case-control Canada 469,438 753 (1071) 736 (985) APOE*, GOLM1,
GWA_15q21.2,
GWA_9p24.3
Bertram (2008) Family-based USA 484,522 941 (2708) 404 (1242) APOE*, ATXN1, CD33,
GWA_14q31,

Modified after content on the AlzGene Web site (http://www.alzgene.org; current on October 31st, 2008). Studies are listed in order of publication date.
‘‘Featured Genes’’ are those genes/loci that were declared as ‘‘associated’’ in the original publication, note that criteria for declaring association may vary across
studies.
*
Indicates that surrogate markers were used for APOE.
a
Numbers of ‘‘AD cases’’ and ‘‘controls’’ refer to sample sizes used in initial GWA screening, whereas ‘‘total’’ refers to initial sample plus any follow-up
samples (where applicable); please consult AlzGene Web site for more details on these studies.
 CURRENT STATUS OF ALZHEIMER’S GENETICS 171

Again, with the exception of a single SNP in strong LD with APOE-e4, no other
genome-wide significant signals were observed. In a follow-up paper (Reiman
et al., 2007), the same group reported evidence of association with variants in the
gene encoding GRB2-associated binding protein 2 (GAB2) on chromosome
11q14, which only became evident after their samples were stratified for APOE-
e4, that is, when AD cases and controls were divided into carriers and non-carriers
of the e4-allele. A third group (Li et al., 2008) tested nearly "470,000 markers and
reported association with variants in golgi membrane protein 1 (GOLM1) on
chromosome 9q22 and two currently uncharacterized loci on chromosomes 9p
and 15q. Finally, our own group (Bertram et al., 2008a) recently reported the
results of the first GWAS using family-based samples ("1400 DNAs from over
400 families), as opposed the three previously summarized studies which were
solely based on case-control datasets. Applying the same 500 K marker array as in
Coon et al. (2007) and Li et al. (2008) we found—in addition to APOE-e4—
evidence for a number of potential AD loci (Table I). Although the findings
from these first GWAS hold the promise of pinpointing novel pathways and
mechanisms potentially important in AD pathogenesis, it will be important to
await consistent replication by independent investigators.
While these and several of the forthcoming GWAS have the potential to
significantly advance our understanding of the genetics and pathogenetic
mechanisms of AD and other neurodegenerative disorders, it needs to be empha-
sized that in many ways genome-wide screens are actually not so diVerent from
conventional candidate gene association analyses. Both search for significantly
diVerent allele or genotype distributions or transmissions in subjects aVected by
the disease/phenotype as compared to presumably healthy individuals. The two
approaches diVer mostly on a quantitative level: instead of testing a few tens of
markers (or less), GWAS simultaneously screen a few hundreds of thousands of
markers (or more). The major qualitative diVerence between a GWAS and candi-
date gene analysis is that the former investigates the whole genome in a more or
less unbiased fashion, whereas the latter only investigates a limited number of
specific loci proved or thought to be involved in disease predisposition or progres-
sion (e.g., in AD many of these loci are involved in the production, traYcking, or
removal of A!). On the downside and owing to their sheer number of polymorph-
isms tested, GWAS actually substantially compound the problem that has plagued
genetic studies of complex phenotypes in the past, that is, to determine which of
the many reported putative risk alleles are ‘‘real’’ as opposed to which merely
reflect statistical artifacts. The first essential step in diVerentiating these two
alternatives is to provide independent replication of the association (McCarthy
et al., 2008), just as for any result emerging from ‘‘old-fashioned’’ candidate gene
analyses.
172 LARS BERTRAM

III. Systematic Field Synopsis and Meta-Analyses: The AlzGene Database

In an attempt to facilitate the interpretation of association findings regardless

of the technology used for initial detection, we have recently created a publicly
available database, ‘‘AlzGene’’ (http://www.alzgene.org), which systematically
collects, summarizes and meta-analyzes all genetic association studies published
in the field of AD, including GWAS (Bertram et al., 2007). After thorough (and
ongoing) searches of the available scientific literature, studies published in peer-
reviewed journals that are available in English are included in the database. Key
variables (such as ancestry, type of AD diagnosis, sample size, onset age, and
genotype distributions) are extracted from the original publications. Furthermore,
published genotype data from independent case-control samples are systemati-
cally meta-analyzed. Because this approach quantitatively synthesizes all of the
published genotype data for each polymorphism, it facilitates the overall interpre-
tation of association findings: rather than relying on the either ‘‘positive’’ (that is,
statistically significant) or ‘‘negative’’ (that is, insignificant) outcomes of individual
studies, it produces a summary risk estimate (called the odds ratio) that takes into
consideration all data at once and accounts for within and between study
variation.
Currently, AlzGene includes more than 1100 individual studies and show-
cases the results of over 200 individual meta-analyses. In these, more than 20
genes that are not related to the well-established APOE-e4 allele show nominally
significant risk eVects (Table II). Interestingly, about one fourth of these were
originally implicated by one of the four published GWAS, although independent
replication by other groups is still lacking for most of these findings. As can be seen
in Table II, the average allelic summary odds ratio (OR), for non-APOE-related
eVects are very modest ("1.2 for ‘‘risk’’ alleles and "0.8 for ‘‘protective’’ alleles)
compared to an OR of "3–4 for a single copy of the APOE-e4 allele. These
modest eVect sizes are in good agreement with those found in other large-scale
studies on the genetics of complex diseases (Allen et al., 2008; Ioannidis et al., 2001;
Lohmueller et al., 2003) and have important (and well known) implications for the
design of future genetic association studies in AD, as sample sizes will need to be
vastly increased to detect or exclude ORs of 1.25 or below with suYcient
confidence. For instance, to detect an allelic OR of 1.25 with 80% power at a
P-value of 0.05 sample sizes between "1400 and 6000 combined cases and
controls are needed for disease allele frequencies ranging from 0.50 to 0.05,
respectively (Bertram, 2008). Sample sizes need to be increased approximately
fivefold to detect such modest eVects with the same power at P-values below
5 # 10$8, that is, one proposed threshold for declaring genome-wide significance
(Hoggart et al., 2008; McCarthy et al., 2008).
 TABLE II
ALZGENE ‘‘TOP RESULTS’’ (CURRENT ON OCTOBER 31ST, 2008)

AlzGene OR No. No.

Locus/Gene Polymorphism (95% CI)a P-value No. AD controls Samplesb Ethnicity

APOEc "2/3/4 3.81 (3.38-4.29) <1 # 10$30 2325 3574 23 CAU

CHRNB2 rs4845378 0.67 (0.50-0.90) 0.007 576 787 4 ALL
GAB2 rs10793294 0.69 (0.54-0.88) 0.0025 2073 1836 5 CAU
CH25H rs13500 1.44 (1.08-1.93) 0.01 1549 1506 6 ALL
SORL1 SORL1-18ex26 0.70 (0.50-0.98) 0.04 743 913 3 CAU
CALHM1 rs2986017 1.42 (1.27-1.59) 1.2 # 10$9 2043 1361 5 ALL
CST3 50 UTR-157 1.28 (1.05-1.56) 0.02 804 571 3 CAU
ACE rs1800764 0.79 (0.68-0.92) 0.002 818 747 4 CAU
PGBD1 rs3800324 1.25 (1.04-1.51) 0.02 2736 2964 6 ALL
MAPT/STH rs2471738 1.24 (1.01-1.53) 0.04 1734 1411 6 ALL
SORCS1 rs600879 1.24 (1.04-1.48) 0.02 1361 1495 4 ALL

173
hCG2039140 rs1903908 1.23 (1.06-1.44) 0.007 1368 1497 4 ALL
TFAM rs2306604 0.82 (0.72-0.94) 0.003 1059 792 5 ALL
IL1B rs1143634 1.18 (1.03-1.34) 0.02 1011 1244 5 ALL
TF rs1049296 1.18 (1.04-1.33) 0.01 1916 4058 9 ALL
TNK1 rs1554948 0.86 (0.80-0.93) 0.0002 2743 2984 6 ALL
LOC439999 rs498055 1.15 (1.03-1.29) 0.02 2787 2498 7 ALL
GAPDHS rs4806173 0.87 (0.75-1.00) 0.05 1687 1775 4 ALL
DAPK1 rs4878104 0.88 (0.82-0.95) 0.002 2753 3036 7 ALL
PRNP rs1799990 0.88 (0.81-0.96) 0.03 2280 2943 10 CAU
GWA_14q32.13 rs11622883 0.88 (0.80-0.97) 0.01 2685 2893 6 ALL
GALP rs3745833 1.13 (1.00-1.29) 0.05 2739 2975 6 ALL

(Continued)
 TABLE II (Continued)

AlzGene OR No. No.

Locus/Gene Polymorphism (95% CI)a P-value No. AD controls Samplesb Ethnicity

LOC651924 rs6907175 0.89 (0.82-0.96) 0.005 2359 2522 6 ALL

NEDD9 rs760678 0.89 (0.81-0.97) 0.01 3452 3245 8 ALL
MTHFR rs1801133 1.11 (1.02-1.21) 0.02 2887 4663 24 ALL
ENTPD7 rs911541 1.10 (1.01-1.21) 0.03 3429 3743 4 ALL
BDNF rs6265 1.09 (1.02-1.18) 0.015 5299 4671 15 CAU
IL1A rs1800587 1.09 (1.00-1.18) 0.04 5296 5321 25 ALL

174
List of loci, in descending order of genetic eVect size, containing at least one polymorphism showing nominally significant (P-value %0.05) summary ORs in
AlzGene on October 31st, 2008. To be considered as ‘‘Top Result,’’ summary OR needs to be significant across samples from all ethnic backgrounds (‘‘ALL’’) or
in Caucasians only (‘‘CAU’’). Whenever nominally statistically-significant results are observed for both, that is, ALL and CAU, only the analysis that has the
largest genetic eVect size (OR deviating the most from 1) is reported here. Note that AlzGene is continuously updated, so results displayed online may diVer from
the results above; consult the AlzGene Web site for up-to-date numbers and additional meta-analyses in these and other loci (http://www.alzgene.org) (see also
Table I).
a
Summary ORs and 95% confidence intervals (CI) are based on random-eVects allelic contrasts comparing minor versus major alleles at each
polymorphism.,
b
Number of samples refers to the number of independent case-control samples used in the meta-analyses; multiple samples may be reported in the same
publication and are considered separately if they are independent, that is, non-overlapping. Samples overlapping across publications are only used once, usually
by including the datasets with the largest number of available genotypes,
c
Results are based on comparing "4- versus "3-alleles at this locus.
 CURRENT STATUS OF ALZHEIMER’S GENETICS 175

IV. Strengths and Limitations of the AlzGene Approach

The strengths of AlzGene are obvious: assuming that the literature searches,
inclusion criteria, data management, and data analysis procedures actually provide a
correct and exhaustive account of the available literature, AlzGene is the single most
comprehensive resource for the status of genetics research in AD available to date. In
our original data freeze (Bertram et al., 2007) we could show that literature searches
in AlzGene outperformed those of several other literature/genetics databases, and
that the results of our meta-analyses were in very good agreement with estimates
published previously in nearly two dozen individual papers. Similar observations
were made in related database projects from our group (Allen et al., 2008; Bagade
et al., 2006). Published meta-analyses, however, have one important disadvantage:
by nature of their design, they run the risk of becoming outdated quickly, possibly as
soon as new data from one or two additional studies are published. Provided that
suYcient funding remains available, AlzGene does not have this caveat. Also, any
meta-analysis in the database can be updated literally within days after the publica-
tion of novel data. Another strength of AlzGene is that it is not limited to meta-
analyses on certain genes or networks of genes (e.g., those that are in the same
pathway or gene family), but considers all published loci simultaneously, making the
comparison of results across studies, genes, pathways, chromosomal regions, and so
on extremely easy. Finally, as outlined above, all loci containing at least one
polymorphism nominally significant by meta-analysis are separately highlighted
on the database’s homepage in a section called ‘‘Top Results.’’ Thus, consulting
this section of the AlzGene Web site will provide the user with a complete—and
essentially real time—snapshot of the ‘‘most promising’’ AD candidate genes, based
on the systematic evaluation of literally hundreds of individual studies and thousands
of data points. As such, the ‘‘Top Results’’ list could help prioritize future genetic
association studies (e.g., for further independent replication, or fine mapping), and
guide functional genetics and molecular studies investigating the potential pathoge-
netic mechanisms underlying the genetic associations.
While AlzGene undoubtedly represents a leap forward in managing and
displaying the data gathered within the domain of AD genetics research, its overall
approach, too, comes with some strings attached. First and foremost, despite our
comprehensive and systematic searches of the scientific literature, we cannot
exclude the possibility that some AD association studies were overlooked or
entered erroneously. This can be partly alleviated with the help of database users
who are explicitly encouraged to alert the curatorial team of any errors or omis-
sions, which will be fixed as soon as possible. Other limitations include our
restriction to allele contrasts in the meta-analyses (which allows no inference
of the true underlying mode of inheritance and is usually less powerful than
genotype-based tests), the non-consideration of haplotype-based genotype data or
176 LARS BERTRAM

imputed single-locus genotypes (possibly missing important associations), the exclu-

sive focus on ‘‘main eVects’’ (and the inherent inability to account for gene-gene and
gene-environment interactions), and the lack of adjustment for certain co-variates
such as age or gender (which is impossible to do systematically without access to
subject-level raw data). Further, protection from bias, in particular publication bias
and other sorts of reporting biases, is particularly diYcult to ensure or assess, and is
likely to aVect some of the meta-analysis results. Finally, the single most important
caveat of the AlzGene approach is that the number of ‘‘true’’ associations is almost
certainly going to be smaller than the number of nominally significant findings listed
at any time on the AlzGene Web site (see also: Ioannidis, 2005; Wacholder et al.,
2004). This has a number of causes, including multiple testing, linkage disequilibrium
among associated variants, undetected publication or other reporting biases, as
well as study-level technical artifacts that may have gone unnoticed or may be
impossible to detect. Furthermore, most of the ‘‘positive’’ meta-analysis outcomes
currently do not reach very high levels of statistical significance (see Table II), only
two attaining the threshold for genome-wide significance, for example, a P-value
%5 # 10$8. While this, too, could be due to a number of factors including small
eVect size and insuYcient power even after combining all of the available data, it is
important to emphasize that the possibility of a false-positive finding always exists,
even for the highest ranked ‘‘Top Result.’’ Eventually, genuine risk eVects can only
be ‘‘proved’’ by the accumulation of suYcient unbiased and high-quality genotype
data (e.g., originating from case-control and family-based designs, see below) in
favor of the presumed association in combination with functional genetics and
biological evidence suggesting a direct biochemical effect of the associated variant
(McCarthy et al., 2008). Of course, such evidence can be diYcult to come by. For
instance, despite the unambiguous role of the APOE-e4 allele in increasing the risk
for AD (see above), the precise mechanism underlying this association remains
only poorly understood (Tanzi and Bertram, 2005). Notwithstanding these limita-
tions, there is good reason to believe that the variants and loci highlighted in the
‘‘Top Results’’ section of AlzGene and related databases currently represent our
best bets as to which of the hundreds of putative candidate genes might genuinely
contribute to disease susceptibility and pathogenesis. As such, they probably
warrant follow-up with high priority.

V. Assessment of Case-Control Associations Using Family-Based Methods

A first round of genetic follow-up of the most promising of these associations

was recently completed in a number of projects from our group (Bertram et al.,
2008b; Schjeide et al., 2009a,b). In particular, we assessed whether or not any of
the AlzGene ‘‘Top Results’’ and/or any of the loci pinpointed by the two
 CURRENT STATUS OF ALZHEIMER’S GENETICS 177

high-density case-control GWAS (Li et al., 2008; Reiman et al., 2007) showed
association in a total of four family-based datasets comprising nearly 4200 DNAs
from over 1300 independent AD families. This was an important question as many
of the investigated variants had been thoroughly tested across relatively large
numbers of independent case-control datasets, but only a handful were also
previously assessed in family-based samples, which may be genetically diVerent
from unrelated, population-based cases and controls. Family-based methods have
the additional advantage of being robust against bias due to undetected population
stratification and phenotype misspecifications (Laird and Lange, 2006), which may
have aVected some of the case-control meta-analysis results. After combining the
results across all four datasets, we observed nominally significant association with
variants in ACE, CHRNB2, GAB2, TF, and an as yet unidentified locus on chromo-
some 7p15.2 (Table III). Two of these loci, that is, ACE and TF, were also found to
be associated with A! levels in CSF in an independent collection of AD cases and
controls (Kauwe et al., 2009). The independent convergence of (i) significant meta-
analysis results across case-control samples, (ii) replication of these associations in
AD family samples, and (iii) in the case of ACE and TF, a significant genotype-
dependent correlation with one of the few established biomarkers in AD, strongly
implies a genuine disease-risk modifying role of these loci, arguably more so than
for any of the other hundreds of suggested AD candidate genes besides APOE.
Functionally, all of these potential new AD susceptibility loci are interesting
and, if confirmed, may not only lead to a better understanding of the pathogenetic
mechanisms driving neurodegeneration, but may also help to pinpoint novel
treatment options for AD. ACE encodes angiotensin converting enzyme-1
(ACE-1), a ubiquitously expressed zinc metalloprotease that is involved in blood
pressure regulation. Several epidemiological studies suggest that high mid-life
blood pressure may increase the risk for AD in later life (Takeda et al., 2008).
More recently, ACE-1 activity has been reported to be increased in AD brains
proportionately to parenchymal A! load (Miners et al., 2008). The interpretation
of ACE’s role in AD pathogenesis is complicated by the observation that it is able
to degrade naturally secreted A! in vitro (Hu et al., 2001), which would predict an
increased risk in individuals with reduced ACE-1 levels/activity, that is, opposite
to what would be expected from the epidemiological data and the genetic associ-
ation results. CHRNB2 encodes the neuronal beta-2 nicotinic cholinergic receptor
(!2nAChR). Nicotinic acetylcholine receptors (nACcRs) are widely expressed in
the CNS, where the !2nAChR subunit is particularly abundant, forming hetero-
pentameric receptors with !4nAChR subunits (#4!2; Kalamida et al., 2007).
Pathologically, the reduction of nAChRs and the loss of cholinergic neurons in
disease-relevant brain regions is one of the major neurochemical hallmarks of
AD (Oddo and LaFerla, 2006), and several studies have suggested that an
age-dependent decrease in protein and/or mRNA levels of the #4!2-subtype
(in particular !2nAChR) occurs in the cortex and hippocampus of healthy
 TABLE III
ASSESSMENT OF CASE-CONTROL ASSOCIATIONS IN AD FAMILY DATASETS

Case-control (AlzGene) Family based (combined family datasets)

Gene SNP Ethnicity Model OR (95% CI) P-value No. Fams OR $2 P-valuea

ACE rs4291 CAU T vs. A 0.87 (0.76-0.99) 0.03 425 0.94 14.6 0.07
CHRNB2 rs4845378 ALL T vs. G 0.67 (0.50-0.90) 0.007 170 0.79 17.4 0.03
GAB2 rs7101429 CAU G vs. A 0.74 (0.59-0.93) 0.008 432 0.76 24.4 0.002

178
GWA_7p15.2 rs1859849 ALL C vs. T 1.11 (0.97-1.29) 0.1 335 1.26 17.5 0.03
TF rs104296 ALL C2 vs. C1 1.18 (1.04-1.33) 0.01 295 1.17 21.1 0.007

Comparison of the association evidence of AlzGene ‘‘Top Results’’ (current on October 31, 2008) and family-based analyses (Schjeide et al., 2009a,b). Note
that the meta-analyses for rs1859849 in GWA_7p15.2 are currently only marginally significant (P-value 0.1), but were nominally significant at the time of
genotyping in the Schjeide et al. (2009a) project. For up-to-date meta-analysis results on these variants, please consult the AlzGene Web site (http://www.alzgene.
org). ALL ¼ combining samples of all ethnic groups; CAU ¼ combining samples of Caucasian ethnicity only; No. Fams ¼ No. informative families; ‘‘OR’’
¼ summary odds ratio; ‘‘95% CI’’ ¼ 95% confidence intervals.
a
Test statistics are based on combining one-tailed P-values for each variant across all four samples using Fisher’s combined probability test, which results in
an 8 d.f. test. Single-locus analyses with variants in ACE only show marginally significant eVects (P-value 0.07), while haplotype-based analyses yielded P-values
<0.05 (see Schjeide et al.(2009a) for more details).
 CURRENT STATUS OF ALZHEIMER’S GENETICS 179

individuals (Tohgi et al., 1998), which could be exacerbated in carriers of the AD

risk allele. GAB2 encodes GRB2-associated binding protein 2 (Gab2) which is a
member of a family of evolutionarily highly conserved scaVolding/adapter pro-
teins that are involved in multiple signaling pathways, and in particular in the
transduction of cytokine and growth receptor signaling (Liu and Rohrschneider,
2002; Sarmay et al., 2006). Gab2 is ubiquitously expressed, but is found at
particularly high levels in white blood cells, prefrontal cortex, and hypothalamus.
It was suggested that changes in Gab2 expression could potentially aVect Gsk3-
dependent phosphorylation of tau and the formation of neurofibrillary tangles
(Reiman et al., 2007). Moreover, growth factor receptor-bound protein 2, which
binds Gab2, has been reported to bind both tau (Reynolds et al., 2008), APP, and
presenilin 1 and 2 (Nizzari et al., 2007), and these interactions have been proposed
to regulate signal transduction. TF encodes transferrin which is the major circu-
lating glycoprotein involved in iron metabolism and is highly expressed in the
brain. There is a vast body of literature suggesting that iron dysregulation
promotes neurodegeneration, possibly via the generation of reactive oxygen
species (Brewer, 2007). In AD, iron has been found to be increased in the brains
of AD patients (LoeZer et al., 1995), where it is associated with plaques and NFTs
(Smith et al., 1997). More recently, it was suggested that iron may also play a role
in the aggregation of hyperphosphorylated tau into insoluble paired helical fila-
ments, one of the core ingredients of NFTs (Yamamoto et al., 2002). Thus it is
conceivable, although not yet experimentally proved, that the AD-associated
amino acid changing variant in TF (Pro570Ser) may interfere with all or some
of these roles in AD pathogenesis. Finally, the chromosome 7p15.2 association signal
maps close to a predicted gene, NT_007819.514, encoding a protein of 358
residues, whose N-terminus exhibits a strong homology to a family of ubiquitin-
like proteins, for example, human ubiquitin C. Thus, the predicted protein
possibly plays a role in protein degradation.
Figure 1 summarizes the potential pathogenetic implications of these and several
other of the currently most compelling AD susceptibility genes. Note that this
summary represents only a snapshot of the presently available data, and that the
set of genes thought to be involved in predisposing for LOAD today is likely going to
change over time. For a more detailed review on the functional implications of these
and other compelling AD candidate genes see Bertram and Tanzi (2008).

VI. Conclusions

Despite intensifying eVorts to unravel the genetic underpinnings of AD, suc-

cesses to date have been modest. This situation is expected to change dramatically
with the advent of novel, genome-wide analysis tools that are becoming increasingly
180 LARS BERTRAM

APOE

GWA CST3 ACE GAB2 MAPT TF

CH25H SORL1 CHRNB2 PRNP
14q
??

Ab ACh transmission Ab-aggregation Ab-clearance Tau-dysfunction

CNS cholesterol Neuroprotection Ab-degradation Cerebrovascular Oxidative stress

Non-
genetic Inflammation
Neurodegeneration

FIG. 1. Potential pathogenetic roles of AD susceptibility genes. Simplified summary of the potential patho-
physiologic implications of the currently most promising AD susceptibility loci, including those of recent
GWAS. Note that none of the genetic associations (except APOE ) can be considered unequivocally
established; the same is true for any of the proposed potential functional implications. Highlighted
eVects are likely further influenced by currently unknown gene-gene interactions and the contribution
of nongenetic factors as well as inflammatory reactions (which themselves are likely genetically con-
trolled). For didactic purposes, not all presumed or established functional implications have been
indicated, for example, GAB2’s role on APP metabolism via binding of Grb2. GWA 14q indicates
GWAS locus identified by Bertram et al. (2008a). For a more detailed discussion of the potential role of
these and other AD candidate genes see Bertram and Tanzi (2008).

popular, but it remains to be seen whether GWAS will live up to these expectations.
In the interim, systematic bioinformatics approaches synthesizing the results from
both candidate gene and genome-wide analyses will help researchers to keep track
of the myriad of genetic association findings to come. One such approach, the
AlzGene database, is now available, and already highlights a number of promising
AD loci by means of systematic, unbiased meta-analysis.
As should be clear from the above discussion, AlzGene does not aim to deliver
the last piece in the puzzle that AD genetic epidemiology research is trying to
solve. Rather, it attempts to provide a tool that can help researchers of many
disciplines decide which piece of the puzzle to try next. In the best case scenario, it
will also help to sharpen the overall picture of the genetic forces driving AD
predisposition and pathogenesis. Eventually, only the concerted eVorts of genet-
ics, genomics, proteomics, and clinical disciplines will give rise to new diagnostic
and therapeutic targets that, hopefully in the not too distant future, will benefit the
millions of patients aZicted with this devastating disorder.

Acknowledgments

Funding for AlzGene was provided by the Cure Alzheimer’s Fund (to LB). We are grateful to the
Alzheimer Research Forum (http://www.alzforum.org) for hosting AlzGene on their Web site.
 CURRENT STATUS OF ALZHEIMER’S GENETICS 181

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 FRONTOTEMPORAL LOBAR DEGENERATION: INSIGHTS FROM
NEUROPSYCHOLOGY AND NEUROIMAGING

Andrea C. Bozoki and Muhammad U. Farooq

Department of Neurology, Michigan State University, East Lansing, Michigan, 48824, USA

I. Introduction
A. Diagnosis of FTLD
B. Clinical Criteria
C. Histopathology
D. Genetics
II. Classification of FTLD Subtypes and Their Features
A. Frontotemporal Degeneration
B. Primary Progressive Aphasia or Progressive Nonfluent Aphasia
C. Semantic Dementia
III. Neuropsychological Assessment
A. Distinguishing FTLD from AD
B. Distinguishing FTLD Subtypes
IV. Neurobehavioral Assessment
A. FTD
B. PPA
C. SD
V. Neuroimaging of FTLD
A. Differentiation of FTLD from AD
B. Differentiation of Different Subtypes of FTLD
VI. Summary
References

Frontotemporal lobar degeneration (FTLD) is a diagnostic term that encom-

passes three distinctly diVerent syndromes, united by historic as well as pathologic
commonalities. We briefly review the origins of the current classification scheme
for diagnosing the three major subtypes—frontotemporal dementia, semantic
dementia, and primary progressive aphasia, highlighting the diVerences between
subtypes as well as from Alzheimer’s disease (AD). We briefly examine current
understanding regarding the histopathology and genetics of FTLD but note that
there is a poor correspondence of these features with specific subtypes of FTLD.
For clinicians and clinical researchers, this implicates the need for other diagnos-
tic strategies. Neuropsychological and neurobehavioral testing currently oVers the
most sensitive and specific method for identifying subtypes, and discriminating
FTLD from other forms of dementia. Multiple studies from the relevant literature

INTERNATIONAL REVIEW OF 185 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00410-3 0074-7742/09 $35.00
186 BOZOKI AND FAROOQ

are reviewed, highlighting those findings that are likely to be most valuable to
physicians. Finally, we analyze some of the major findings from the large body of
work on neuroimaging of FTLD, again focusing on those studies that potentially
help discriminate FTLD subtypes or assist with the discrimination of FTLD
from AD.

I. Introduction

Frontotemporal dementia used to be considered a rare disorder-one almost

never seen by the average clinician. The typical patient with ‘‘Pick’s disease’’ (PD)
as it was known synonymously was about 65 years old, socially inappropriate,
frequently hyperoral and became progressively more demented over a period of
5-7 years before dying.
In 1882, Arnold Pick described the clinical features of a patient with circum-
scribed lobar atrophy with an aphasic dementia. His initial cases had only gross
examination without any histological data. The clinical pattern and its relation to
focal atrophy were the basis of the syndrome. In 1911, Alzheimer described the
now-characteristic hallmark inclusion bodies, called Pick’s bodies. Other histolog-
ical findings such as ballooned achromatic neurons (Pick cells), gliosis, and
superficial cortical spongiform changes were also identified in these patients.
These histopathological findings were associated with the circumscribed frontal
and anterior temporal atrophy which Pick described in 1882, and the clinical
syndrome came to be known as Pick’s disease.
We have come a long way from these early findings. We now know that Pick’s
initial patients belong to a group of related dementias. The preferred term for this
rather heterogeneous group is frontotemporal lobar degeneration (FTLD), and it
is believed to be the second most common type of dementia in individuals younger
than 65 years (Ratnavalli et al., 2002). It remains clinically under-recognized both
due to its frequent misdiagnosis as psychiatric disease or Alzheimer’s disease (AD),
as well as limited recognition of the diVerent entities within the FTLD spectrum.
Overall, estimated prevalence ranges from 6 to 12% of dementias (Kertesz, 2006).
Currently, FTLD is divided into three main subgroups; frontotemporal
degeneration (FTD), primary progressive aphasia (PPA) (also referred to as
progressive nonfluent aphasia; PNFA), and semantic dementia (SD) (Neary
et al., 1998). Each subtype of FTLD has distinguishing features and characteristic
progression that help to distinguish it from ‘‘garden variety’’ AD. In addition,
both neuropsychological testing and neuroimaging have extended the clinician’s
ability to distinguish FTLD from AD as well as other related dementias.
 FTLD: INSIGHTS FROM NEUROPSYCHOLOGY AND NEUROIMAGING 187

A. DIAGNOSIS OF FTLD

Clinically and pathologically, FTLD is distinct from AD, although the distinc-
tion is sometimes clinically challenging (Klatka et al., 1996; Mendez et al., 1993).
A proportion of patients who meet the criteria for AD have FTLD confirmed at
autopsy, occasionally co-occurring with AD pathology. A recent pathologic study
examining the overlap of FTLD and AD clinical phenotypes described coexisting
histopathological AD in almost one fourth of FTLD cases (Liscic et al., 2007).
Autopsy-proved FTLD cases, alone or in combination with AD, can meet the
National Institute of Neurological and Communicative Disorders and Stroke, and
the Alzheimer’s Disease and Related Disorders Association (NINDS-ADRDA)
clinical criteria for AD during life (McKhann et al., 1984; Snowden et al., 2001),
suggesting a lack of specificity in the criteria for both diseases. Despite these
concerns (or perhaps because of them), several groups have put forward criteria
for the clinical diagnosis of FTLD. The sophistication of these classifications and
rating scales for FTLD has evolved since the 1980s.

B. CLINICAL CRITERIA

Gustafson and Nilsson (1982) studied 57 patients for diVerential diagnosis

between dementias. They used three rating scales for identification of Alzheimer’s
disease, Pick’s disease, and multi-infarct dementia. The rating scale for PD
contained nine items, including assessment of early loss of insight, early signs of
disinhibition, echolalia, mutism, and amimia.
Lund-Manchester groups (1994) published criteria in 1994 which required the
presence of at least two of the following features: loss of personal awareness,
strange eating habits, perseveration, and mood change. In addition, patients had
to have one or more of the following: frontal executive dysfunction, reduced
speech, and preserved visuospatial ability. Finally, the authors of the criteria
cited several important supporting features, including onset before age 65, a
family history of FTD, early urinary incontinence, motor neuron disease, and
(in the late stages) akinesia, rigidity, and tremor.
Neary and colleagues (Neary et al., 1998) incorporated most of the above features
and added some others. However, the authors subdivided patients into three
separate clinical presentations: frontotemporal dementia (characterized primarily
by personality change and disordered social conduct), PNFA (in which patients
have diYculty with initiation but not comprehension of speech; see Section II.B),
and semantic aphasia (distinguished by impaired understanding of word meaning
and/or object identity). The general term FTLD was used to refer to any of the
three syndromes.
188 BOZOKI AND FAROOQ

ECAPD Consortium, 1998. The European Concerted Action on Pick’s disease

(ECAPD) was based on the review of 50 cases of pathologically verified disease for
which adequate clinical, neuropsychological, and neuroimaging data were avail-
able. This resulted in the definition of provisional criteria for definite, clinically
probable and clinically possible Pick’s disease which emphasized the importance
of impairment of language and praxic skills.
The Work Group on Frontotemporal Dementia and Pick’s Disease (McKhann et al.,
2001). An international group of clinical and basic scientists developed these
consensus criteria in July 2000. Intended for clinicians rather than researches,
these criteria were considerably simpler than the Neary criteria and lumped
together all patients under the terminology of FTD, although the authors did
note that patients would have either a ‘‘behavioral presentation’’ or a ‘‘language
presentation.’’

C. HISTOPATHOLOGY

Originally, Pick’s disease was classified pathologically as type A (with Pick’s

bodies), type B (with only swollen neurons), and type C (with only gliosis)
(Constantinidis et al., 1974). However, in common usage, Pick’s disease referred
to patients with atrophy and disinhibition and Pick’s bodies on histopathology.
It resulted in the impression that Pick’s disease was a rare entity and diYcult to
diagnose before autopsy. Later, it was found that patients with lobar atrophy only
rarely have Pick’s bodies and often do not show the typical histologic picture on
autopsy (Constantinidis et al., 1974). Therefore, the term FTLD came into use and
a new label was given to clinical Pick’s disease; those cases without the typical
histologic picture were called frontal lobe degeneration (FLD) (Gustafson, 1987;
Neary et al., 1988). A similar clinical picture was described under the label of
‘‘dementia lacking distinctive histology’’ (DLDH) (Knopman et al., 1990).
There are a few histological features including neuronal loss, gliosis, and
superficial linear spongiosis, which are common to all histological subtypes of
FTLD. Pick cells occur with variable frequency in all variants. These are called
ballooned neurons because of their swollen appearance under light microscopy.
These cells show neuronal achromasia and express phosphorylated neurofila-
ments. Spongiform changes are seen in layers II and III of the cortex. Various
distinct features such as Pick’s bodies, astrocyte plaques (common in Corticobasal
Degeneration), tufted astrocytes (common in Progressive Supranuclear Palsy),
and ubiquitin-positive tau-negative inclusions (common in Amyotrophic Lateral
Sclerosis) known as motor neuron disease type inclusions or MNDI, have been
described but can also occur with each of the FTLD variants and are non-specific.
However, MNDI are found in more than half of the FTD cases on autopsy and
 FTLD: INSIGHTS FROM NEUROPSYCHOLOGY AND NEUROIMAGING 189

Type A (classic PD) : characterized by

Pick bodies
Pick cells
Prominent frontotemporal and
limbic degeneration

Type B: Characterized by Clinical features can

No pick bodies overlap in all these types.
Type C: Characterized by
Pick cells, which are numerous No pick bodies
throughout the superior frontal and No pick cells
parietal lobes
Either diffuse or circumscribed
Now sometimes referred to as atrophy grossly and variable
frontotemporal dementia with involvement of gray matter
parkinsonism linked to chromosome 17
Now sometimes referred to as
Sub-types which are based on inclusions: -dementia lacking distinctive histopathology
tau (MAPT mutation)
ubiquitin (PGRN mutation); has been
associated with motor neuron disease.

FIG. 1. Classification of Pick’s disease based on histopathologic features. It is important to note that
all three major clinical phenotypes have been documented with each of the pathologic subtypes.

now form the largest single pathological variety of Pick’s complex (Hodges et al.,
2004; Kertesz et al., 2005; Munoz et al., 2003) (Fig. 1).

D. GENETICS

FTLD is a ‘‘presenile’’ dementia with a strong genetic component (Chow et al.,

1999; Stevens et al., 1998). The first genetic correspondence, a linkage to chromo-
some 17 q21-22, was discovered in a large family with variable symptomatology
of frontotemporal dementia, aphasia, parkinsonism, and amyotrophy
(Wilhelmsen et al., 1994). Later, the clinical features and pathology of 12 families
resembling sporadic cases were described and the term ‘‘dominant inherited
chromosomal 17-linked frontotemporal dementia with Parkinsonism’’ (FTDP-
17) was accepted as a definite entity in a consensus conference (Foster et al., 1997).
The tau protein was suspected as the candidate gene for mutation and several tau
mutations have been identified since then which occur only in familial cases
(Hutton et al., 1998). However, tau-positive pathology is not the only substrate
of the disease, as the ubiquinated MNDI patients demonstrate (Hodges et al.,
190 BOZOKI AND FAROOQ

2004; Jackson et al., 1996). The phenotypic and pathologic variations of these
mutations closely match sporadic disease and provide strong evidence for the
cohesion of Pick’s complex.
Like histopathology, genetic testing is also not specific for the subtypes of
FTLD, with significant syndromic overlap within single mutation types. Tau
protein mutations were first reported for the phenotypes of the FTDP-17 com-
plex, which varied widely (some patients with parkinsonism, some with prominent
aphasia, some with obvious amyotrophy. Several tau mutations have been dis-
covered so far (Clark et al., 1998; Hutton et al., 1998; Spillantini et al., 1998).
DiVerent tau mutations diVerently alter the biochemical properties of tau iso-
forms, but so far these mutations do not predict the clinical presentation. In
addition, the tau protein is not abnormal in all forms of FTLD. The amount of
hyperphosphorylated tau in FTLD can be low and sometimes even absent.

II. Classification of FTLD Subtypes and Their Features

A. FRONTOTEMPORAL DEGENERATION

FTD is the most common diagnostic subgroup of FTLD; over half of FTLD
patients fall in this category (Hodges et al., 2003). FTD also has the earliest age at
onset, often between 55 and 65, and almost never after age 75 ( Johnson et al.,
2005; Rosso et al., 2003). FTD is characterized by personality and behavioral
changes. The initial manifestations can be subtle and diYcult to diagnose begin-
ning with apathy and disinterest which is often misdiagnosed as depression
(Kertesz, 2003). These patients later develop lack of insight and disinhibition,
impulsive and inappropriate behavior, poor financial judgment, changes in libido
and inappropriate sexual behavior, blunting of appropriate behavioral response
and at the extreme, self-destructive behavior (McKhann et al., 2001). Their
dietary habits may change, resulting in overeating or eating of only certain
types of food. The overall appearance and personal hygiene of these patients is
frequently aVected as they show little personal concern for their actions. These
patients can have problems with their memory, and formal memory testing can be
abnormal, but they can track day-to-day events and do not have a typical
amnestic syndrome (McKhann et al., 2001). Frontal lobe functions are impaired
in these patients but some can continue to perform well on formal measures of
frontal tasks early in the disease course. Orientation and episodic memory is also
relatively preserved; problems of forgetfulness are mainly due to inattention and
poor organization of incoming information (Kertesz, 2003). Language is not
aVected early in the course of this disease; however, most patients eventually
develop decreased verbal output and often progress to mutism in later stages
(Kertesz, 2003).
 FTLD: INSIGHTS FROM NEUROPSYCHOLOGY AND NEUROIMAGING 191

B. PRIMARY PROGRESSIVE APHASIA OR PROGRESSIVE NONFLUENT APHASIA

The term PPA was first used by Mesulam (1982) to describe a group of six
patients who developed a slowly progressive aphasic disorder that ‘‘began in the
presenium’’ (before age 65). These patients present with language diYculty
characterized by a combination of word finding diYculties, abnormal speech
patterns, decreased comprehension, and impaired spelling. In the early part of the
disease these patients are able to perform their daily activities and have normal
memory and visuospatial function. Mesulam’s original description stressed the
lack of a generalized dementia, and his criteria eventually included a stipulation
that the patient’s language diYculties should remain the only feature for at
least 2 years before more generalized deficits develop (Weintraub et al., 1990).
Language deficits ultimately progress to mutism, however, these patients instead
of developing a severe dementia in the advanced stages of their disease may have
relatively preserved memory and can function well in the community, further
helping to distinguish them from patients with AD (Kertesz, 2003). While the
typical PPA patient does not have florid psychiatric features the way many FTD
patients do, some can develop the behavioral problems seen in patients with other
forms of FTLD in the later part of the disease and the distinction may become
diYcult in advanced cases, when both mutism and inappropriate behavior are seen.

C. SEMANTIC DEMENTIA

Snowden et al. described a distinct, fluent form of PPA that is diVerent from
the more common nonfluent type and called this semantic dementia (Snowden
et al., 1989). In this condition patients slowly and progressively lose the meaning of
words; however, fluency remains intact and they are able to carry on a (somewhat
empty) conversation. They have diYculty naming and comprehending even
single nouns (Hodges et al., 1992; Kertesz, 2003). These patients diVer from the
fluent aphasia of AD as they have relatively preserved episodic and autobiograph-
ical memory with a rather selective loss of semantic memory. These patients retain
information that has immediate relevance to their environment or to their person;
however, they lose the meanings of other common things. Some of these patients
have visual agnosia (Kertesz, 2003). Patients with SD ultimately become non-
fluent and even mute. They also develop behavioral problems in the later part of
their disease.
We note that some authors categorize PPA and SD together as the language
and aphasic variant of FTLD. In this nosologic schema, FTD represents the
frontal variant of FTLD and PPA/SD together represent the temporal/parietal
variant (Kertesz, 2003).
192 BOZOKI AND FAROOQ

In addition, there is controversy regarding the separate existence of a fluent

form of PPA distinct from both the more common dysfluent PPA and SD (Adlam
et al., 2006). In this schema, PPA is thought to present in both fluent and nonfluent
forms. Some patients who meet the criteria for fluent PPA show nonverbal and
verbal deficits in conceptual knowledge and other tasks that depend upon such
knowledge, provided that the measures used allow for the vital impact of concept
and typicality. If more emphasis is placed on the prominent language disorder,
these individuals can be classified as fluent PPA; if more emphasis is placed on the
multimodal pattern of deficits, these individuals can be seen as having SD.

III. Neuropsychological Assessment

A. DISTINGUISHING FTLD FROM AD

1. Comments Regarding the MMSE and FTLD

Although neuropsychologists typically disdain the Folstein Mini Mental State
Exam (MMSE; Folstein et al., 1975) as being far too cursory to be useful, it is
commonly used by clinicians as a screening tool for the presence of dementia and
therefore worthy of comment in this chapter. The MMSE is heavily weighted
toward verbal skills and gives relatively short shrift to executive processing. As
such, compared with AD, it may underestimate dementia severity for FTD and
overestimate it for PPA/SD. Clinicians are especially cautioned not to consider a
normal-range MMSE score in a patient with suspected FTD as indicating the
absence of disease. A recent study (Osher et al., 2007) which compared FTD and
PPA (but did not include AD), found that MMSE scores over time did correlate
with changes on a measure of activities of daily living (the Activities of Daily
Living Questionnaire or ADL-Q; Johnson et al., 2004). However, PPA patients
showed relatively greater declines, suggesting that the MMSE overestimates
dementia severity for PPA patients but that the score may accurately measure
functional impairment in FTD (Fig. 2).

2. FTD
Attempts to distinguish FTD from AD based only on neuropsychological
testing have a long and controversial history. Numerous papers on this topic,
spanning several decades, have failed to agree on whether it is possible to do this
reliably. One group (Gregory et al., 1997) failed to find diVerences between patient
groups in memory, attention, language, and executive abilities, while another
(Pasquier et al., 1995) did not find any diVerence in letter and category verbal
fluency (a frequently used bedside test for evaluating frontal lobe function).
 FTLD: INSIGHTS FROM NEUROPSYCHOLOGY AND NEUROIMAGING 193

Neuropsychological profiles in FTLD subtypes and AD

Factor analysis composite indices: Between-group comparisons

1

0.8

0.6 Declarative memory

Working memory/
0.4 visuoconstruction
Lexical retrieval
0.2
Semantic memory

0 Processing speed/mental
flexibility
FTD SD PPA AD
−0.2

−0.4

−0.6

−0.8

FIG. 2. Factor analysis of a multitest neuropsychological battery demonstrated five major cognitive
factors. Between- and within-group analyses of the factors demonstrate that each patient group is
associated with a specific profile of neuropsychological impairment, in which each group is significantly
worse than the others on at least one factor (data from Libon et al., 2007).

Conversely, several more recent studies have found the opposite; that a double
dissociation between AD and FTD exists and can be identified with careful
neuropsychological assessment. Perri and colleagues (2005) performed a stepwise
discriminant analysis on a number of neuropsychometric variables and deter-
mined that subjects with AD were significantly worse on the Rey figure copy
(a measure of visuospatial praxis) and significantly better on letter fluency than the
FTD group, such that a combination of these two tests plus a measure of apathy
(see Section IV) was suYcient to distinguish the two diseases with approximately
83% sensitivity and 82% specificity.
Also in 2005, a group from the UK (Thompson et al., 2005), observing that
patients with FTD tend to make diVerent types of mistakes from those with AD,
developed a way to assess qualitative performance and error types on their
neuropsychometric battery. They found that ‘‘FTD patients displayed features
associated with frontal lobe dysfunction, such as concrete thought, perseveration,
confabulation, and poor organization, which disrupted performance across the
range of neuropsychological tests.’’ They advise that keeping track of the types and
not just the number of errors made in performing neuropsychological tests can
greatly enhance discrimination of these patient populations.
194 BOZOKI AND FAROOQ

Nonetheless, while this chapter finds that FTD and AD can be discriminated
neuropsychologically, they agree with the findings of the first two studies cited,
that actual scores did not diVer significantly between groups, especially on the
classic tests of executive functioning. They attribute this to the idea that AD
patients are failing at executive tasks ‘‘for non-frontal reasons.’’ That is, executive
tasks are complex and actually make demands on multiple cognitive domains
(particularly memory and visuospatial abilities) that are weak in AD.
This is similar to the findings from the most recent group to weigh in on the
matter. This year, a relatively large study (40 FTD, 77 AD, and 91 normal
controls) (Giovagnoli et al., 2008) was unable to find a significant diVerence
between the patient groups with regard to executive functions. In this study, the
AD patients were significantly more impaired than the FTD group in episodic
memory, selective attention, visual perception, visuomotor coordination, and
constructive praxis, whereas no diVerences were found in executive, intellective,
and linguistic abilities between the two patient groups. Logistic regression ana-
lyses revealed that episodic memory significantly predicted the diagnosis of AD
while no executive deficit was able to predict the diagnosis of FTD. The authors
hypothesize that this may be due to a more widespread distribution of executive
functions in the brain than is currently acknowledged, with other brain regions
providing an extended network of functions that are interrelated with prefrontal
cortex.
Another reason for the failure of some groups to find diVerences between
FTD and AD may be that not all studies distinguished between FTD and SD in
their samples; that is, they included both types of patients in their testing. Because
FTD and SD overlap with AD deficits in very diVerent ways, the net eVect may
have been to ‘‘cancel out’’ the diVerences between groups. This is the hypothesis
of a study which in fact did find a double dissociation between AD, FTD and SD
groups in their study (Perry and Hodges, 2000).
3. PPA
In contrast to the relatively diYcult AD-FTD distinction neuropsychologi-
cally, distinguishing between AD and PPA is more straightforward. PPA patients
maintain relatively normal episodic memory function—the hallmark decline of
early AD, while developing progressively worsening language impairments. The
original report on this clinical syndrome was published in 1982 by Mesulam, who
reported on six patients with progressively worsening language impairment in the
absence of dementia (Mesulam, 1982). Some years later, his lab published a
follow-up study (Weintraub et al., 1990) further characterizing three patients
with sequential neuropsychological assessments. They demonstrated progressive-
ly worsening decline on measures such as the Token Test, sentence repetition and
the Boston Naming test. Importantly, cognition was stable over time on measures
such as spatial and temporal orientation, design recall, line orientation, and face
 FTLD: INSIGHTS FROM NEUROPSYCHOLOGY AND NEUROIMAGING 195

recognition. Another report on the longitudinal neuropsychological profile of

PPA (Grossman et al., 1996) concurred with the original description; they too
found that individuals became progressively less fluent, naming and repetition
declining over several years. Ultimately, their patients became mute. Grossman
hypothesizes that the critical feature of PPA appears to be a grammatical im-
pairment which interferes with speech production. This distinguishes them from
SD, in whom speech may also appear nonfluent at times owing to word-finding
pauses, as well as those with FTD who may have a paucity of speech output due to
abulia or apathy.

4. SD
In 1975, Elizabeth Warrington described three patients with a combination of
visual associative agnosia (diYculty recognizing objects based on their visual
features), anomia, and impaired comprehension of word meaning (Warrington,
1975). The diagnostic term ‘‘Semantic Dementia’’ was coined by Snowden and
colleagues, in their description of a diVerent three patients in whom they found
not only a progressive fluent aphasia (in contradistinction to the slowed, agram-
matic and eVortful speech characteristic of PPA), but also deficits in word com-
prehension and in knowledge of objects and people (Snowden et al., 1989). That is,
spontaneous speech is characterized by anomia in the context of relatively normal
phonology and grammar. As the disease progresses, patients will more and more
replace specific terms with more nondescript words such as ‘‘thing’’ or ‘‘that.’’
Neuropsychologically, the hallmark of SD is an associative agnosia and/or
prosopagnosia (inability to recognize faces), coupled with a ‘‘loss of memory for
words’’ which is quite diVerent from the impairment of episodic memory seen in
early AD. In addition, orientation to time and place, simple calculation and
drawing skills are all preserved in SD. In the study by Perry et al. cited above,
subjects with SD showed severe deficits in semantic memory (Pyramid Palm trees
and the Graded Naming test) with preservation of attention and executive
function, while the AD subjects had very little trouble on those same semantic
memory tasks but were grossly impaired in episodic memory, as measured by the
logical memory portion of the Wechsler Memory Scale-R and the Rey figure
recall.
A final point of distinction between SD and AD regards the temporal gradient
of their amnesia. In general, SD patients do not have a significant impairment of
episodic or recent memory, but several authors have found that autobiographical
memory for remote events can be significantly impaired in SD (Hou et al., 2005;
Nestor et al., 2002). This is distinct from the relatively intact remote memories of
most early AD patients, and speaks to the presumed extrahippocampal localiza-
tion of the damage in SD. Overall, the consensus opinion seems to be that, like
PPA, the neuropsychological profile of SD is suYciently diVerent from that of AD
to make discrimination relatively straightforward on this basis alone.
196 BOZOKI AND FAROOQ

B. DISTINGUISHING FTLD SUBTYPES

Given how tricky it is to distinguish FTD from AD on the basis of neuropsy-

chological testing alone, one might expect that the distinctions among the thee
phenotypes of FTLD would be nearly impossible, yet this turns out not to be the
case. The entities are suYciently dissimilar to one another that it turns out to be
more straightforward to tell them apart than to distinguish them from other
dementias (i.e., AD or vascular dementia).

1. FTD vs PPA
In contrast to the relatively small distinction between executive processing
deficits in AD vs FTD, those between FTD and PPA are considerable, as patients
with PPA have essentially normal executive processing ability. PPA also seems to
have more intact episodic memory function than FTD (Libon et al., 2007), which
is somewhat surprising because early FTD is not generally acknowledged to have
significant declines in episodic memory function. Quite recently, Marra et al.
published a study comparing both neuropsychological and neurobehavioral char-
acteristics of 22 FTD and 10 PPA patients (Marra et al., 2007). The latter results
are given in Section IV. Their findings on the neuropsychological profiles corrob-
orate the Libon et al. group’s documentation of better (normal-range) scores on
immediate and delayed recall measures and executive processing. In turn, their
group of FTD patients did significantly better on letter fluency. Surprisingly, the
two groups were about nearly equal on a test of category fluency (both groups
performed poorly).

2. FTD vs SD
In addition to being dramatically worse on tasks that hinge on semantic
knowledge, SD patients are also clearly worse than FTD patients on naming
and other language-based tasks. An early study comparing FTD and SD (Hodges
et al., 1999) found that patients with SD were significantly worse on a category-
fluency task, while being quite closely matched on the letter-fluency version of
that task. The study by Libon et al. (2007) replicated this finding. In a related
study, subjects with SD showed severe deficits in semantic memory with preser-
vation of attention and executive function. Subjects with FTD showed the reverse
pattern. The double dissociation in performance on semantic memory and
attention/executive function clearly separated the temporal and frontal variants
of FTD (Perry and Hodges, 2000).
3. SD vs PPA
The overarching diVerence between these two dementias neuorpsycho-
logically is the diVerence between a pure speech/language impairment (PPA)
and a relatively pan-modal agnosia (SD) which includes (but is not limited to)
 FTLD: INSIGHTS FROM NEUROPSYCHOLOGY AND NEUROIMAGING 197

language-based expression. In a recent review article on the distinctions between

SD and PPA, Hodges and Patterson write the following: In SD, repetition is
almost invariably perfect, but the definitions oVered are either generalized and
lacking in detail (e.g., ‘‘Hippopotamus, can you say that?,’’ ‘‘Yeah, hippopota-
mus,’’ ‘‘What is a hippopotamus?,’’ ‘‘A big animal’’) or simply absent (‘‘I think I’ve
heard of a hippopotamus but I can’t say what it is’’). Patients with PPA typically
show the opposite pattern (i.e., an advantage for defining over repeating these
long words) (Hodges and Patterson, 2007).
In addition, and somewhat surprisingly, surface dyslexia (selective diYculty in
reading words that have irregular pronunciation, such as ‘‘colonel’’ or ‘‘chamois’’)
seems to be much more characteristic of SD than PPA. While both types of
patients have diYculty with all verbal fluency tasks, PPA patients are compara-
tively worse at letter fluency than SD patients, while being indistinguishable from
them on category-fluency (Libon et al., 2007).

IV. Neurobehavioral Assessment

A. FTD

By far the most challenging of the FTLD subtypes to care for is the individual
with FTD, also known as behavioral-variant FTD. This is due not to the cognitive
impairment that develops, but to the challenging set of aberrant behaviors.
Neuropsychiatric symptoms are usually the earliest manifestation of this subtype,
and such patients are often referred to psychiatrists with working diagnoses of
depression, bipolar disorder and even late-onset schizophrenia. Because the
cognitive impairments early on are rather subtle, careful neuropsychological
testing is necessary (as described in detail earlier ) to determine that such indivi-
duals actually have a dementia rather than a purely psychiatric condition. Up
until about 10 years ago, when these patients finally did get to the neuropsychol-
ogist, there was a paucity of instruments to delineate and quantify the often florid
behavioral problems. Two eVorts to better characterize these behavioral changes
resulted in a measurement instrument called the frontal behavioral inventory
(FBI), a 24-item questionnaire aimed at assessing the most commonly seen
psychopathologies present in FTD (Kertesz et al., 1997), and a shortened form
of the Neuropsychiatric Inventory (Cummings et al., 1994), called the NPI-Q
(Kaufer et al., 2000), which contains 12 items that must be assessed as to presence/
absence and if present, the severity (mild, moderate, or severe).
The authors compared three groups of patients, those with FTD, those with
AD and those with ‘‘depressive dementia’’ (aka pseudo- or psychodementia).
They found that the FTD group scored much higher on the FBI then either
198 BOZOKI AND FAROOQ

Pathologic behaviors observed in FTLD subtypes and AD

Frequency ! severity product score

9
8
7
6 FTD
5 SD
4
PPA
3
AD
2
1
0

Ea p b .

∧
+

Irr n ~
Ap h..

ee ..
An n
s

Ag ns

ep ion

eh
y
y

Sl beh
lu ion

y
io

ilit
et

/O
p
th
tio

tio
ss
t

xi

eu

Ab itab
ita

a
s

D
na

bi
re
u

or
n/
el

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hi
ci

ot
io

tin
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in

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at
D

is
al

El

D
H

FIG. 3. Frequency of behaviors and mean frequency by severity product score for all individual
Neuropsychiatric Inventory (NPI) behaviors across groups. Significant diVerences (p < 0.05) between
groups are indicated by the special characters (data from Rosen et al., 2006).

group of ‘‘controls.’’ Individual item analysis showed loss of insight, indiVerence,

distractibility, personal neglect and apathy as the most frequent negative symp-
toms, and perseveration, disinhibition, inappropriateness, impulsivity, and irre-
sponsibility as the most significant positive symptoms. In their (admittedly small)
group, using a cutoV score of 27 on the FBI resulted in only a single false positive.
The Marra et al. group which administered a large neuropsychological battery
also compared AD, FTD, and PPA by use of the NPI-Q. They determined that
aggression/agitation and apathy were both significantly more elevated in FTD
than in either of the other two groups and concluded that, if a behavioral measure
like the NPI-Q was included along with the neuropsychological evaluation, one
could readily distinguish all three groups by their profiles—something that was
nearly impossible based on the neuropsych data alone (Fig. 3).

B. PPA

Conversely, individuals with PPA have traditionally been considered to have

little or no behavioral disturbances early on (Weintraub et al., 1990), though more
recent studies have demonstrated the evolution of neuropsychiatric symptoms,
particularly after a few years of illness (Banks and Weintraub, 2008; Marczinski
et al., 2004). The earlier of these studies utilized the FBI and found that while
initial evaluations failed to demonstrate scores above the cutoV value for PPA, by
 FTLD: INSIGHTS FROM NEUROPSYCHOLOGY AND NEUROIMAGING 199

the end of the third year the PPA group met criteria for FTD. The more recently
published study by Banks and Weintraub uses the NPI-Q. This study, which
compared individuals with FTD and those with PPA and divided the subjects into
short-duration (<5 years) and long-duration (!5 years) symptoms, found that the
number of symptoms in long-duration PPA patients did not significantly diVer
from patients with FTD regardless of their disease duration. However, when
comparing the short- and long-duration PPA patients, a trend toward decreased
depression and increased disinhibition and nocturnal behavior was noted.

C. SD

Patients with SD are widely perceived by behavioral neurologists to have

behavioral problems that are about midway on the continuum between FTD and
PPA, however, formal investigations of behavioral deficits in SD have been rare.
In 2001, Snowden and colleagues published a comparison of SD with both
apathy-predominant and disinhibition-predominant FTD (Snowden et al.,
2001). Using semi-structured interviews, they found that a pervasive lack of
emotional response was characteristic of FTD but in SD was limited to the
capacity to show fear. They found a tendency toward social-seeking (preference
for being with others), and somewhat exaggerated responses to sensory stimuli, in
contrast to social-avoidance and reduced pain responses typical of FTD. Con-
versely, SD patients seemed to show more frequent compulsive repetitive beha-
viors such as clock-watching, adherence to daily routines and verbal stereotypies.
A few years later and utilizing the NPI rather than interviews, Rosen et al.
compared SD with FTD and PPA. He measured the mean frequency by severity
product score across all 12 behavioral domains and confirmed this empirically
(Rosen et al., 2006). In his post hoc comparisons between groups, he found similar
degrees of elation/euphoria as the FTD group, but much less apathy (suggesting a
generally more upbeat/outgoing profile than that of FTD). The SD group also
had significantly more disinhibition and abnormal motor behavior than those
with PPA. Furthermore, he found that these behavioral abnormalities increased
in severity with disease duration in SD.

V. Neuroimaging of FTLD

Historically, structural neuroimaging of degenerative dementias has not played a

critical role in diagnosis. Characteristic changes consist primarily of atrophy in
certain regions, and this is often rather subtle in early stages of disease, although at
later stages the atrophy can result in a ‘‘knife blade’’ appearance of the eVected gyri
200 BOZOKI AND FAROOQ

(GraV-Radford and WoodruV, 2007). The utility of brain imaging lay in determining
whether additional neuropathology was seen (e.g., ischemia, subdural hematoma).
The advent of sensitive, automated methods for quantifying regional atrophy has
provided a new and better way to evaluate this distinguishing feature of FTLD. In
addition, functional studies which are used to measure neurochemical breakdown
products, regional cerebral blood flow or cerebral metabolism can help to diagnose
FTLD at the earlier stages, and can distinguish FTLD from AD. Functional imaging
with SPECT or PET can achieve a >90% sensitivity of detecting FTLD (Mendez
et al., 2007). It is also becoming possible to distinguish the diVerent types of FTLD
with these more advanced imaging techniques. Nonetheless, there is still a need for
larger randomized studies to determine the sensitivity and specificity of functional
imaging modalities in the diagnosis of FTLD, its phenotypes and their diVerential
from other types of dementia especially AD.

A. DIFFERENTIATION OF FTLD FROM AD

1. Structural and Volumetric MRI Studies

Structural MRI and MR-volumetric analysis of diVerent brain regions can help
discriminate FTLD from AD. Structural MRI in patients with FTLD often reveals
atrophy in the frontal and temporal lobes, which can be quite asymmetric. The
ventricles may be enlarged and the head of the caudate may be atrophic. These
findings vary depending on the stage of the disease. Initially, prominent mesial
temporal lobe and hippocampal atrophy were demonstrated to be a key diagnostic
finding on volumetric MRI studies in AD ( Jack et al., 1997), whereas selective
frontal volume decreases were suggestive of FTLD (Fukui and Kertesz, 2000).
Therefore, it was thought that simply measuring hippocampal volume would
determine whether an individual had AD or FTLD. Unfortunately, more recent
studies suggest that hippocampal/mesial temporal atrophy alone does not reliably
distinguish AD from FTLD (Bocti et al., 2006; Galton et al., 2001). However, a
severe or asymmetrical pattern of amygdala atrophy (along with hippocampal
atrophy) suggests FTLD (Barnes et al., 2006), as does a topographical pattern of
atrophy involving the frontal lobes and anterior temporal regions (Bocti et al., 2006).
Directly comparing frontal versus temporal volume changes over time is another,
and more sensitive approach to distinguishing disease states (Chan et al., 2001a),
though this approach requires two scans taken a year apart (Fig. 4).

2. MR Spectroscopy
Proton magnetic resonance spectroscopy (MRS) allows in vivo noninvasive
estimation of brain metabolites. MRS analysis reveals peaks which correspond to
diVerent compounds and metabolites in brain tissue. Two of these compounds are
 FTLD: INSIGHTS FROM NEUROPSYCHOLOGY AND NEUROIMAGING 201

FIG. 4. Distribution of cerebral atrophy in a patient with AD (A) and frontotemporal dementia
(FTD) (B). Both patients had similar interscan intervals (11 months) and annualized rates of global
cerebral atrophy (approximately 4%). Areas of volume loss are highlighted in red. Note the generalized
distribution of atrophy in AD and the preferential anterior volume loss in FTD (Reprinted from
Neurology 57, Chan, D., Fox, N. C., Jenkins, R., Scahill, R. I., Crum, W. R., and Rossor, M. N.
(2001a) with permission from Lippincott, Williams and Wilkins).

relevant in the work up of patients with dementia, N-acetyl aspartate (NAA) which
is predominantly intracellular, and myoinositol (MI) which is predominantly
found in glial cells. NAA is a marker of neuronal activity and MI is a marker of
gliosis. MRS can help to diVerentiate FTLD from AD as these disorders are
accompanied by relatively distinct neurochemical abnormalities. Ernst et al. found
that patients with FTLD had a statistically significant increase in myoinositol (MI)
and decrease in N-acetyl (NA) and glutamate in the frontal region, which was
distinct from AD. The NA concentration in a frontal region of interest allowed the
best discrimination of FTLD from AD and controls. In the temporoparietal
regions, changes in MI concentration occurred prior to observable changes in
NA concentration, indicating that glial proliferation may be more readily
detected than neuronal loss in the early stages of FTLD (Ernst et al., 1997).

3. Positron Emission Tomography

Functional imaging methods have significantly improved our ability to detect
early changes and to distinguish neurodegenerative diseases. PET imaging has
become the most commonly used and promising modality to diVerentiate FTLD
from other dementia syndromes, including AD.
The cerebral metabolic rate of glucose in diVerent areas of brain can be
measured with 18F-FDG PET, and the pattern of hypometabolic regions can be
used to diVerentiate various types of dementia (Foster et al., 2007; Ibach et al.,
2004; Silverman et al., 2002). This metabolic decline occurs quite early in the
202 BOZOKI AND FAROOQ

course of disease, making PET a relatively sensitive imaging tool for discerning
both the presence and the type of neurodegeneration. In fact, the Centers of
Medicaid and Medicare recently approved reimbursement of clinical 18F-FDG-
PET for the indication of distinguishing AD from FTLD. FTLD patients have
prominent hypometabolism of the frontal and anterior temporal cortices as
compared with AD patients who show decreased metabolism in the posterior
cingulate and parietotemporal cortices (Diehl-Schmid et al., 2007; Ishii et al., 1998;
Jeong et al., 2005a; Mosconi et al., 2008). PET statistical parametric mapping
studies in patients with FTLD have shown hypometabolism in other areas of
brain such as the anterior cingulate, uncus, insula, and subcortical regions
including basal ganglia ( Jeong et al., 2005a). Moreover, hemispheric metabolic
asymmetry is common in patients with FTLD (Garraux et al., 1999; Jeong et al.,
2005a) (Fig. 5).
The novel PET tracer 11C-PIB has a high aYnity for fibrillar A-beta protein
which is a pathological hallmark of AD and is not a part of the FTLD spectrum
(Klunk et al., 2003). Because of this, 11C-PIB can help to discriminate AD from
FTLD. Engler et al. conducted a study of 10 patients with FTLD using PIB. Eight
of these FTLD patients showed significantly lower PIB retention as compared to

MCI

AD

FTD

DLB

FIG. 5. Representative cortical 18F-FDG PET patterns in NL, AD, DLB, and FTD. 3D-SSP maps
and corresponding Z scores showing CMRglc reductions in clinical groups as compared with the NL
database are displayed on a color-coded scale ranging from 0 (black) to 10 (red). From left to right: 3D-
SSP maps are shown on the right and left lateral, superior and inferior, anterior and posterior, and right
and left middle views of a standardized brain image (Reprinted by permission of the Society of Nuclear
Medicine from Mosconi, L., Tsui, W. H., Herholz, K., Pupi, A., Drzezga, A., Lucignani, G., Reiman, E. M.,
HolthoV, V., Kalbe, E., Sorbi, S., Diehl-Schmid, J., Perneczky, R., et al. (2008)).
 FTLD: INSIGHTS FROM NEUROPSYCHOLOGY AND NEUROIMAGING 203

AD in diVerent brain regions. In fact PIB uptake in these FTLD patients did not
diVer significantly from healthy controls in any region (Engler et al., 2008).
Another novel PET tracer, which is relatively a small molecule, is called
FDDNP. It is an in vivo chemical marker for cerebral amyloid and tau proteins.
Initial FDDNP studies of FTD show binding in the frontal and temporal regions
but not in the parietal regions suggesting that FDDNP labels regional tau tangles
and thus can diVerentiate FTD from AD according to the binding patterns
(Silverman et al., 2002). However, these are preliminary studies and further
pathological correlation and larger scale studies are warranted to confirm the
utility of this promising modality in clinical practice.

4. Single Photon Emission Computed Tomography

Unlike FDG-PET, which is a marker of cell metabolism, SPECT is based on the
brain uptake of a technetium 99m-based lipid-soluble radionucleotide (ethyl cystei-
nate dimer or hexamethylpropylene amine oxime) which stays within vascular
channels and is therefore a marker of brain perfusion. It has been shown to
diVerentiate FTLD from AD with high sensitivity. Charpentier et al. demonstrated
that 100% of patients with FTLD and 90% of AD patients could be correctly
classified by using a SPECT-image-derived algorithm that included analyzing
regions of interest in frontal and temporoparietal lobes (Charpentier et al., 2000).
Sjogren et al. demonstrated the successful utility of SPECT in diVerentiating FTLD
from other forms of dementia including AD using an anterior to posterior ratio of
technetium uptake to classify these patients, with a sensitivity of 87.5% and a
specificity of 78.6% (Sjogren et al., 2000). Many investigators have also found that
there is a reduction in tissue metabolism in the posterior cingulate cortex of patients
with AD. Bonte et al. highlighted the significance of this ‘‘posterior cingulate sign’’ in
the diagnosis of FTLD by using SPECT RCBF studies to distinguish AD from
FTLD based on presence or absence of this sign (Bonte et al., 2004).

B. DIFFERENTIATION OF DIFFERENT SUBTYPES OF FTLD

1. Structural and Volumetric MRI Studies

MRI studies can help diVerentiate subtypes of FTLD, as they exhibit diVerent
patterns of regional atrophy on volumetric analysis, although reported sensitivity
and specificity of these techniques has varied greatly. Typically, FTD is associated
with bilateral frontal atrophy, SD is associated with predominantly left anterior
temporal lobe atrophy and PPA is associated with left perisylvian atrophy (Chan
et al., 2001b; Gorno-Tempini et al., 2004; Rosen et al., 2002). It has been shown
that there is more frontal lobe gray matter atrophy in FTD compared with SD
cases (Rosen et al., 2002). Patients with SD show bilateral, typically asymmetrical,
204 BOZOKI AND FAROOQ

atrophy of the anterior temporal lobes. As the disease progresses this degenerative
process evolves caudally to the posterior temporal lobes or rostrally to the
posterior, inferior frontal lobes, or both. Utilizing volumetric MRI methods,
Chao et al. demonstrated that patients with SD had both white matter and gray
matter atrophy in the temporal lobes, and that therefore adding temporal white
matter volume to temporal gray matter volume significantly improved the
discrimination between SD and FTD (Chao et al., 2007).
Gorno-Tempini et al. in their voxel-based morphometry MRI study showed
that all of their patients with PPA had atrophy of the left perisylvian region,
anterior temporal lobes bilaterally and the basal ganglia bilaterally (Gorno-
Tempini et al., 2004). Their study also showed distinctive patterns for PPA,
SD, and logopenic progressive aphasia. PPA was associated with left inferior
frontal and insular atrophy, SD with anterior temporal damage and logopenic
progressive aphasia with atrophy of left posterior temporal cortex and inferior
parietal lobule (Gorno-Tempini et al., 2004). Mummery et al. conducted a voxel-
based morphometry study of SD patients and identified well-circumscribed
regions of atrophy in individual patients including the bilateral temporal poles
(left more than right), the left inferior temporal gyrus, the left middle temporal
gyrus, the left amygdaloid complex, and the ventromedial frontal cortex
(Mummery et al., 2000). The degree of semantic deterioration correlated with
the extent of left anterior temporal damage and not with that of adjacent
ventromedial frontal cortex.
An excellent recent summary of the ‘‘triple dissociation’’ between the three
subtypes of FTLD can be seen in the recent study by Schroeter, et al. (2007). This
group undertook a large quantitative meta-analysis of 267 FTLD patients (and
351 control subjects) across 19 MRI and PET studies. Their results indicated
specific neural networks for each of the three clinically defined subtypes that did
not overlap. The study further related each subtype’s clinical features to its neural
substrate, demonstrating a close structure-function correlation for the diseases
(Schroeter et al., 2007) (Fig. 6).

2. MRI DiVusion Tensor Imaging

Historically, most neuroimaging studies have focused on gray matter changes
in the brain, as FTLD has traditionally been regarded as a gray matter disease.
More recently, white matter changes in FTLD have received some attention, both
because there is a greater understanding of the interplay between gray and white
matter degeneration, and because of the evolution of MRI diVusion tensor
imaging, a technique that detects microstructural alterations in white matter by
measuring the directionality of molecular diVusion. Borroni et al. found a diVer-
ence in the pattern of white matter loss in early stages of frontal and temporal
variants of FTD which might be helpful to diVerentiate these two variants of
 FTLD: INSIGHTS FROM NEUROPSYCHOLOGY AND NEUROIMAGING 205

y = 12 x = −5 z = −7
0.016

0.010
FTLD

y = 37 x = −1 z = −7
0.014

FTD 0.008

y = 11 x = −29 z = −9
0.015

SD 0.008

y = 11 x = −49 z = −5
0.008

PNFA 0.006

FIG. 6. Results of the quantitative meta-analyses (using activation likelihood estimates) for the three
subtypes of FTLD individually, and for FTLD all subtypes pooled. Left side is left (Reprinted from
NeuroImage 36(3), Schroeter, M. L., Raczka, K., Neumann, J., and Yves von Cramon, D. (2007) with
permission from Elsevier).

FTLD (Borroni et al., 2007). Another study using tensor-based morphometry has
reported white matter atrophy in temporal lobes of patients with SD (Studholme
et al., 2004).
206 BOZOKI AND FAROOQ

3. MR Spectroscopy
NAA and creatine (Cr) on MRS have been reported to diVerentiate not only
AD from FTLD, but the diVerent types of FTLD as well. Coulthard et al.
performed a study on FTLD patients showing that MRS can reveal regionally
selective abnormalities in patients with FTLD. MRS was performed on the
temporal, parietal, and anterior cingulate cortices of five patients with established
SD, and two patients with FTD. All the patients with FTLD had reduced NAA/
Cr in frontal and temporal lobes and not in parietal lobes; however, the patients
with FTD had increased MI/Cr in their cingulate cortices diVerentiating then
from SD (Coulthard et al., 2006).

4. Positron Emission Tomography

FDG studies in patients with SD have shown temporal cortical hypometabo-
lism with the left temporal lobe often being more severely eVected (Diehl et al.,
2004; Hodges et al., 1999). Other studies in patients with PPA showed left
temporal and perisylvian defects early in the disease course and parietal and
frontal region abnormalities occurring later on (Chawluk et al., 1986; Kempler
et al., 1990; Tyrrell et al., 1990). Grossman et al. reported a group of patients with
PNFA who had global left hemisphere hypometabolism and more specific
hypometabolism in the left inferior frontal, superior, and middle temporal gyri
(Grossman et al.). Nestor et al. conducted a study on patients with problem of
progressive dysfluency using 18F-FDG PET and analyzed with the technique of
statistical parametric mapping. They identified seven patients with PPA who
showed hypometabolism in several regions, most notably in the left anterior
insula/frontal opercular region (Nestor et al., 2003). They also assessed regional
atrophy with MRI voxel-based morphometry and this analysis revealed only a
small area of atrophy in the left peri-Sylvian region.
FTD can coexist with MND (FTD/MND) and the clinical features of this
entity are somewhat diVerent from FTD patients. Garraux et al. reported that
FTD/MND showed hypometabolism in the bilateral frontal, anterior temporal
lobes, and in putamen. When compared with FTD, FTD/MND patients had
more hypometabolism in medial temporal regions (Garraux et al., 1999). Another
study by Jeong et al. showed that patients with FTD/MND showed glucose
hypometabolism only in the frontal region, whereas most patients with FTD
had hypometabolism in the frontal and temporal areas. Moreover, FTD/MND
patients had a more symmetric pattern of hypometabolism than FTD ( Jeong
et al., 2005b). In addition to the above findings, FTD/MND patients also had
hypometabolism in the basal ganglia region and thalamus. A key finding from
these studies was that asymmetric degeneration is not a feature of FTD/MND as
compared to FTD which is well known for asymmetric hemispheric degeneration
(Garraux et al., 1999; Jeong et al., 2005b).
 FTLD: INSIGHTS FROM NEUROPSYCHOLOGY AND NEUROIMAGING 207

5. Single Photon Emission Computed Tomography

SPECT has been shown to diVerentiate between the frontal and temporal
variants of FTD (Perry and Hodges, 2000). Utilizing a region of interest ap-
proach, both Talbot and Newberg (Newberg et al., 2000; Talbot et al., 1995b)
conducted SPECT studies and found hypoperfusion in bi-frontal and left tempor-
oparietal region and in the left dorsolateral prefrontal cortex and left subcortical
nuclei in patients with PPA. Neary et al. found hypometabolism confined to frontal
lobes in patients with FTD/MND (Neary et al., 1990). Another study by Talbot
et al. using ROI analysis of SPECT mages found no significant diVerences
between FTD and FTD/MND (Talbot et al., 1995a).

VI. Summary

The accurate diagnosis of FTLD in all of its guises is very important for the
development of new therapeutic options and disease modifying therapies. Clinical
diagnosis is based on the recognition of all the core and necessary neurologic,
neuropsychological, and neuropsychiatric features of FTLD. However, patients
often lack all the core features at the initial assessment, and subtle personality or
behavioral changes can be caused by a range of other disorders, making diagnosis
diYcult (Mendez and Perryman, 2002; Mendez et al., 2007). Furthermore, there is
no single hallmark genetic mutation or susceptibility locus that can be tested to
provide the diagnosis in most cases. Therefore, careful neuropsychological and
neurobehavioral assessment should be performed in all suspected cases to increase
the reliability of discrimination between AD and FTLD, esp. FTD. Several
authors have come to the same conclusion (Marra et al., 2007; Perri et al., 2005).
Furthermore, neuroimaging plays a significant role in diagnosis, not only in
excluding alternative pathologies, but as a positive, ‘‘rule-in’’ test in which the
characteristic features of frontal and anterior-mid temporal atrophy and hypo-
metaboloism should be evaluated. New and improved methods for evaluating
these features are on the horizon, and adoption of a quantitative volumetric
approach to MR as well as the addition of PET or SPECT to the clinical
evaluation algorithm will add greatly to our diagnostic acumen.

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 LEWY BODY DEMENTIA

Jennifer C. Hanson and Carol F. Lippa

Drexel University College of Medicine, Mail Stop 423, Philadelphia,
Pennsylvania 19107, USA

I. Introduction
II. DLB Clinical Features
III. PD-D
IV. DLB and PD-D
V. Pathology
VI. Genetics
VII. Biomarkers
VIII. Management
References

Dementia is becoming increasingly prevalent since elderly patients are living

longer due to the development of treatments for other diseases and conditions.
The percent of our population over 60 is also increasing with the wave of aging
baby boomers. Additionally, more individuals seek medical assistance for cogni-
tive problems as visibility for treatments improves. This combination of factors
results in the dementia syndromes becoming more common, causing physicians to
encounter more patients with dementia as well as more caregivers of these
patients.
Of dementia subtypes, Alzheimer’s disease (AD) is the most common.
Dementia with Lewy bodies (DLB) is thought to be the second most common
subtype. DLB’s typical symptoms include cognitive impairment, visual hallucina-
tions, spontaneous parkinsonism, and fluctuating confusion. Supportive features
include a variety of sleep disruptions that may occur before manifestations of
dementia. Psychiatric symptoms include vivid visual hallucinations and depres-
sion. The clinical features of DLB are strikingly similar to those of dementia in
Parkinson’s disease (PD).
The underlying biology of DLB is complex, but the presence of alpha-
synuclein containing Lewy bodies (LB) is a common factor. These inclusions
also contain ubiquitin. PD dementia shares these pathological findings with
DLB, as well as neural degeneration of the substantia nigra. DLB and dementia
in PD may represent the same pathological process along a disease spectrum.

INTERNATIONAL REVIEW OF 215 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00411-5 0074-7742/09 $35.00
216 HANSON AND LIPPA

Additionally, many DLB cases are also associated with beta-amyloid and tau-
containing neurofibrillary tangles, features that are associated with AD. Frequently,
AD patients are also found to have LB. The reason for this overlap is unknown.
However, the greater the Alzheimer’s pathology in DLB patients, the more the
clinical features of DLB overlaps with AD.
In this chapter, we will review DLB including clinical, pathological, and
radiological features as well as biomarkers and treatments.

I. Introduction

Dementia is defined as a syndrome of progressive cognitive impairment that

interferes with daily function (DSM IV-TR, 2004). The cognitive areas involved
include memory, language, abstract thinking, visuo-spatial skills, behavior, and
personality. Alzheimer’s disease (AD) is the most common dementia subtype,
representing over half of all dementias. Dementia with Lewy bodies (DLB) is
the second most common type of dementia at 20%, aVecting 15–25% of
elderly demented patients (McKeith et al., 1996). Of those patients with Parkin-
son’s disease (PD), 30% will develop dementia during the course of their illness
(Emre et al., 2007). Many more Parkinson’s patients will experience some type of
cognitive change. Table I compares the most common forms of dementia.
The four main components of the DLB syndrome are dementia, visual hallu-
cinations, parkinsonism, and fluctuation of symptoms, particularly confusion. The
cognitive decline associated with DLB includes pronounced variation in attention
and alertness. Visual hallucinations are recurrent, consist of formed or detached
figures and typically occur early in the disease course. The parkinsonian motor
features include myoclonus, bradykinesia, rigidity, and less commonly tremors.
Additional associated features include sleep anomalies, repeated falls, syncope,
transient loss of consciousness, delusions that are often paranoid, urinary inconti-
nence, and depression. DLB patients are sometimes oversensitive to neuroleptic
agents, and use of such medication may precipitate a change in functional status.
DLB exhibits a clinical overlap with both the dementia of AD and the motor
symptoms of PD. DLB is characterized by intracytoplamic proteinaceous inclu-
sions called Lewy bodies (LB). These collections of alpha-synuclein (AS) plaques
occur throughout the cortex and subcortical regions. Additionally, DLB has a loss
of acetylcholine producing neurons similar to those seen in AD and a loss of
dopaminergic neurons, as seen in PD.
This chapter will review DLB clinical and pathologic features, radiographic
findings, biomarkers, and current treatment modalities.
 TABLE I
COMPARISON OF THE MOST COMMON FORMS OF DEMENTIA

Epidemiology Pathology Clinical features

Alzheimer’s Most common >65 years old General cortical atrophy, especially in Memory impairment
disease medial temporal lobe
Genetic susceptibility factors Amyloid plaques in cortex DiYculty in learning new information
(mostly for late-onset)
Autosomal dominant inheritance Neuritic plaques Little fluctuation or hallucinations
(more often present in early onset) Neurofibrillary tangles containing tau Apraxia
and ubiquitin
Amyloid angiopathy Rigidity may be a late feature
Vascular dementia >40 years old Multiple infarcts—often in subcortical Step-wise deterioration
areas
Risk factors: May improve

217
Hypertension Fibrous and hyaline degeneration of Pyramidal signs
small arteries
Smoking
Vascular disease
Other vascular risk factors White matter infarction Pseudobulbar palsy
Dementia with Usually sporadic General cortical atrophy; may be normal Parkinsonism
Lewy body Often elderly, especially when Depigmentation of substantia nigra Fluctuating mental state with slow processing,
(DLB) cognitive presentations attentional, and visuo-spatial problems
LB in limbic and cortical neurons; often Visual hallucinations
brainstem LB
Amyloid deposits are common Neuroleptic sensitivity
REM behavioral disorder
Parkinson’s 30% of PD patients Neuronal cell death in substantia nigra Parkinsonism before onset of dementia
disease Usually sporadic LB in nigral neurons; often in limbic and Fluctuating confusion with similar features
dementia cortical regions (attentional problems, slow processing) to DLB
Visual hallucinations
218 HANSON AND LIPPA

II. DLB Clinical Features

In 2005, the DLB consortium issued its third report on the Current Interna-
tional Consensus Diagnostic Criteria for DLB (McKeith et al., 2005). The central
features necessary for a diagnosis of DLB include the presence of a dementia,
fluctuating cognition, hallucinations, and parkinsonian symptoms. Numerous
supportive features are commonly found in DLB patients, but are not necessary
for the diagnosis.
As in AD, DLB patients have a progressive cognitive decline suYcient enough
to interfere with normal social or occupational functioning (DSM IV-TR, 2004).
However, in contrast to AD, the memory impairment of DLB may not be
prominent in the early stages (McKeith et al., 2005). The cognitive problems
fluctuate with pronounced variation in attention and alertness. This feature is
hard to monitor in clinical practice due to its diYculty to observe on a consistent
basis. When they do appear, the deficits on tests of attention, executive function,
and visuo-spatial ability in DLB are generally prominent (McKeith et al., 2005).
Subjects with DLB have better delayed memory and spared recall, but worse
executive function and visuo-spatial abilities than patients with early AD. Such
diVerences in visuo-spatial abilities can be demonstrated by the intersecting
pentagons used as part of the mini mental-status exam. An example of this is
shown in Fig. 1.
In DLB, the cognitive deficits represent both cortical and subcortical impair-
ments, with greatest deficits being verbal fluency, visual perception, and perfor-
mance tasks while there is preservation of confrontation naming, recognition, and
short-term recall (Connor et al., 1998; Mormont et al., 2003; Walker et al., 1997).

A B C D

FIG. 1. Figure drawings of normal, Alzheimer’s dementia, and Dementia with Lewy body (DLB)
patients. Patient drawings demonstrate the visuo-spatial dysfunction in DLB patients compared with
normal aging patients and AD patients. Image A is a model of connecting pentagons, normally used to
test visuo-spatial function. The patient is asked to copy this image during the test. Image B shows a
normal patient’s response. Note that this image has five sides and that the adjacent sides intersect
in both pentagons. Image C is drawn by an AD patient. This subject drew a hexagon rather than
a pentagon. This is a cognitive error. Image D is from a patient meeting the criteria for probable
DLB. There is marked loss of visuo-spatial relationships, and it is hard to tell what they are trying
to copy.
 LEWY BODY DEMENTIA 219

Both DLB and Parkinson’s disease dementia (PD-D) patients have more pro-
nounced subcortical cognitive impairment profiles with less marked memory
impairment than AD patients. However, those patients with a pattern of promi-
nent cortical involvement have more severe memory impairment like that of AD
( Janvin et al., 2006).
Recurrent visual hallucinations are prominent and are typically well formed
and detailed in DLB patients. Hallucinations of animals and people are common.
They are usually frightening and it is diYcult to convince the patient that they are
not real. This may pose safety problems, as the patient will feel that they will be
attacked or their home invaded. In contrast, visual hallucinations are uncommon
in AD, particularly early in the disease course. Therefore, report of such vivid
hallucinations in the context of dementia should alert the physician to the
likelihood of DLB. LB concentrations in the posterior temporal lobes and amyg-
dale, areas critical for emotion and visual processing, are associated with the
presence of these hallucinations (Harding et al., 2002). As such, it has been
speculated that visual hallucinations are positive phenomenon, caused by an
irritating eVect of the LB in relevant areas.
The onset of parkinsonian symptoms occurs spontaneously in DLB. At the
time of diagnosis, approximately 50% of DLB patients have extrapyramidal
motor symptoms, with 75% developing them during some stage of the disease
course (McKeith et al., 1992b). Patients have postural instability, gait disorders
that may be characterized by hunched posture and festination, and facial
immobility (Burn et al., 2003). Tremor may be present, but is not as prominent
as in PD. The Unified PD Rating Scale can be used to monitor parkinsonian
progression, but only for those symptoms that can be assessed in the face of
dementia (Fahn et al., 1987). Objective findings include tremor at rest, intention
tremor, bradykinesia, rigidity, and facial expression. When compared to AD
patients of a similar cognitive level, DLB patients have greater functional
impairment due to the presence of extrapyramidal symptoms (McKeith et al.,
2005).
Many DLB patients have parasomnias. The most common is REM behavior-
al disorder (RBD) which often begins concurrently or after the onset of parkin-
sonism or dementia (Boeve et al., 2007). It is marked by lack of muscle atonia in
the presence of vivid dreams. In RBD that lack of muscle paralysis allows the
patient to engage fully in the physical activities of the dream, resulting in vocaliza-
tions and sometimes wildly violent behavior. Patients are often unaware of the
disorder, but bed partners may report it as a presenting symptom when asked.
RBD is associated with daytime somnolence. It can be diagnosed by polysomno-
graphy which shows elevation in EMG tone during REM sleep and unusual
movements during sleep (Fantini et al., 2005).
DLB patients are notorious for their neuroleptic sensitivity, and reactions
occur in 30–50% of DLB patients (Aarsland et al., 2005b). Such neuroleptic
220 HANSON AND LIPPA

sensitivity reactions area characterized by sudden onset of impaired conscious-

ness, acute confusion, psychotic episodes, and exacerbation of parkinsonian
symptoms such as rigidity and immobility (McKeith et al., 1992a). These reac-
tions may even result in decreased survival within several days. A 2005 study by
(Aarsland et al., 2005b) demonstrated that there was a 58% frequency of
neuroleptic sensitivity to olanzapine, with only 11% to clozapine and 6% to
thioridazine. This confirmed previous studies that showed unacceptable safety
profiles for some neuroleptics in LB dementias. Additionally, DLB patients are
often activated by sedatives and awakened by sleep medications (Rogan and
Lippa, 2002).
Other common findings in DLB include autonomic instability which results in
orthostatic hypotension and urinary incontinence. Falls may be frequent, and can
be the result of truncal ataxia or syncope. Hallucinations of other modalities,
depression, and severe delusional symptoms may be present. Transient episodes
of loss of consciousness occur and are often unexplained. Increased fluctuations of
consciousness have been associated with increased thalamic and decreased occip-
ital perfusion (O’Brien et al., 2005).

III. PD-D

PD-D is a dementia syndrome that develops in the context of an established

PD. PD-D has an insidious onset with slow progression, and is defined as having
impairment in more than one cognitive domain representing a decline from
premorbid level. The deficits present must be severe enough to impair daily life
and the deficits must be independent of the impairment by motor or autonomic
symptoms (Emre et al., 2007). Such impairments may aVect social functioning,
occupational productivity, or personal care.
PD-D patients share many common deficits with DLB patients. PD-D
patients demonstrate fluctuating impaired attention with diYculty in preforming
tasks. Executive functions are impaired especially with tasks that require initia-
tion, planning, and concept formation. Bradyphrenia is common. Visuo-spatial
functions are impaired with problems of orientation, perception, and construc-
tion. Memory impairment is greatest in recalling recent events and new informa-
tion, but memory can improve with cueing. Core language functions are
preserved, but word recall and complex sentence comprehension may be limited.
PD-D patients are often apathetic, with concomitant anxiety and depressive
symptoms. Visual hallucinations are complex and include formed visions of
people, animals, or objects. Delusions are often paranoid, and patients suVer
from sleep disorders that result in daytime somnolence.
 LEWY BODY DEMENTIA 221

IV. DLB and PD-D

There is no clinical rational or pathological basis that determines a definite

time interval between development of motor symptoms and onset of dementia in
diVerentiating PD-D from DLB. In general, a diagnosis of PD-D should be made
when dementia develops within the context of established PD, while DLB should
be diagnosed when dementia occurs before or concurrently within 1 year of
parkinsonism (McKeith et al., 2005).
Often patients do not fit into either pattern above. Many times early cognitive
change is recognized in patients with PD, or DLB patients present with parkin-
sonism at the same time as their cognitive symptoms. The neuropsychological
profiles in DLB and PD-D share basic similarities with abnormalities in attention,
executive function, visuo-spatial function, language function, memory retrieval,
and behavior (Lippa et al., 2007a,b). There is no symptom or sign that absolutely
distinguishes DLB and PD-D, as both have fluctuating cognitive dysfunction,
visual hallucinations, parasomnias, and autonomic dysfunction.
There are, however, some subtle diVerences that can be used to elicit a more
precise diagnosis. DLB patients make executive function errors (Aarsland et al.,
2003), and have more hallucinations and psychosis than PD-D patients
(Mosimann, 2006). DLB patients have fewer parkinsonian signs than PD-D
patients and little resting tremor. The parkinsonism of DLB is more weighted
with generalized slowing with postural and gait disturbances (Burn and McKeith,
2003). They also have greater symmetry of their motor features than PD-D
patients. Additionally, adverse reactions to antipsychotic agents may be greater
in DLB patients.

V. Pathology

Found in 50% of dementia patients (Hamilton, 2000; Lippa et al., 1998), the
main identifying pathologic feature of DLB is the LB. LB are spherical intracy-
toplasmic protein deposits around the nucleus and throughout the dendrite of
subcortical and cortical neurons. They consist of filamentous protein granules
composed of AS and ubiquitin, and are surrounded by a halo of neurofilaments.
Widespread LB diVerentiate the LB dementias from other dementia subtypes.
The number of LB present does not correlate strongly with either the duration or
severity of the dementia (Harding et al., 2001). However, the number of cortical
LB is variably correlated with the severity of DLB (Samuel, 1996). When located
in the temporal lobe, LB are associated with the visual hallucinations of DLB
(Harding et al., 2002).
222 HANSON AND LIPPA

AS is a synuclein protein primarily found in the neocortex, hippocampus,

substantia nigra, thalamus, cerebellum, and with the highest proportion in the
basal ganglia (Rockenstein et al., 2001). Cortical-LB sites include the cingulate
gyrus, entorhinal cortex, insular cortex, frontal cortex, and amygdale. AS is a
small protein that shares a structural resemblance with apolipoproteins
(Mukaetova-Ladinska et al., 2006). It is a neuronal presynaptic protein found
widely in the central nervous system (CNS). Normally a soluble and unstruc-
tured protein, it can aggregate to form the insoluble neurotoxic fibrils that
characterize LB. Epitope mapping shows similar patterns in AD, DLB, and
PD (Lippa et al., 2001).
A 2007 study by Kramer found that small individual AS aggregates are
more common than LB. These aggregates are located at presynaptic terminals,
and result in almost a complete loss of dendritic spines at the postsynaptic areas
(Kramer and Schulz-SchaeVer, 2007). Additionally, AS has been found to have
a role in the reducing dopamine synthesis (Mukaetova-Ladinska et al., 2006).
Although the mechanism of AS activity is incompletely understood, it is clear
that it plays a large and complex role in the pathogenesis of DLB.
There is no clear pathologic diVerentiation between DLB and PD-D. Both
disease entities result in end-stage disease with diVuse brain involvement and
clinical phenotypes that are nearly indistinguishable. However, there are subtle
pathological diVerences that can be seen at autopsy. Neuronal loss in the sub-
stantia nigra is greater in PD-D than in DLB, while beta-amyloid patterns are
more consistent in DLB. AS pathology is greater in the striatum in DLB than
PD-D (Duda et al., 2002). The AS aggregates into fibrils in LB and Lewy neurites
in DLB, PD-D, and PD, with the LB being indistinguishable between the syn-
dromes. AS is the primary protein in all the LB, and solubility and epitope studies
show similar features of the AS among the syndromes (Baba et al., 1998). This
suggests that DLB, PD-D, and PD may represent diVerent points on a continuum
of LB disorders, with motor and nonmotor features reflecting the regional burden
and distribution of pathology.
Most patients with DLB also have pathology typically seen in AD patients.
LB and Lewy neurites occur in cortical and brainstem nuclei in association
with cortical-amyloid plaques and neurofibrillary tangles (McKeith et al., 2004).
The degree of AD characteristics seen in DLB patients correlates with the
amount of AD pathology, with the main components seen being beta-amyloid
and tau. Tau aggregates are known to increase the formation of LB in suscepti-
ble brain regions, such as the amygdale (McKeith et al., 2004). This finding
has been noted in both DLB and AD patients, showing significant overlap
between the two types of dementia with regard to pathological findings
(Figs. 2 and 3).
 LEWY BODY DEMENTIA 223

FIG. 2. Lewy bodies (LB) and Lewy neurites. This is a moderately high-power magnification of
brain tissue from the amygdale of a patient with DLB. Tissue is stained with antibodies against alpha-
synuclein (AS). It demonstrates numerous AS containing Lewy bodies and Lewy neurites.

A B C

FIG. 3. High-power magnification images of LB. Image A is stained using a routine H & E stain. It
shows the classical nigral LB with an eosinophilic core and clearer peripheral region. Note the
neuromelanin pigment. Image B is a nigral LB from the same case, but stained with antibodies to
AS. It demonstrates that AS is concentrated at the periphery of the LB (the clearer region on H & E
stains). Image C shows a cortical LB stained with AS. These typically occur in smaller neurons, and
they stain more uniformly with AS; cortical LB lack a halo.

VI. Genetics

In most cases, the LB diseases occur sporadically. Fully penetrate genetic

causes for DLB are rare; however, there are likely additional genetic and environ-
mental susceptibility factors that are still unidentified. There are a variety of
genetic etiologies for dementia, with most being caused by abnormal CNS protein
processing, expression, or aggregation. Many diVerent types of cellular damage
224 HANSON AND LIPPA

cause aggregation of a variety of CNS proteins, and no single cause has been
linked to dementias. Additionally, mutations causing dementia and Parkinsonism
may lead to mixed or variable protein aggregates (Rajput et al., 2006).
Genetic abnormalities in AS or other proteins that cause LB diseases are rare,
but may lead to the cognitive or motor features of the disease. Dementia and
parkinsonism are not always related to pathology; other genetic localizations may
also lead to symptoms of parkinsonism and dementia. For example, some patients
with tau mutations may have features of PD-D and DLB but lack LB, while others
may have clinical and neuropsychological features that diVer.
Factors determining the distribution of pathology in relation to the symptoms
are incompletely understood. Schiesling et al. (2008) aptly stated that, ‘‘The
identification of the first gene in familial Parkinson’s disease (PD) only 10 years
ago was a major step in the understanding of the molecular mechanisms in
neurodegeneration. AS aggregation was not only recognized as a key event in
neurodegeneration in patients carrying mutations in this gene, but it turned out to
be the most consistent marker to define LB pathology also in nonheritable
idiopathic PD.’’ Numerous other genes have been found associated with PD,
and many individuals with ‘‘idiopathic’’ forms may prove to carry susceptibility
factors.

VII. Biomarkers

There are currently no highly sensitive clinical diagnostic criteria that

distinguish DLB from other dementia subtypes with certainty, but this could
be aided by biomarkers for DLB. Aarsland recently reviewed antemortem
markers that aid in the diagnosis (Aarsland et al., 2008). This study determined
that, ‘‘The best evidence was for scintigraphy of the striatal dopamine trans-
porter system using FP-CIT SPECT. Several small scintigraphy studies of
cardiovascular autonomic function using metaiodobenzylguanidine SPECT
have reported promising results. Studies exploring innovative techniques based
on CSF have reported interesting findings for the combination of amyloid beta
(abeta) isoforms as well as AS, and there are interesting results emerging from
preliminary studies applying proteomic techniques.’’ Other recent studies of
modalities, including MRI scanning, SPECT, and EEG, were less useful for
establishing a diagnosis in individual patients (Aarsland et al., 2008). Of note, is
the finding that DLB patients may show less medial temporal lobe atrophy on
MRI when compared with the patients of AD (Lippa et al., 1999). A large
portion of future DLB research will be in field of identifying usable biomarkers
to aid in clinical diagnosis.
 LEWY BODY DEMENTIA 225

VIII. Management

The treatment and management of DLB patients is complicated by their

neuropsychiatric profile and extrapyramidal signs. Cognitive impairment must
be addressed in the context of hallucinations, apathy, depression, and sleep
disorders. Functional status is compounded by the increased morbidity of physical
symptoms. Postural instability, continence, bradykinesia, syncope, falls, and auto-
nomic instability worsen DLB functional impairment. All these factors must be
considered when deriving a treatment program for the aVected patient.
The management of DLB patients should focus on having an accurate
diagnosis and identification of target symptoms that concern the patient and
caregiver (Barber et al., 2001). Nonpharmacological interventions such as physical
and occupational therapy, community resources, and home care should be
considered in addition to pharmacological interventions. Caregiver education is
paramount because sometimes identifiable triggers for the patient’s fluctuations
can be identified.
Although there are no pharmacologic treatments aimed specifically at DLB,
patient symptoms can be addressed by giving them the treatments for AD and
PD. Medications should be kept to a minimum since adverse responses are not
uncommon. In particular, traditional neuroleptics should be avoided, due to the
high rate of severe neuroleptic sensitivity in DLB. Low-dose newer antipsychotic
drugs are safer but sensitivity reactions have been documented and they should be
monitored carefully (McKeith et al., 2004).
DLB patients have greater cholinergic loss than AD patients (Perry et al., 1994),
and respond to cholinesterase inhibitors more eVectively than AD patients (Samuel
et al., 2000). Significant improvement in fluctuating cognitive impairments, visual
hallucinations, apathy, anxiety, and sleep disturbance are seen with cholinesterase
inhibitors when used in the typical dose range for AD (McKeith et al., 2004).
Improvement of attention upon treatment was most notable in patients with visual
hallucinations (McKeith et al., 2004). Significant and extensive reduction in beta-
amyloid deposits has been noted in DLB patients treated with cholinergic enhan-
cers (Ballard et al., 2007). Symptomatic response to cholinesterase inhibitors is
comparable in PD-D and DLB, with neither having significant compromise of
motor function (Burn and McKeith, 2003). Care should be used to monitor DLB
patients for orthostatic hypotension when on cholinesterase inhibitors.
Dopaminergic therapy is the mainstay treatment for extrapyramidal symp-
toms in DLB and PD-D. The lowest eVective level of levodopa should be used
(McKeith et al., 2004). Although the eVectiveness in the LB dementias has not
been extensively studied, the improvement of symptoms may be less than those
seen in pure PD due to their additional intrinsic striatal pathology and dysfunc-
tion (Duda et al., 2002).
226 HANSON AND LIPPA

Management of additional DLB symptoms is complicated. Depression is

common in both DLB and PD-D and can be treated with selective serotonin
reuptake inhibitors (McKeith et al., 2005). RBD can be treated with clonazapam,
melatonin, or quetiapine (Boeve et al., 2004). Tricyclic antidepressants, low
potency neuroleptics, antiparkinsonian anticholinergic drugs, and antispasmodics
for bladder or gastrointestinal tract should be avoided in DLB and PD-D patients
as they may not only worsen cognition and psychotic symptoms but may be
associated with orthostatic hypotension (McKeith and Mosimann, 2004).
When treating dementia patients, physicians need to assess the individual
needs of their patient. The safety and tolerability of pharmacologic agents should
be considered, along with their risk of side eVects and worsening of both motor
and cognitive functioning in PD-D and DLB. It is also important to remember
when treating these patients, that they are often frail and can clinically decom-
pensate quickly in the face of minor infection, metabolic stress, or environmental
changes. Physician should carefully review medications, reduce doses if possible,
carefully search for infections, normalize patient environment, and introduce
medications one at a time (Rogan and Lippa, 2002).

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 DEMENTIA IN PARKINSON’S DISEASE

Bradley J. Robottom and William J. Weiner

Department of Neurology, University of Maryland School of Medicine, Baltimore,
Maryland 21230, USA

I. Introduction
II. Epidemiology
III. Early Cognitive Changes in Parkinson’s Disease
IV. Clinical Features of Parkinson’s Disease Dementia
V. Pathology
VI. Neuroimaging
VII. Diagnosis
VIII. Treatment
References

Parkinson’s disease is the second most common neurodegenerative illness

diagnosed in the United States. Dementia is recognized as a common component
of advanced Parkinson’s disease (PD). In patients with early PD, cognitive changes
occur and primarily reflect impairment in executive function. It is unknown if the
early cognitive changes detected on neuropsychological testing in Parkinson’s
disease are predictive of the subsequent development of Parkinson’s disease with
dementia (PDD). Many patients with PD develop dementia characterized by a
wide range of cognitive deficits distinct from those seen in Alzheimer’s disease
(AD). Neuropsychiatric problems frequently accompany PDD. This chapter
reviews the epidemiology, clinical characteristics of early and late cognitive
changes, pathology, neuroimaging, diagnosis, and treatment of PDD.

I. Introduction

In the 1817 monograph, ‘‘An Essay on the Shaking Palsy,’’ James Parkinson
wrote that ‘‘the senses and intellect remain uninjured’’ (Parkinson, 1817). PD is
still diagnosed based on the motor features that Parkinson described (resting
tremor, bradykinesia, rigidity), but it has become clear that cognitive changes
and dementia in PD are common. The cognitive eVects of PD are varied, ranging
from subtle executive dysfunction in the early stages of illness to dementia in

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NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00412-7 0074-7742/09 $35.00
230 ROBOTTOM AND WEINER

advanced PD. For the purpose of this chapter, cognitive changes in early PD will
be defined as changes seen in patients with recent onset of disease (<5 years
disease duration) or with mild motor symptoms (Hoehn and Yahr stages I or II).
This chapter will review epidemiology of PDD, clinical features of early and late
cognitive changes, pathology, neuroimaging, diagnosis, and treatment of PDD.

II. Epidemiology

Prevalence estimates of PDD vary widely, with recent studies showing a

19-78% prevalence of PDD (Biggins et al., 1992; de Lau et al., 2005; Emre,
2004; Hobson and Meara, 2004; Levy et al., 2002c). Amongst the general
population older than 65 years of age, prevalence of PDD is 0.2-0.5% (Aarsland
et al., 2005). Lack of diagnostic accuracy, diVerence in sampling methods, varia-
bility in study populations, and lack of clear diagnostic criteria may all contribute
to widely varying prevalence. Estimates of incidence also indicate that PDD is
common with rates varying from 42.6 to 112.5 per 1000 person-years (Aarsland
et al., 2001a; Hobson and Meara, 2004; Hughes et al., 2000; Marder et al., 1996).
The relative risk for a PD patient to develop dementia is 5.1 compared to age
matched controls (Hobson and Meara, 2004).
Risk factors for the development of dementia include older age at onset of PD,
greater severity of neurologic symptoms, longer duration of PD, greater disability,
and male sex according to a longitudinal study by Hughes et al. (2000). Similar
findings were reported by Aarsland et al. (2001a), whose data show that baseline
factors predictive of the development of dementia include age, Hoehn and Yahr
score >2, and Mini-Mental State Examination score <29. Non-dopaminergic
signs of motor impairment such as dysarthria, postural instability, and gait
disorder may have a particular association with PDD (Levy et al., 2000; Pillon
et al., 1989). Consistently reported risk factors for incident PDD include age and
severity of parkinsonism (Levy et al., 2002c). In a prospective study evaluating risk
factors for incident dementia, Levy et al. (2002c) showed that the combination of
older age and high severity of extrapyramidal symptoms confer a relative risk
incident dementia of 9.7 compared to a PD population of younger age and low
severity. In their study, it was necessary to have both older age and higher severity
to have an increased risk of developing dementia.
Other risk factors for the development of PDD include cigarette smoking and
family history of dementia. The finding that cigarette smoking increases risk of
PDD is of particular interest (Ebmeier et al., 1990; Levy et al., 2002b), as there is a
decreased risk of developing PD in cigarette smokers (Morens et al., 1995). Family
history of a first-degree relative with dementia is more common in patients with
PDD (Marder et al., 1990), including Alzheimer’s disease (Marder et al., 1999).
 DEMENTIA IN PARKINSON’S DISEASE 231

The association between family history of dementia and the development of PDD
has led to a number of gene alleles being evaluated as risk factors for PDD.
However, no conclusive evidence has been found (Rippon and Marder, 2005).

III. Early Cognitive Changes in Parkinson’s Disease

Deficits in executive function are among the first cognitive changes demon-
strable in early PD and may be present in a majority of patients with PD (Cooper
et al., 1991; Levin et al., 1989). Intact executive functioning is necessary for
cognitive tasks that require planning, anticipation, goal selection, and using
feedback to guide behavior (Levin and Katzen, 2005). Patients may perceive
these diYculties as bradyphrenia, or slowness of thought (Fahn and Jankovic,
2007). Deficits may be subtle and diYcult to detect on standard memory testing
such as the Mini-Mental State Examination. More in-depth neuropsychological
tests such as the Wisconsin Card Sorting Task show a tendency toward persever-
ative errors (Canavan, 1989; Levin et al., 1989). Abnormalities of set shifting and
maintaining set can be demonstrated in early PD using Raven’s Progressive
Matrices (Farina et al., 2000). The modified Tower of London task may also
show diYculty with set shifting and maintaining the correct response set, even
in early PD patients (Owen et al., 1992). In Owen’s study of non-medicated
patients with PD, there were no diVerences in accuracy and initial thinking
time, reinforcing that executive function deficit may be subtle. These early, subtle
changes in executive function may not have clinical consequence. There are
many early patients with high level professional and management positions.
Memory impairment occurs early in PD and may be related primarily to
executive dysfunction leading to disruption of the memorization process (Levin
and Katzen, 2005). Memory impairment in early PD is independent of dementia.
Patients with PD perform comparably to controls on tasks of recall of unrelated
words and spatial position (Taylor et al., 1990). However, there may be deficits in
the recall of semantically related words (California Verbal Learning Test), defi-
cient source memory, and increased sensitivity to interference (Taylor et al., 1990).
PD patients are less likely to use strategies such as clustering that facilitate recall.
Supporting the findings from Taylor’s study, increased sensitivity to interference
was also found in newly diagnosed PD patients by using the Brown-Peterson
Distractor Task (Cooper et al., 1993). Impaired inhibition is theorized to be the
cause of PD patients’ inability to maintain relevant information during distraction
tasks (Kensiger et al., 2003). These studies support the contention that memory
impairment in early PD is related to executive dysfunction, causing a disruption in
the necessary processes of sequencing and encoding new memories.
232 ROBOTTOM AND WEINER

Patients with PD often complain of slowness of thought (Fahn and Jankovic,

2007), but this is hard to demonstrate in early PD. Many cognitive tasks have a
motor component, so this must be accounted for in tests designed to evaluate
processing speed in PD. One study comparing newly diagnosed, untreated PD
patients with medicated PD patients and healthy controls found increased reac-
tion time in both groups of PD patients. Based on their findings, the authors
hypothesized that prolonged response time had a cognitive basis that was not
dopaminergic ( Jordan et al., 1992). Cognitive processing time has been linked to
the diYculty of the task. Early, untreated PD patients were compared to ad-
vanced, untreated PD patients and healthy control subjects. Untreated PD
patients and controls performed similarly on simple reaction tasks; however,
reaction time decreased with complex tasks (Zimmerman et al., 1992). The
authors concluded that the decision making process in PD patients is impaired
when confronted with tasks that demand higher cognitive functioning. Zimmer-
man’s findings of increasing reaction time in response to task complexity have
been replicated by Cooper et al. (1994), who refer to the ‘‘cognitive-analytical’’
deficit which becomes apparent as cognitive complexity increases.
Visuospatial abnormalities are reported to be the most common deficits
in PD, partly because of the wide range of abnormalities that are referred to
as visuospatial (Levin and Katzen, 2005). Some of the more commonly tested
visuospatial tasks which have shown abnormalities include facial recognition,
spatial memory, spatial planning, visual attention, and visual orientation (Farina
et al., 2000; Levin, 1990; Postle et al., 1997; Sharpe, 1990). In addition to diYculty
with facial recognition, patients with PD also have diYculty recognizing emotion-
al facial expressions (Dujardin et al., 2004). Along with memory deficits in early
PD, visuospatial deficits are also hypothesized to result from executive dysfunction
leading to a failed integration of information (Levin and Katzen, 2005; Rippon
and Marder, 2005).
Language ability is largely preserved in PD. The language deficits that do exist
are subtle, consisting of hesitations at the beginning of speech (Illes, 1989),
perseverative intrusions on word fluency tasks (Lees and Smith, 1983), and
decreased categoric and letter fluency (Jacobs et al., 1995; Levin et al., 1989).
There is no evidence for aphasia. The language deficits that are present appear to
involve planning and execution of the motor aspect of language. These findings
are suggestive of impaired executive function, a unifying factor in early cognitive
changes in PD.
The cognitive changes observed in early PD are of uncertain significance.
They are generally mild and detectable only on formal cognitive testing. There is
no evidence suggesting that findings of executive dysfunction in the early stages of
PD predispose a patient to developing dementia, although decreased perfor-
mance on verbal fluency was predictive of development of dementia in a cohort
of nondemented PD patients of longer disease duration (Levy et al., 2002a).
 DEMENTIA IN PARKINSON’S DISEASE 233

Current evidence does not suggest that these findings are analogous to mild
cognitive impairment and AD. Further research is needed to determine the
significance of executive dysfunction in early PD.

IV. Clinical Features of Parkinson’s Disease Dementia

Impairment of executive function is one of the earliest cognitive changes

detectable in PD, and it is the core feature of PDD (Emre, 2003; Pillon et al.,
1996). The most prominent features of executive impairment include diYculty
with problem solving, concept formulation, set shifting, and attention (Rippon
and Marder, 2005). Performance of tests such as the Raven’s Progressive Matrices
and Wisconsin Card Sorting Test show impairment in PDD compared to controls
or nondemented PD patients (Aarsland et al., 2003; Litvan et al., 1991; Noe et al.,
2004; Paolo et al., 1996). In comparison to the most common cause of dementia,
AD, PDD patients have more impairment on executive tasks (Litvan et al., 1991).
Other features distinguishing PDD from AD include decreased speed of informa-
tion processing in PDD and a direct association between memory function and
degree of executive impairment (Huber et al., 1989b; Pillon et al., 1993). PDD
patients have diYculty switching set and maintaining attention (Girotti et al.,
1988; Noe et al., 2004). Impaired attention in PDD is similar in severity to that
seen in AD and dementia with Lewy bodies (DLB) (Aarsland et al., 2003; Litvan
et al., 1991). However, attention may fluctuate more in PDD than AD (Ballard
et al., 2002). Perseverative errors are common and may be lessened by dopami-
nergic medication (Owen et al., 1993). Cognitive reaction time and vigilance, both
markers of attention, are impaired in PDD (Litvan et al., 1991). Patients with PDD
actually perform comparably to patients diagnosed with DLB on tasks of attention
(Ballard et al., 2002).
Memory impairment in PDD is characterized by a failure of retrieval rather
than a failure to encode information (Emre, 2003). It is the presenting problem in
67% of patients with PDD, as opposed to DLB (94%) and AD (100%) (Noe et al.,
2004). Semantic and episodic memory is impaired, but benefit from cueing,
reflecting that failure of retrieval rather than encoding is the primary problem
(Rippon and Marder, 2005). Inability to eVectively encode and retrieve informa-
tion is thought to represent the eVects of striatofrontal dysfunction (Pillon et al.,
1993). The primacy of the retrieval problem diVerentiates PDD from AD, where
encoding is the primary problem (Stern et al., 1993). The degree of memory
impairment is probably less than that seen in AD (Emre et al., 2007), and the
increased burden of AD pathology in the hippocampus and temporal cortex may
explain these diVerences (Pillon et al., 1993).
234 ROBOTTOM AND WEINER

Visuospatial deficits are common in PDD. Deficits may be present before a

diagnosis of dementia can be made and consist of abnormalities in facial recogni-
tion, spatial memory, spatial planning, visual attention, and visual orientation
(Farina et al., 2000; Levin, 1990; Postle et al., 1997; Sharpe, 1990). The deficits are
thought to have both a perceptual and motor basis (Boller et al., 1984). Compared
to AD patients with a similar dementia severity, the visuospatial deficits of
PDD are more severe (Huber et al., 1989b; Mosimann et al., 2004; Stern et al.,
1993). It is hypothesized that visuospatial deficits of PDD are mediated in
caused in part by executive dysfunction (Levin and Katzen, 2005; Rippon and
Marder, 2005).
Language deficits in PDD are varied. Aphasia is rare and should call into
question the diagnosis of PDD (Emre et al., 2007). Impaired verbal fluency is often
seen before a diagnosis of dementia and is a common feature of PDD (Emre,
2003; Stern et al., 1993). The severity of verbal fluency impairment is similar to
that observed in AD (Cahn-Weiner et al., 2002; Pillon et al., 1993). Other features
of language involvement include less content to speech, impaired naming, shorter
phrase length, and dysarthria (Cummings et al., 1988). Comprehension diYculties
have also been noted, particularly with interpreting ambiguity and figurative
language (Grossman et al., 1992; Lewis et al., 1998). When compared to the
language deficits of AD, PDD patients display greater motor speech problems
but fewer language problems (Cummings et al., 1988).
Neuropsychiatric and behavioral symptoms are common in PDD, including
psychosis, mood disturbance, and apathy. Psychosis in PDD is common, with
hallucinations in 45–65% of patients and delusions occurring in 25–30%
(Aarsland et al., 2001, 2007; Fenelon et al., 2000). Visual hallucinations occur
twice as often as auditory hallucinations, and the visual hallucinations are usually
complex, formed visions. The most common hallucination is of unknown people
(Fenelon et al., 2000; Mosimann et al., 2006). The phenomenology is similar to that
observed in DLB (Emre et al., 2007). Delusions in PDD most often have a
paranoid component, while the ‘‘phantom boarder’’ delusion is the second most
commonly reported (Aarsland et al., 2001b). Delusions and hallucinations may
co-occur and lead to nursing home placement (Aarsland et al., 2000).
Mood disturbances are not uncommon in PDD, with depression and anxiety
being the most common. The frequency of major depression in PDD was 13%
in one community-based study (Aarsland et al., 2001b). While major depression
was more common in PDD than AD, the prevalence of dysphoric mood was
similar (Starkstein et al., 1996). Anxiety often appeared with depression or
dysphoric mood, and it was a common problem in PDD (Aarsland et al., 2007;
Menza et al., 1993). PDD patients also have high rates of apathy, with apathy
and depression being common comorbidities (23-54%) (Aarsland et al., 2001b,
2007).
 DEMENTIA IN PARKINSON’S DISEASE 235

V. Pathology

The pathologic hallmarks of PD are Lewy neurites, thread-like bodies found

in cellular processes, and Lewy bodies, found in neuronal perikarya (Pollanen
et al., 1993). The major component of these inclusion bodies is an aggregated form
of ! -synuclein. In PD, !-synuclein binds with other proteins to form insoluble
Lewy neurites and Lewy bodies (Braak et al., 2003). Pathological change in PD
develops before the disease is symptomatic, and it is proposed to follow a
predictable course (Braak et al., 2003). The first sites thought to be aVected are
the dorsal motor nuclei of the glossopharyngeal and vagal nerves, the olfactory
bulb, and the anterior olfactory nucleus. The sites involved diVerentiate PD from
multiple system atrophy and possibly from DLB (Braak et al., 2003; Galvin et al.,
2001). Pathological changes are hypothesized to proceed up the brainstem and
through areas adjacent to the olfactory nucleus including piriform cortex and
entorhinal cortex. As the disease spreads through the brainstem, the pars com-
pacta of the substantia nigra becomes involved, leading to neuronal loss and the
motor features of PD. According to this hypothesis, pathology is next found in the
temporal mesocortex, and eventually spreads to multiple cortical areas including
sensory association areas, premotor fields, primary sensorimotor cortex, and
limbic structures including the amygdala and hippocampus (Braak et al., 2003).
Involvement of limbic structures and other cortical structures with Lewy body
pathology may be the basis for PDD (Braak et al., 2000); although, non-dopaminergic
transmitter systems including noradrenergic, cholinergic, and serotonergic have
been implicated (Rippon and Marder, 2005; Zgaljardic et al., 2004).
Involvement of non-dopaminergic systems in the pathophysiology of PDD is
supported by neuropathological studies. Neuronal loss in the locus ceruleus, a
noradrenergic site, is more severe in PD patients with dementia than those
without dementia (Chui et al., 1986; Zweig, 1993). The degree of cell loss in the
locus ceruleus correlates with neuronal loss in other areas including the nucleus
basalis of Meynert, medial substantia nigra pars compacta, ventral tegmental
area, and the burden of Lewy bodies in the anterior cingulate gyrus (Zweig, 1993).
Cholinergic dysfunction is caused by involvement of the nucleus basalis of
Meynert, with neuronal loss in PDD equal or greater to that seen in AD
(Bohnen et al., 2003). Involvement of the cholinergic system is thought to be the
cause of decreased processing speed and contribute to the cognitive decline of
PDD (Korczyn, 2001; Whitehouse et al., 1983). Serotonergic loss in PDD is a
result of neuronal loss in the dorsal raphe nuclei and is thought to account for
some of the cognitive impairment of PDD ( Jellinger, 1997; Zweig, 1993).
Concurrent AD pathology may further cognitive decline in PDD. Typical AD
pathology including neurofibrillary tangles, neuritic plaques, and neuropil threads
has been found more often in PDD than PD patients without dementia
236 ROBOTTOM AND WEINER

(Braak and Braak, 1991; Paulus and Jellinger, 1991). In particular, there is a
higher burden of cortical AD pathology found in PDD patients (Paulus and
Jellinger, 1991). It has been hypothesized that Lewy body and AD pathology
are triggered by a common cause, which would explain the correlation between
the two (Apaydin et al., 2002). Unlike the early involvement of sensory association
areas seen in AD (Vermersch et al., 1992), AD pathology found in PDD patients is
found predominantly in frontal, temporal, and entorhinal cortices (Vermersch
et al., 1993). It seems likely that a combination of disrupted neurotransmitter
systems, AD pathology, and Lewy body pathology all contribute to the clinical
manifestations of PDD.

VI. Neuroimaging

Neuroimaging is not used routinely in the diagnosis of PDD. However, studies

are available detailing common imaging findings of PDD in magnetic resonance
imaging (MRI), single-photon emission computed tomography (SPECT), posi-
tron emission topography (PET), and proton magnetic resonance spectroscopy
(MRS). Early studies detailing results of MRI in PDD stated that there were no
specific structural abnormalities that could be identified (Huber et al., 1989a).
More recently, preferential atrophy has been found in the substantia innominata
(Hanyu, 2002), amygdala ( Junque et al., 2005), and hippocampus ( Junque et al.,
2005; Laakso et al., 1996). The degree of hippocampal atrophy is greater than
would be seen in AD (Laakso et al., 1996). Generalized atrophy is also present, and
the rate of atrophy is greater than seen in PD patients without dementia (Burton
et al., 2005).
SPECT studies in PDD show a consistent pattern of bilateral temporal-
parietal hypoperfusion, a pattern that is also seen in AD (Antonini et al., 2001;
Firbank et al., 2003; Tachibana et al., 1993). Using SPECT to track progression of
dopaminergic degeneration demonstrates significant progressive loss that corre-
lates to both motor impairment and dementia severity in PDD and DLB (Colloby
et al., 2005). The usefulness of SPECT as a diagnostic tool is limited due to its
relative inability to distinguish PDD from other forms of dementia, and PET
imaging shares a similar shortcoming. Studies of PET imaging in PDD show a
pattern of bilateral temporal-parietal hypometabolism which cannot be reliably
distinguished from AD (Goto et al., 1993; Peppard et al., 1992; Vander Borght
et al., 1997). Although PDD patients do appear to have a characteristic change of
lower N-acetylaspartate levels in the occipital cortex on MRS (Summerfield et al.,
2002), MRS remains primarily a research tool and its clinical utility in diVeren-
tiating PDD from other parkinsonian neurodegenerative disorders is unclear
(Seppi and Schocke, 2005).
 DEMENTIA IN PARKINSON’S DISEASE 237

VII. Diagnosis

Prior to 1997, PDD was diagnosed according to DSM IV criteria, which were
relatively nonspecific (Rippon and Marder, 2005). In 2007, the Movement Dis-
orders Society created a task force which developed clinical diagnostic criteria for
PDD. PDD is a slowly progressive dementia that develops with the context of
established PD. There must be deficits in at least two of four core cognitive
domains (attention, memory, executive, and visuospatial). The deficits must be
severe enough to interfere with normal functioning. Behavioral features such as
hallucinations, delusions, apathy, and changes in mood are frequently present but
not necessary for diagnosis of PDD. The label of ‘‘possible PDD’’ is given to
patients who do not have behavioral features, who have an atypical cognitive
profile, or who have another abnormality which may explain the cognitive
dysfunction (such as significant vascular disease, major depression, or a concur-
rent toxic/metabolic encephalopathy). A diagnosis of ‘‘probable PDD’’ requires a
diagnosis of PD, a slowly progressive dementia defined by deficits in at least two of
four core cognitive domains (attention, memory, executive, and visuospatial), and
the presence of a behavioral feature (Emre et al., 2007).

VIII. Treatment

There are no pharmacologic agents that have been developed specifically for
the treatment of PDD. The agents that are currently used were first developed for
AD and were subsequently studied in PDD. Randomized, double-blind, placebo
controlled trials (RCTs) are limited in number and are confined to acetylcholin-
esterase inhibitors. Three small, RCTs of donepezil for treatment of PDD showed
improvement in Mini-Mental State Examination of two points (Aarsland et al.,
2002; Ravina et al., 2005) and improvement in the memory subscale of the Mattis
Dementia Rating Scale (Leroi et al., 2004). Overall the drug was well tolerated
with few reports of increased parkinsonism. The overall benefit of donepezil is
modest, and the American Academy of Neurology Practice Parameters state that
donepezil ‘‘should be considered for the treatment of dementia in PD’’ (Miyasaki
et al., 2006). One large, RCT of rivastigmine was performed, and the results
showed moderate improvements in dementia that were accompanied by worsen-
ing tremor in 10% of patients (Emre, 2004). Like donepezil, the AAN recom-
mends that rivastigmine ‘‘should be considered for the treatment of dementia in
PD’’ (Miyasaki et al., 2006). Small, open label studies of tacrine and galantamine
also report modest benefits on cognition (Aarsland, 2002; Hutchinson and
Fazzini, 1996), but no RCTs of these agents have been performed. Memantine,
238 ROBOTTOM AND WEINER

an NMDA antagonist used in the treatment of AD, has not been studied for the
treatment of PDD.
Treatment of the neuropsychiatric or behavioral features of PDD may take a
variety of approaches. The first strategy employed in the treatment of psychosis is
to reduce the dose of those drugs which are least potent with respect to motor
impairment (Fig. 1). Medications that are known to cause psychosis (e.g., dopa-
mine agonists, monoamine oxidase B (MAO-B) inhibitors, catechol-O-methyl
transferase (COMT) inhibitors, amantadine) should be discontinued. If this is
unsuccessful in resolving psychosis, then the daily levodopa dose should be reduced
until unacceptable motor complications arise. If psychosis persists after reducing
dopaminergic medications, then the addition of an antipsychotic medication may
be necessary. The AAN Practice Parameters state that clozapine is ‘‘probably an
eVective treatment and improves psychosis’’ and quetiapine ‘‘possibly improves
psychosis’’ in PD (Miyasaki et al., 2006). Clozapine is the only antipsychotic that
has been proved eVective for psychosis in PD as both RCTs of quetiapine have
failed to show benefit (Ondo et al., 2005; Rabey et al., 2007). However, quetiapine is
often prescribed first because of the risk of agranulocytosis seen with clozapine.
Other antipsychotics are not recommended because of their eVects on motor
function in PD. Open label trials of rivastigmine and donepezil have suggested
that acetylcholinesterase inhibitors may be beneficial for psychosis in PDD

Psychosis in parkinson’s disease

dementia

Step 1:
Reduce dopaminergic medications
• Discontinue dopamine agonists, MAO-B inhibitors,
COMT inhibitors, amantadine
• Reduce levodopa dosage

Step 2:
Psychosis persists
• Start quetiapine at a low dose (25 mg)
• Titrate up as tolerated

Step 3:
Psychosis persists
• Transition to clozapine
• Monitor complete blood counts for agranulocytosis

FIG. 1. Treatment of psychosis in PDD.

 DEMENTIA IN PARKINSON’S DISEASE 239

(Bergman and Vladimir, 2002; Reading et al., 2001). One RCT of rivastigmine
suggested that PDD patients with psychosis (visual hallucinations) may have
greater cognitive benefit from rivastigmine than those without psychosis. The
study was not powered to examine behavioral diVerences (Burn et al., 2005).
Acetylcholinesterase inhibitors may be a reasonable treatment option for psychosis
in PD, though they do not have the proved eYcacy of antipsychotic medications.

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 EARLY ONSET DEMENTIA

Halim Fadil,* Aimee Borazanci,* Elhachmia Ait Ben Haddou,y

Mohamed Yahyaoui,y Elena Korniychuk,* Stephen L. Jaffe,* and Alireza Minagar*
*Department of Neurology, Louisiana State University School of
Medicine-Shreveport, Shreveport, Louisiana 71103, USA
y
Service de Neurologie B et Neurogenetique, Hopital des Specialties, Rabat, Morocco

I. Introduction
II. Diagnostic Approach
III. DiVerential Diagnosis
A. Vascular Diseases
B. Infectious Diseases
C. Toxic-Metabolic Disorders
D. Immune-Mediated Disorders
E. Neoplastic/Metastatic Disorders
F. Neurodegenerative Disorders
G. Miscellaneous Causes of EOD
References

Dementia is characterized by a decline in cognitive faculties and occurrence of

behavioral abnormalities which interfere with an individual’s activities of daily
living. Dementing disorders usually affect elderly individuals but may occur in
individuals younger than 65 years (early-onset dementia or EOD). EOD is often
misdiagnosed or its diagnosis is delayed due to the fact that it has a more varied
differential diagnosis than late-onset dementia. EOD affects individuals at the
height of their career and productivity and produces devastating consequences
and financial loss for the patient’s family as well as society. EOD is not uncommon
and is diagnosed in up to a third of patients presenting with dementia. Most
importantly, some of the causes of EOD are curable which makes the need for a
specific and timely diagnosis crucial. The present chapter presents a systematic
approach to the differential diagnosis of EOD and provides readers with the
clinical and neuroimaging features of these disorders as well as important con-
siderations for their diagnostic evaluation. Specifically, the nuances of assessing
the history and examination are discussed with careful attention to the various
methods of cognitive and behavioral evaluation. A step-wise approach to diag-
nostic testing is followed by a discussion of anatomical localization, which often
aids in identifying specific etiologies. Finally, in order to organize the subject for

INTERNATIONAL REVIEW OF 245 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00413-9 0074-7742/09 $35.00
246 FADIL et al.

the reader, the various etiologies are grouped under the general categories of
vascular, infectious, toxic-metabolic, immune-mediated, neoplastic/metastatic,
and neurodegenerative.

I. Introduction

Dementia is defined by the Diagnostic and Statistical Manual of Mental

Disorders (DSM-IV-TR), fourth edition (American Psychiatric Association) as a
group of disorders which is characterized by the development of multiple cogni-
tive deficits which include memory loss and dysfunction in at least another
cognitive domain, severe enough to interfere with activities of daily living
(ADLs). Other cognitive domains include executive function, language, praxis,
and gnosis. While dementia is usually regarded as a disorder of old age (i.e., 65
and older) it can aVect younger individuals under age 65. Early onset dementia
(EOD) is not uncommon and has been reported in approximately one third of all
patients presenting with dementia in developed countries, with a prevalence
varying from 67 to 81/100,000 persons in the 45- to 65-year-old age group
(Harvey et al., 2003). McMurtray et al. (2006) reported EOD in 29.3% of 948
US veterans diagnosed with dementia in a memory disorders clinic. Its prevalence
may be higher in less developed countries; 46.6% of 311 patients were found to
have EOD in a Brazilian study (Fujihara et al., 2004). EOD aVects individuals
during their most productive phase of life and has a devastating impact upon their
families as well as a major economic impact upon society. In this chapter, we will
review the diagnostic approach to EOD emphasizing the diVerential diagnosis,
with the objective of presenting a paradigm which will aid in clinical recognition
of curable subtypes.

II. Diagnostic Approach

The EOD diagnostic process consists of the following steps: obtaining the
patient’s history including interviewing a caregiver or a family member, and
performance of a physical/neurological examination, formal cognitive assess-
ment, laboratory testing, and neuroimaging. Important historical information
includes the patient’s age at onset of cognitive impairment; other associated
neurological or systemic symptoms; the presence of co-morbidities (i.e., hyperten-
sion, diabetes mellitus, hyperlipidemia); dementia risk factors such as repetitive
head trauma, alcohol abuse, or a family history of dementia; and the course of
illness pattern (i.e., gradual in Alzheimer’s disease versus stepwise in vascular
 EARLY ONSET DEMENTIA 247

dementia). Interviewing a caregiver or a family member separately to obtain a

more complete and accurate picture may provide useful diagnostic clues which
they may not feel comfortable in disclosing with the patient being present.
Moreover, patients may omit important aspects of their history because of poor
insight into their illness or simply due to cognitive decline.
The neurological examination may provide significant findings further nar-
rowing the diVerential diagnosis and directing the diagnostic work-up (Table I).
For instance, the presence of focal findings such as corticospinal tract signs raises
suspicion for stroke or a neoplastic process, while the presence of gait apraxia and
sphincter incontinence suggests normal pressure hydrocephalus (NPH). Peripher-
al neuropathy may suggest B12 deficiency. Examination of other systems is also
necessary to exclude the possibility of a multi-systemic process such as vasculitis,
infection, metastases, or metabolic disorder (Table II). For example, the presence
of a facial ‘‘butterfly’’ rash may suggest systemic lupus erythematosus; and uveitis
may indicate sarcoidosis or Behcet’s disease.
When dementia is suspected, a formal cognitive evaluation is necessary.
Cognitive domains that need to be assessed are orientation, attention, language,
memory, executive function, praxis, and visuospatial function. The most popular
bedside cognitive test is the Mini-Mental State Examination (MMSE) (Folstein
et al., 1975). As a practical bedside tool, the MMSE can be administered quickly.
While the MMSE is highly sensitive and specific in detecting moderate to
severe dementia, it remains an inaccurate tool for assessing mild dementia.
Other limitations of the MMSE include restricted evaluation of executive
function (i.e., limited to working memory) and inability to accurately assess non-
educated patients. The clock-drawing test is another popular bedside test that can
be administered in 5–10 min. It is used to evaluate mainly visuospatial, parietal lobe
function as well as general executive functions of the frontal lobes. However, just like
the MMSE, it lacks sensitivity for the diagnosis of mild dementia. To address the
shortcomings of these tests, a number of more sensitive cognitive tests have been
developed. Examples are the Addenbrooke’s Cognitive Assessment (Mathuranath
et al., 2000), DemTect (Kalbe et al., 2004), the Montreal Cognitive Assessment
(Nasreddine et al., 2005), and the Behavioral Neurology Assessment, short form
(Darvesh et al., 2005). Review of all these cognitive tests is beyond the scope of this
article. However, it is important to mention that none is as extensive as neuropsy-
chological testing which clearly determines the extent of cognitive dysfunction and
establishes a neuropsychological profile. Often the disclosed pattern of cognitive
decline can identify the EOD subtype.
At the end of the clinical evaluation, it may be useful to categorize the
dementia into cortical, subcortical, or mixed types. Cortical dementia is clinically
characterized by impairment of memory, language, gnosis, and praxis (i.e.,
Alzheimer’s disease, Creutzfeld-Jakob disease). Subcortical dementia is character-
ized by less severe memory dysfunction, bradyphrenia, and executive dysfunction
248 FADIL et al.

TABLE I
NEUROLOGICAL SIGNS OR SYNDROMES AND CORRESPONDING POTENTIAL DIAGNOSES

Physical sign Potential diagnosis

Papilledema Brain tumor, subdural hematoma, hydrocephalus

Optic disc pallor Multiple Sclerosis (MS), B12 deficiency
Blindness Cerebrovascular disease, Alzheimer’s disease (AD),
Creutzfeld-Jakob disease (CJD)
Pigmentary retinal degeneration Panthotenate kinase-associated neurodegeneration (PKAN)
Visual field defect Cerebrovascular disease, Neoplasm, CJD
Kayser-Fleischer ring Wilson’s disease
Argyll Robertson pupil (reactive to Neurosyphilis
accomodation but not to light)
Optic neuritis MS, Sarcoidosis, Lyme disease
Anosmia Subfrontal meningioma, AD, Parkinson’s disease (PD),
Traumatic brain injury, Huntington’s disease (HD)
Abnormal eye movements Progressive supranuclear palsy (PSP), Corticobasal
degeneration (CBD), Wernicke-KorsakoV syndrome,
Whipple’s disease, CJD, mitochondrial disorders
Parkinsonism Dementia with Lewy bodies (LBD), PD, Vascular dementia
(VaD), PSP, CBD, HD, Wilson’s disease, PKAN,
Dentatorubral-Pallidoluysian atrophy (DRPLA),
Neuroacanthocytosis, CADASIL, Multiple system atrophy
(MSA), Neuroferritinopathy
Myelopathy Neurosyphilis, B12 deficiency, HIV, MS, spinocerebellar
ataxia (SCA)
Pyramidal signs Cerebrovascular disease, Brain tumors, Hydrocephalus,
MS, AD, CJD, CBD, Leukodystrophies, Frontotemporal
Dementia (FTD)
Alien hand CBD
Myoclonus CJD, AD, Subacute sclerosing panencephalitis (SSPE),
CBD, LBD, Hashimoto’s encephalopathy
Early onset incontinence Hydrocephalus, Frontal lobe tumor, PSP
Bulbar signs FTD (in association with Motor neuron disease)
Ataxia Paraneoplastic syndromes, Whipple’s disease, CJD, AIDS
dementia complex, SCA, Wernicke-KorsakoV syndrome,
PKAN, Mitochondrial disorders, Leukodystrophies, Lead
poisoning
Peripheral neuropathy B12 deficiency, paraneoplastic disorders, SLE, PKAN,
Neuroacanthocytosis, SCA, Lead poisoning
Seizures Cerebrovascular disease, Vasculitis, Neoplasms, Limbic
encephalitis, AIDS dementia complex, Neurosyphilis,
SSPE, Hashimoto’s encephalopathy
Early gait disorder Hydrocephalus, PSP, MSA, LBD

Reference: Cooper and Greene (2005).

 EARLY ONSET DEMENTIA 249

TABLE II
NON-NEUROLOGICAL SIGNS OR SYNDROMES AND CORRESPONDING POTENTIAL DIAGNOSES

Physical sign Potential diagnosis

Uveitis Sarcoidosis, Behcet’s disease

‘‘Butterfly’’ facial rash Systemic lupus erythematosus (SLE)
Dermatitis Niacin deficiency
Macrocytic anemia B12 deficiency

(i.e., Huntington’s disease, Parkinson’s disease). Certain conditions such as

dementia with Lewy bodies (LBD) and corticobasal degeneration (CBD) cause a
mixed type of dementia with both cortical and subcortical signs.
Recommended diagnostic studies include complete blood count, erythrocyte
sedimentation rate, complete metabolic panel, thyroid profile, rapid plasma
reagin, serum folate/vitamin B12 levels, ANA, urinalysis, urine toxicology, chest
X-ray, and computerized assisted tomographic (CAT) brain imaging. Other
investigations such as HIV serology, determination of angiotensin converting
enzyme (ACE) level (serum/CSF), paraneoplastic antibodies, cerebrospinal fluid
analysis, electroencephalography, and brain magnetic resonance imaging (MRI)
will be directed by the history/physical examination and abnormal results of
screening tests. Specialized tests such as slit lamp examination and genetic
screening for certain hereditary disorders are considered if specific disorders are
strongly suspected. At times, brain biopsy will be required. Functional neuroim-
aging including positron emission tomography (PET) with 2-fluoro-2-deoxy-D-
glucose, single photon emission computed tomography (SPECT), and functional
magnetic resonance imaging (f MRI), even though not considered part of the
routine work-up for dementia, may provide data to diVerentiate various types of
neurodegenerative diseases.

III. Differential Diagnosis

A diagnosis of dementia cannot be established before excluding mental

retardation, depression, and delirium. Mental retardation is excluded during
history taking when the patient’s level of cognition is determined to be deteriorat-
ing as compared to baseline. Depression may imitate dementia since it impairs
concentration, and thus blocks eVective data input and memory formation (i.e.,
pseudodementia). Depressive symptoms should be actively sought after during the
interview with both the patient and family members. Occasionally, a detailed
neuropsychological evaluation is required to diVerentiate dementia from depres-
sion. However, depression may coexist with dementia or even be one of the
250 FADIL et al.

clinical manifestations of the dementing illness. Delirium must also be excluded

when evaluating a patient presenting with dementia. Delirium is defined as a
transient acute confusional state with fluctuating level of consciousness and is
considered to be a medical emergency with high risk of morbidity and mortality.
Toxic and metabolic disorders are primary causes, and urgent medical investiga-
tion and proper treatment of the delirium are necessary. Additionally, a diagnosis
of dementia cannot be established during a delirious state, even though demented
patients are more prone to develop delirium.
Once the diagnosis of dementia is established, the specific etiology should be
determined. Many underlying pathologies must be considered, and a systematic
diagnostic approach is required. Vascular, infectious, toxic-metabolic, immune-
mediated, metastatic/neoplastic, iatrogenic, and neurodegenerative problems
can be etiologic and will be discussed in detail (Table III).

A. VASCULAR DISEASES

Dementia related to cerebrovascular disease (initially termed ‘‘arteriosclerotic

dementia,’’ then ‘‘multi-infarct dementia,’’ and later ‘‘vascular dementia’’ (VaD))
recently has been incorporated under the broader umbrella of ‘‘vascular cognitive
impairment’’ (Bowler, 2005). Certain studies have found it to be the most com-
mon cause of EOD (McMurtray et al., 2006), while others rank it as second to
Alzheimer’s disease (Harvey et al., 2003; Shinagawa et al., 2007). Clinically and
neuropathologically, VaD represents a heterogeneous group of disorders which
manifests with various neurological signs and behavioral syndromes as well as
variable cognitive profiles depending on the location (cortical, subcortical, or
mixed) of the vascular lesions. The underlying neuropathology is also variable
and may be ischemic or hemorrhagic, focal or diVuse, and predominantly either
cortical or subcortical. Based on these findings and other characteristics such as
the size, location, and number of infarcts, multiple morphologic classifications
exist ( Jellinger, 2007). One classification system divides this type of dementia into
large vessel disease (LVD) and small vessel disease (SVD). LVD, which is usually
associated with atherosclerosis leading to classical multi-infarct encephalopathy, is
the cause of only about 15% of VaD cases. SVD is the most common cause of
VaD and comprises multiple subtypes such as strategic infarct dementia, Bins-
wanger’s syndrome, and hereditary vasculopathies.
Strategically located strokes in areas such as the thalamus, frontocingulate
cortex, basal forebrain, hippocampus, caudate nucleus, and angular gyrus may
cause dementia. For example, thalamic dementia secondary to bilateral ischemic
infarction in the distribution of the paramedian thalamic arteries is a subcortical
dementia characterized by marked apathy and impaired attention, as well as
anterograde and retrograde amnesia. Typically, thalamic dementia occurs in a
 EARLY ONSET DEMENTIA 251

TABLE III
DIFFERENTIAL DIAGNOSIS OF EARLY ONSET DEMENTIA

Vascular diseases Metastatic/Neoplastic disorders

Cerebrovascular disease (multi-infarct state, Brain metastatic disease

strategic infarct dementia)
Binswanger’s syndrome Primary CNS lymphoma
Hereditary vasculopathies: (CADASIL) Intravascular lymphoma
Infectious diseases Lymphomatoid granulomatosis
HIV-associated dementia Gliomatosis cerebri
Neurosyphilis Iatrogenic disorders
Lyme disease Alcohol related
Whipple’s disease Drug related
Subacute sclerosing panencephalitis Bismuth toxicity
Neurocysticercosis Lithium toxicity
Progressive multi-focal leukoencephalopathy Mercury toxicity
Chronic meningitis Arsenic toxicity
Toxic-metabolic disorders Neurodegenerative diseases
Thyroid disease Alzheimer’s disease
Parathyroid disturbance Dementia with Lewy bodies
Adrenal disease Frontotemporal dementia,
Hepatic encephalopathy Parkinson’s disease
Renal failure and dialysis dementia Progressive supranuclear palsy
B12, thiamine, niacin, folate deficiencies Corticobasal degeneration
Porphyria Huntington’s disease
Leukodystrophies Wilson’s disease
Mitochondrial disorders Neurofilament inclusion body disease
Electrolyte abnormalities Pantothenate kinase-associated degeneration
Immune-mediated diseases Neuroferritinopathy
Paraneoplastic syndromes Neuroacanthocytosis
Multiple sclerosis Miscellaneous disorders
Primary CNS angiitis Traumatic brain injury (dementia pugilistica)
Systemic vascultides Normal pressure hydrocephalus
Lupus cerebritis Down syndrome (trisomy 21)
Hashimoto’s encephalopathy Obstructive sleep apnea
Nonvasculitic autoimmune inflammatory
meningoencephalitis

patient with multiple vascular risk factors such as hypertension and diabetes
mellitus. It may also be observed in association with cocaine abuse. Subcortical
microvascular leukoencephalopathy (also known as Binswanger’s syndrome) was
initially described by Binswanger (1894), and is clinically characterized by an
insidiously progressive dementia in association with persistent hypertension.
Brain imaging usually reveals multifocal and confluent lesions aVecting the
periventricular regions and/or deep white matter ( Jellinger, 2007).
The most common hereditary cerebral angiopathy is cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy
252 FADIL et al.

(CADASIL). CADASIL is caused by mutations in the Notch 3 gene on chromo-

some 19q12. The Notch 3 gene encodes a receptor protein which is expressed on
vascular smooth muscle cells and, when mutated, leads to formation of a non-
amyloid, non-atherosclerotic microangiopathy. It is clinically characterized by the
tetrad of migraine with aura, recurrent stroke, cognitive impairment leading to a
subcortical dementia, and psychiatric manifestations.

B. INFECTIOUS DISEASES

Dementia may occur in association with several infectious diseases, of which

the most common ones are discussed below.

1. HIV-Associated Dementia
HIV-associated dementia (HAD) is the most devastating neurological complica-
tion of HIV infection consisting of a constellation of progressively disabling symp-
toms involving cognitive faculties, motor function, and behavior (Minagar et al.,
2008). AIDS patients with less serious degrees of cognitive and motor impairments
not meeting the diagnostic criteria for dementia are diagnosed as HIV-associated
cognitive/motor disorder (MCMD). The classical neuropsychological deficits in
patients with HAD indicate dysfunction of frontal and subcortical circuits. HAD,
as a predominantly subcortical dementia, presents with memory loss (mainly for
retrieval of recorded information), psychomotor slowing, depression, and withdrawal
from ADLs. Price and Brew (1988) developed the Memorial Sloan Kettering scale
for HAD which classifies these patients as normal, mild, moderate, severe, and end
stage (Table IV). Neuropathological findings in HAD consist of frontotemporal
atrophy, and the presence of multiple small nodules (microglial nodules) containing
macrophages, lymphocytes, and microglia scattered throughout the cerebral white
matter, and the subcortical gray matter of the thalamus, basal ganglia, and brain-
stem. Brain imaging, particularly MRI with gadolinium, is necessary to exclude
other causes of dementia which may imitate the HAD clinical picture. These other
disorders in AIDS patients include toxoplasmosis, progressive multifocal leukoence-
phalopathy, cryptococcal infection, cytomegalovirus encephalitis, and CNS lympho-
ma. Brain MRI in patients with HAD reveals diVuse, non-enhancing, ill-defined
areas of hyperintense signal in deep white matter along with cerebral atrophy,
ventricular enlargement, and caudate region atrophy. Proton magnetic resonance
spectroscopy (MRS) in HAD patients demonstrates increased myoinositol (indicat-
ing gliosis) and choline (indicating demeyelination) levels in gray and white matter
along with decrease in levels of N-acetyl aspartate in gray matter (indicating
neuronal/axonal loss). HAART treatment has been reported to have decreased
the present incidence of HIV dementia (Sacktor et al., 2003). However, HAD
 EARLY ONSET DEMENTIA 253

TABLE IV
CLINICAL STAGING OF THE AIDS DEMENTIA COMPLEX

Stage 0 (normal)
Normal mental and motor function
Stage 0.5 (equivocal and subclinical)
Absent, minimal, or equivocal symptoms without impairment of work or capacity to perform ADLs.
Mild signs (snout response, slowed ocular, or extremity movements) may be present. Gait and
strength are normal
Stage 1 (mild)
Able to perform all but the more demanding aspects of work or ADLs, but with unequivocal evidence
(signs or symptoms that may include performance on neuropsychological testing) of functional
intellectual or motor impairment. Can walk without assistance
Stage 2 (moderate)
Able to perform basic activities of self-care, but cannot work or maintain the more demanding aspects
of daily life. Ambulatory, but may require a single prop
Stage 3 (severe)
Major intellectual incapacity (cannot follow news or personal events, cannot sustain complex
conversation, considerable slowing of all outputs) and motor disability (cannot walk unassisted,
requires walker, or personal support, usually with slowing and clumsiness of arms as well
Stage 4 (end stage)
Nearly vegetative. Intellectual and social comprehension and output are at a rudimentary level. Nearly
or absolutely mute. Paraparetic or paraplegic with urinary and fecal incontinence
Developed by Price and Brew at Memorial Sloan Kettering (Price and Brow 1988)

prevalence has actually risen due to the increasing number of infected subjects as a
result of increased life expectancy.

2. Syphilitic Dementia
Syphilis is caused by Treponema pallidum, and worldwide is still a common
disease. Certain factors such as poverty, illiteracy, and prostitution contribute to
the prevalence of this infection with its tertiary stage dementia. Neurological
manifestations of syphilis include meningoencephalitis and chronic vasculitis
which can both cause stroke, tabes dorsalis, myelopathy, and dementia. Syphilitic
dementia (which, since the advent of penicillin, is now a rare complication)
occurs 20 years following the primary infection and presents with memory loss,
apathy, seizures, dysarthria, and cortical deficits such as aphasia and apraxia.
Examination of the serum and CSF demonstrates positive serology, and the CSF
examination shows pleocytosis, elevated protein, and an increased IgG index.

3. Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) usually manifests itself several
years after the primary measles infection and occurs in immunocompetent indivi-
duals. SSPE presents with gradual cognitive decline and behavioral abnormalities,
254 FADIL et al.

followed by myoclonus, ataxia, motor deficits, and spasticity. In its final stage,
autonomic abnormalities and coma develop. The EEG is pathognomonic with
periodic high-amplitude polyspike and sharp- and slow-wave complexes lasting
0.5–2 s. Neuropathological examination demonstrates patchy areas of demyelin-
ation and gliosis as well as the presence of Cowdry types A and B eosinophilic
inclusions. There is no specific treatment for SSPE and preventive vaccination
against measles virus remains the only way to avoid this complication.

4. Prion Diseases
The transmissible spongiform encephalopathies are an uncommon group of
neurodegenerative diseases causing rapid onset dementia. This group of disorders
is linked to abnormal metabolism of the prion protein. Prion diseases aVect both
human and animal hosts and remain invariably fatal. The transmissible agent is
an abnormal isoform of the prion protein (PrP) which is designated as the protease
resistant scrapie form (PrPsc). The gene for the human PrP is located on the short
arm of chromosome 20. Human prion diseases include Kuru, Creutzfeldt-Jakob
disease (CJD), variant Creutzfeldt-Jakob disease (vCJD), Gerstmann-Strussler-
Scheinker disease, and fatal familial insomnia. CJD which occurs worldwide
can be acquired (iatrogenic), familial, or sporadic (sCJD). Acquired cases linked
to iatrogenic transmission have been reported following corneal and dural graft
transplantation. Variant CJD has been linked to bovine spongiform encephalop-
athy. sCJD which accounts for up to 85% of all cases of prion diseases is primarily
a disease of older adults but can also aVect young people. Patients with sCJD
present with the triad of rapidly progressive dementia, myoclonus, and ataxia.
Cognitive decline in these patients is manifested by poor concentration, diYculty
with mental calculations, impaired abstract thought, aphasia, and apraxia, and
can be associated with abnormal involuntary movements such as choreoathetosis
(Eggenberger, 2007). Diagnosis of sCJD depends on the presence of rapidly
progressive dementia associated with at least two of the following four findings:
Myoclonus, visual manifestations or cerebellar signs, pyramidal or extrapyrami-
dal signs, and akinetic mutism. The presence of bilaterally synchronous, periodic
sharp waves or spikes against a slow background on the EEG, and elevated CSF
levels of the 14-3-3 protein support the clinical diagnosis. Brain MRI of patients
with sCJD may reveal the presence of bilateral hyperintense signals in the basal
ganglia, corpus striatum, and thalamus, which are best observed on diVusion
weighted images. In contrast to sCJD, patients with vCJD present primarily
with psychiatric symptoms, and later in the course of disease develop
dementia, ataxia, and involuntary movements. The T2-weighted MRI reveals
abnormal hyperintense signals in the posterior thalamus (pulvinar sign) (Zeidler
et al., 2000).
 EARLY ONSET DEMENTIA 255

5. Lyme Disease
Lyme disease is a systemic infectious disease caused by the spirochete, Borrelia
burgdorferi, which is transmitted to the human host by the bite of the Ixodes tick.
It predominantly aVects the nervous system, skin, heart, and joints. The infection
develops within a period of 3–32 days after tick bite with a characteristic acute
rash, erythema chronicum migrans. About 15% of patients with Lyme disease
develop neurological manifestations, which consist of lymphocytic meningitis,
cranial neuritis, and radiculitis. The cognitive dysfunction in patients with Lyme
disease is characterized by impaired executive function and attention. However, a
clear dementia due to Lyme disease is infrequent. Depression, emotional lability,
irritability and psychosis may also be present. CSF examination shows a pleocy-
tosis with elevated protein levels and the presence of oligoclonal bands and
Borrelia DNA; at times, T2-weighted and FLAIR MRI show increased signal in
the white matter.

6. Whipple’s Disease
Whipple’s disease (WD) is a rare systemic infection caused by the bacterium
Tropheryma whipplei. WD, which aVects particularly middle-aged males, primarily
involves the digestive system and most often manifests with weight loss, diarrhea
associated with malabsorption, abdominal pain, lymphadenopathy, cardiomyop-
athy, hyperpigmentation, and hypotension. WD is responsible for primary neu-
rological disorders in rare cases. The most common neurological manifestations
include slowly progressive dementia (56%), supranuclear ophthalmoplegia, ocu-
lomasticatory myoryhthmia, oculofacioskeletal myorythmia, and myoclonus. The
presence of periodic acid-SchiV (PAS) positive macrophages in biopsy specimens
( jejunal) and the demonstration of ‘‘Whipple’s bacilli’’ by electron microscopy are
diagnostic of active WD. CSF polymerase chain reaction (PCR) analysis for
detection of T. whipplei DNA is a very sensitive diagnostic technique, and the
CSF protein may occasionally be elevated. Brain CT and MRI are often normal
but may show cortical/subcortical atrophy, hydrocephalus, and mass lesions.
All WD patients must be treated and monitored as if they have CNS involvement
if CSF PCR results are positive, even if they are neurologically asymptomatic.

7. Neurocysticercosis
Cysticercosis is a zoonotic infectious disease caused by the parasitic tape worm
Taenia solium which infests both pigs and humans. Cycticercosis is the most
frequent parasitic infection of the human nervous system (neurocycticercosis).
Neurocysticercosis (NCC) may be clinically asymptomatic or present with epilep-
sy, altered mental status, focal neurologic deficits, headache, hydrocephalus, and
dementia (López et al., 2008). Although the cognitive deficits in NCC have been
recognized for a long time, they have been systematically evaluated only recently.
256 FADIL et al.

In a series of 90 patients with untreated NCC, Ramirez-Bermudez et al. (2005)

found that 15.5% of patients developed dementia. Diagnosis of NCC rests on the
clinical picture supported by CAT, MRI, and CSF analysis. On brain imaging,
the presence of cyst-like lesions with a mural nodule associated with degenerative
cysts and calcifications is typical features. Currently, the outcome for patients with
NCC dementia is usually favorable with appropriate treatment.

C. TOXIC-METABOLIC DISORDERS

The most common toxic-metabolic causes of EOD include carbon monoxide

poisoning, lead poisoning, arsenic intoxication, mercury poisoning, alcoholism,
and adverse eVects of prescribed medication, endocrine disorders such as hypo-
thyroidism, uremia, B12 deficiency, hepatic insuYciency, and postirradiation
syndrome. Dementia caused by specific etiologies such as B12 deficiency and
hypothyroidism may be reversible with correction of the underlying problem.
However, lead poisoning, which is common in children and rare in adults, can
cause irreversible encephalopathy with cognitive decline. Arsenic poisoning may
cause memory loss, and mercury intoxication may cause intellectual deterioration
along with behavioral changes such as confusion and irritability. Alcoholism and
alcohol-related dementia pose a significant burden to society. Alcoholic dementia
which presents with progressive cognitive decline results from chronic alcohol
abuse. Neuroimaging of these patients demonstrates cortical atrophy, subcortical
white matter loss, and enlarged ventricles. Chronic use of certain centrally
acting medications such as barbiturates may cause psychomotor retardation
and cognitive impairment, usually reversible when the drugs are discontinued.

D. IMMUNE-MEDIATED DISORDERS

1. Multiple Sclerosis
This group of dementing disorders includes multiple sclerosis (MS), CNS
vasculitis, and Hashimoto’s encephalopathy. MS is an immune-mediated neuro-
degenerative disorder of the human CNS which mainly aVects young adults
(Frohman et al., 2006). The immunopathogenesis of MS is associated with activa-
tion of both the cellular and humoral arms of the immune system against specific
CNS antigens (such as the myelin basic protein family), disruption of the blood-
brain barrier, transendothelial migration of activated leukocytes into the CNS,
and loss of the myelin/oligodendrocyte complex as well as neuronal/axonal
degeneration. Up to 65% of patients with MS present with neuropsychiatric
features and suVer from cognitive decline. In many patients with MS, cognitive
decline and memory loss may be the predominant manifestations causing signifi-
cant disability. Usually dementia occurs late in the course of MS; however, certain
 EARLY ONSET DEMENTIA 257

authors have observed dementia as the initial manifestation. Cognitive decline

which is generally associated with extensive white matter disease and cerebral
atrophy (neuronal loss) presents with frontal executive dysfunction and memory
loss. Based on MRI studies, cognitive impairment severity has shown correlation
with both total lesion load and the severity of corpus callosal atrophy.

2. Central Nervous System Vasculitis

CNS vasculitis or CNS angiitis is a progressive inflammatory disease of the
cerebral arteries, veins, or both which causes significant structural damage to the
vessel wall resulting in thrombosis and thus ischemic infarction. CNS vasculitis is
regarded as primary when the inflammatory process is limited to the nervous
system. However, when a CNS vasculitic syndrome occurs in the context of an
underlying autoimmune systemic disorder such as systemic lupus erythematosus
or an infectious disease such as syphilis, it is classified as secondary. Clinically,
CNS vasculitis manifests with headache, altered sensorium, seizures, hemiparesis
or quadriparesis, cranial neuropathy, and dementia. The cause of primary CNS
vasculitis remains elusive. However, massive activation of the immune system
with migration of lymphocytes, plasma cells, and monocytes into the CNS, and
their subsequent accumulation in the vascular walls of small arteries and veins
(particularly in the leptomeninges) are significant features of its pathogenesis.
Brain MRI reveals signal abnormalities on T2-weighted, FLAIR, and postcontrast
sequences providing evidence of both white and gray matter involvement.
Cerebral angiography may be diagnostic when a ‘‘vessel beading’’ pattern is
observed; however, only meningeal/brain biopsy provides a definitive diagnosis.

3. Hashimoto’s Encephalopathy
Hashimoto’s encephalopathy (HE) refers to a presumably immune-mediated
encephalopathy which is associated with elevated serum titers of antiperoxidase
and antithyroglobulin antibodies. HE has been reported around the globe
aVecting all age groups, with females being more aVected. This uncommon
disorder manifests with fluctuating consciousness followed by cognitive decline
and dementia. HE may have a relapsing course, and almost all cases respond
favorably to high doses of corticosteroids (Mocellin et al., 2007).

E. NEOPLASTIC/METASTATIC DISORDERS

Both primary and metastatic brain neoplasms may cause dementia, with
location and the rate of tumor growth being the major severity determinants.
Another etiology for development of cognitive impairment and dementia in the
context of systemic malignancy involves a paraneoplastic mechanism. Paraneo-
plastic limbic encephalitis is the most common paraneoplastic syndrome and
occurs in association with lung and breast cancer. Limbic encephalitis is
258 FADIL et al.

characterized by hallucinations, personality changes, epilepsy, and dementia and

often precedes the diagnosis of systemic malignancy. Mesial temporal lobe in-
volvement is common, however, other areas such as the hypothalamus and
brainstem may be aVected as well. Neuropathological features include the pres-
ence of infiltrating lymphocytes and neuronal loss in the hippocampus and
cingulate gyrus.

F. NEURODEGENERATIVE DISORDERS

1. Alzheimer’s Dementia and Dementia with Lewy Bodies

Alzheimer’s disease (AD) is a progressive degenerative disorder and is usually
associated with advanced age, but it can be a significant cause of EOD with a
special relationship to Down syndrome. A number of studies have demonstrated
that AD is a frequent cause of EOD (AD age of onset <65), accounting for
20–34% of patients. Neuropathologically, AD is characterized by the extracellu-
lar deposition of !-amyloid plaques and accumulation of intracellular neurofibril-
lary tangles. Clinical features of AD include memory impairment, language
deterioration, and visuospatial deficits. There are no definite laboratory studies
for the diagnosis of AD; although, CSF relative concentrations of tau and
!-amyloid as well as amyloid quantification by PET are being investigated.
Currently, three early onset AD genes with mutations aVecting amyloid precursor
protein, presenilin 1, and presenilin 2 and one late onset AD susceptibility gene
for apolipoprotein E have been identified. Neuropsychological studies have indi-
cated that there may be more cortical visuospatial function impairment in early
onset AD than the late onset form, while PET and neuropathological examina-
tions have suggested greater parietal lobe involvement in early onset AD.
DLB, which is the second most common cause of dementia after AD in elderly
patients, is relatively uncommon in younger individuals. Neuropathological stud-
ies demonstrate the presence of neocortical Lewy bodies in up to 35% of dement-
ed elderly patients. The clinical manifestations of DLB are similar in young and
elderly patients. DLB presents with cognitive decline without prominent early
memory impairment, fluctuating cognitive ability, fully formed and detailed visual
hallucinations, dysautonomia, and parkinsonian features including rigidity and
bradykinesia, are typical findings. These patients also manifest excessive daytime
drowsiness. Brain PET in patients with DLB reveals reduced metabolic activity in
the posterior parietal cortex.

2. Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD) is associated with focal degener-
ation of the frontal and temporal lobes, and after AD and DLB is the third most
common cause of cortical dementia ( Josephs, 2007). FTLD is a heterogeneous
entity consisting of three dementing syndromes: frontotemporal dementia (FTD)
 EARLY ONSET DEMENTIA 259

also known as frontal variant FTD (fv-FTD), semantic dementia (SD) (or temporal
variant), and progressive non-fluent aphasia (PNFA). In addition to these three
clinical forms, FTLD has been linked to CBD, progressive supranuclear palsy
(PSP), motor neuron disease (amyotrophic lateral sclerosis), and apraxia of
speech. FTLD typically aVects individuals between 45 and 65 years of age; in
up to 40% of cases, a positive family history may be identified. fv-FTD which is
more common in males comprises up to 56% of FTLD cases and has the earliest
age of onset (mean ¼ 58 years). Patients with fv-FTD demonstrate behavioral
abnormalities consisting of distractibility, decline in self-care, perseverant behavior,
hyperorality, apathy, disinhibition, and language disturbance. Patients with SD
develop a progressive loss of word knowledge and meaning. While speech fluency
is retained, patients develop problems with word finding and have diYculty with
naming and word recognition. These patients make speech errors which are
typically characterized by circumlocution and overuse of generic words. In
advanced cases, patients with SD may develop prosopagnosia. In patients with
PNFA, the disease process commences insidiously with progressive deficits in
speech or language. These patients have decreased word output and commonly
exhibit diYculties with understanding grammar. Patients develop anomia but
have relatively preserved memory and nonverbal cognition. Some of these
patients may demonstrate upper-limb or orofacial apraxia. Word comprehension
usually remains unchanged. Neuroimaging demonstrates left perisylvian atrophy.

3. Corticobasal Degeneration
CBD (also known as cortical-basal ganglionic degeneration) is a neurodegen-
erative disorder classified as a tauopathy, which presents with asymmetrical motor
dysfunction having both parkinsonian and dystonic components, as well as
postural tremor/myoclonus. Cortical features include aphasia, ideational and
ideomotor apraxia, astereognosis and alien limb syndrome. Patients with CBD
also display intellectual decline as well as frontal lobe release signs. Mean age of
onset is 60 years, but onset may occur as early as 45 years. Neuropathological
examination of the brain reveals intracellular filament accumulation consisting of
microtubule-associated tau protein. PET and MRI studies have demonstrated
symmetrical cortical and basal ganglion hypometabolism (McMonagle et al.,
2006). As a tauopathy, CBD has been linked to FTD and Pick’s disease; however,
its tau is hyperphosphorylated and makes unusual twisted filaments which share
certain similarities with the paired helical filaments observed in Alzheimer’s
disease. The etiology and pathogenesis of CBD remain unknown and currently
there is no specific treatment for this condition.

4. Progressive Supranuclear Palsy

PSP (or Steele-Richardson-Olszewski syndrome) is a progressive neurodegen-
erative disorder, which clinically manifests with rigidity, bradykinesia, postural
instability, supranuclear ophthalmoplegia, pseudobulbar palsy, axial dystonia,
260 FADIL et al.

dysphagia, dysarthria, frequent falls, and dementia. PSP is frequently misdiag-

nosed as idiopathic Parkinson’s disease (IPD). However, unlike IPD, tremor is
uncommon. Neuropathologically, PSP is characterized by neuronal loss, gliosis,
and the presence of neurofibrillary tangles, which are composed of paired helical
filaments and straight filaments of tau protein. These neuropathological changes
are observed in the substantia nigra, globus pallidus, superior colliculus, pretectal
area, cerebellar nuclei, and substantia innominata. PSP aVects males slightly
more than females, and its onset is usually in the sixth decade (range: 45–75
years). Dementia is present in many cases and is characterized by bradyphrenia,
apathy, depression, disinhibition, and progressive non-fluent aphasia. Brain
PET reveals hypometabolism in the frontal lobe and anterior cingulate gyrus.
MRI may show midbrain and superior cerebellar peduncle atrophy, which is
disproportionate to the atrophy of the pons and cerebellum.
5. Huntington’s Disease
Huntington’s disease (HD) is an autosomal dominant progressive neurodegenera-
tive disease which presents primarily with an irrepressible movement disorder, usually
chorea, and various behavioral problems, evolving finally into severe dementia.
Other motor presentations include bradykinesia, dystonia, imbalance, and speech
abnormalities. HD results from an expanded and unstable CAG trinucleotide repeat,
coding for a polyglutamine tract, in the IT15 gene, which is located on chromosome
4 (Huntington’s Disease Collaborative Research Group, 1993). Dementia, which
usually occurs after chorea and psychiatric symptoms have been present for several
years, may precede chorea in about one fourth of cases. Psychiatric manifestations
include irritability, mood lability, antisocial behavior, anxiety, delusional thought
disorder, mania, obsessive behavior, and apathy. The exact cause of the progressive
neurodegeneration in HD remains unknown; however, various hypotheses including
free radical toxicity, glutamate toxicity, and abnormal caspase activity have been
proposed. Brain MRI demonstrates prominent caudate atrophy with various degrees
of cortical atrophy. DNA testing can establish the diagnosis. HD is progressive over a
15- to 25-year period, and most patients succumb to late stage disease complications
such as infection.

6. Idiopathic Parkinson’s Disease

IPD is a progressive neurodegenerative disease that aVects about 1 million
Americans usually over the age of 60, but onset at a much younger age in not
unusual. The etiology of IPD remains poorly understood. Neuropathological exam-
ination has indicated that the pathogenesis of IPD is linked to degeneration of
dopamine-generating neurons in the pars compacta of the substantia nigra. Other
areas within the CNS where neuronal loss occurs in the course of IPD include
pigmented brainstem nuclei, autonomic nuclei, and pyramidal cells in the pre-
supplementary motor cortex. Currently, more than 11 autosomal dominant and
 EARLY ONSET DEMENTIA 261

recessive genes have been linked to PD. IPD remains a clinical diagnosis, and its
major clinical features include bradykinesia, resting tremor, limb rigidity, loss of
corrective postural reflexes, and a gait disorder. Up to one-third of patients with IPD
develop dementia which is characterized by significant impairment of executive
functions, attention, concentration, working memory, and visuospatial function.
Personality changes and behavioral disorders are common.

G. MISCELLANEOUS CAUSES OF EOD

1. Traumatic Brain Injury

Severe closed head trauma which is associated with coma may cause chronic
cognitive impairment. In addition, repeated trauma to the head can have additive
neuronal and axonal pathological eVects producing cognitive decline and finally
dementia. This form of dementia is often accompanied by dysarthria, akinesia,
paranoia, depression, ataxia, and parkinsonism. EOD is particularly associated
with traumatic brain injury secondary to motor vehicle accidents which predom-
inantly involve young individuals.
2. Normal Pressure Hydrocephalus
Patients with NPH demonstrate gait apraxia, dementia, and urinary inconti-
nence. Gait impairment, characterized by short-stepped and broad-based
ambulation with clumsiness of foot placement, usually precedes other symptoms
(GraV-Radford, 2007). Cognitive impairment varies in severity. Dementia in
these patients consists of memory loss, bradyphrenia, frontal lobe executive
dysfunction, and depression. A number of clinical reports have indicated a
possible relationship between NPH and systemic hypertension. NPH, a commu-
nicating hydrocephalus which is objectively diagnosed by CSF flow/pressure
studies, frequently responds to shunting, although dementia may not improve
due to permanent neuronal damage.

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 NORMAL PRESSURE HYDROCEPHALUS1

Glen R. Finney
Memory and Cognitive Disorders Program, University of Florida
Department of Neurology, Gainesville, Florida 32610-0236, USA

I. History
A. History of Present Illness
B. Past Medical History
C. Medications
II. Physical Examination
III. Laboratory Serologies
IV. Neuroimaging
V. Modern Diagnostic Criteria
A. Probable Idiopathic Normal Pressure Hydrocephalus
B. Possible Idiopathic Normal Pressure Hydrocephalus
C. Unlikely Idiopathic Normal Pressure Hydrocephalus
VI. Treatment
VII. Predictors of Response to Shunting in Normal Pressure Hydrocephalus
VIII. Recent Work
References

Normal Pressure Hydrocephalus first became recognized as a treatable,

reversible disorder in the 1960s. The classic triad of magnetic apraxia, urinary
incontinence, and dementia remain relevant into the 21st century as being the
basis for symptomatic diagnosis and predicting potential benefit from ventriculo-
peritoneal shunting, though they have been greatly augmented by the addition of
modern neuroimaging, particularly MRI. Modern criteria recognize a wider
range of diagnostic criteria, and new positive and negative prognostic indicators
for treatment benefit have been discovered, though the mainstay remains initial
drainage of a large volume of cerebrospinal fluid and monitoring for clinical
improvement. Even with our advances in understanding both primary and
secondary normal pressure hydrocephalus, diagnosis, management, and
counseling remain challenging in this disorder.

1
Also known as: Hakim-Adams Syndrome, Hakim’s Disease, Hakim’s syndrome, extraventricular
obstructive hydrocephalus.

INTERNATIONAL REVIEW OF 263 Copyright 2009, Elsevier Inc.

NEUROBIOLOGY, VOL. 84 All rights reserved.
DOI: 10.1016/S0074-7742(09)00414-0 0074-7742/09 $35.00
264 GLEN R. FINNEY

I. History

For decades, students of neurology have been taught the mnemonic of

‘‘Wet, Wacky, and Wobbly’’ for the classic triad of symptoms seen in the entity
primarily known as normal pressure hydrocephalus. Normal pressure hydroceph-
alus is a reversible dementia originally recognized only a little over a half century
ago in the mid-1960s by neurosurgeon Solomon Hakim, M.D., Ph.D, with famed
Massachusetts General Hospital neurosurgeons Robert G. Ojemann and William
H. Sweet and legendary Massachusetts General Hospital neurologists Raymond
D. Adams and C. Miller Fisher.
Solomon Hakim’s first publication on the subject of Normal Pressure
Hydrocephalus was in the form of his 1964 thesis at the Javeriana University
School of Medicine in Bogota, Colombia (Hakim, 1964). He followed up on this
work as a fellow at the Massachusetts General Hospital where in association with
Raymond D. Adams he published the first peer reviewed report on symptomatic
hydrocephalus with high normal pressures (Hakim and Adams, 1965), which
was then followed by the groundbreaking paper, again in collaboration with
Raymond D. Adams, and in addition C. Miller Fisher, Robert G. Ojemann,
and William H. Sweet when they published the first peer reviewed paper on the
subject of patients with symptomatic hydrocephalus but pressures that fell within
the high normal range, and that could be treated by drainage of cerebral spinal
fluid (Adams et al., 1965). The initial three patients showed cerebrospinal fluid
pressures of 150 mm H2O, 160 mm H2O, and 180 mm H2O, thus the coining of
the term normal pressure hydrocephalus due to the relatively normal pressures
found on lumbar puncture. As noted by Raymond D. Adams himself, the idea of
treatment of hydrocephalus by drainage of cerebrospinal fluid had been pro-
posed as early as 1895 by Gartner (Adams, 1966), but it was the critical develop-
ment of an autoclavable one-way shunt that allowed for a practical treatment for
the entity of Normal Pressure Hydrocephalus. Solomon Hakim went on to a
successful career in neurosurgery and continued to contribute to the art and
science of treatment of hydrocephalus, even developing his own shunts starting
in the early 1970s for the treatment of hydrocephalus (Hakim, 1973; Hakim
et al., 1973).
This early work in normal pressure hydrocephalus relied for work up
on lumbar puncture, electroencephalogram, and pneumoencephalography to
interrogate the central nervous system, but even then the classic clinical triad of
alteration in mentation, gait disturbance, and incontinence was part of the
diagnosis (Adams et al., 1965).
 NORMAL PRESSURE HYDROCEPHALUS 265

A. HISTORY OF PRESENT ILLNESS

It is important always to establish a good history in evaluating patients with

cognitive disorders, and doubly so in the case of normal pressure hydrocephalus
where history has a role in not just diagnosis but factor determination for likely
response to treatment via shunting.
Onset is important, both for knowing if there were any precipitating factors
that might indicate a secondary form of normal pressure hydrocephalus as well
as other mimics of normal pressure hydrocephalus. Brain hemorrhage, brain
surgery, head injury, and meningitis both recent and remote are identified risk
factors for normal pressure hydrocephalus. Onset in idiopathic normal pressure
hydrocephalus should be gradual, with slow worsening over time. Onset in
secondary normal pressure hydrocephalus may actually be acute or subacute
and found in relation with a suspected etiology around the time of onset, or like
idiopathic normal pressure hydrocephalus, it may be gradual and have no close
temporal relationship with the presumed original precipitating etiology.
Secondary normal pressure hydrocephalus is more likely to respond to shunting
than idiopathic normal pressure hydrocephalus (Black et al., 1985; De Mol, 1985;
Petersen et al., 1985). Time of onset is also important for determining duration
which is a factor in predicting possible improvement after shunting, with shorter
duration suggesting more response to shunting.
It is also important to know the temporal order and duration of the presenting
symptoms. Patients who had gait disturbances begin simultaneously or before
the cognitive disturbance were more likely to respond favorably to shunting
(Fisher, 1977; GraV-Radford et al., 1989), but patients who have suVered
from the dementia for more than 2 years are less likely to respond to shunting
(GraV-Radford et al., 1989; Petersen et al., 1985).
Screen past medical history for possible congenital hydrocephalus that may
have become significantly symptomatic only later in life. It is also important to
screen medications that may have side eVects similar to those seen in normal
pressure hydrocephalus. In particular, be wary of patients who started with
urinary incontinence and subsequently develop cognitive symptoms only after
initiation of treatment for incontinence with an anticholinergic which can cause
confusion.
It is also important to discern if the reason for urinary urgency or urinary
incontinence is actually due to physical disability in gait disturbance making it
diYcult for the patient to reach the bathroom in a timely fashion. One should
ascertain if the patient has a stress or urge incontinence, especially in older women
who frequently suVer from stress urinary incontinence, which is not a neurogenic
form of urinary incontinence but rather of a structural nature. In men, urinary
frequency may be due to prostatic disease and this too should be screened for.
266 GLEN R. FINNEY

B. PAST MEDICAL HISTORY

As mentioned previously, it is important to find out if there is a history of

previous insult to the central nervous system and surrounding environs which
may be a precipitating factor for a normal pressure hydrocephalus or a mimic
thereof. Most common include brain hemorrhage, brain surgery, head trauma,
and meningitis. Obviously, these can be interrelated and you may find a compli-
cated history of more than one of these occurring. Chronic subdural hemorrhages
can be both a mimic of normal pressure hydrocephalus as well as a predisposing
condition. It is important to screen for history of diseases or conditions that can
mimic all or parts of the presentation of normal pressure hydrocephalus. Many
primary neurodegenerative diseases can have similar sets of symptoms later in
their course or can be negative indicators for likely response to shunting if
occurring in the same patient. These diseases include Alzheimer’s disease, fron-
totemporal lobar degeneration, Lewy body dementia, multisystems atrophy,
Parkinson’s disease, and progressive supranuclear palsy.

C. MEDICATIONS

Anticholinergic drugs are often prescribed for urinary frequency or urinary

incontinence. When urinary symptoms precede confusion and initiation of anti-
cholinergic medications for the urinary symptoms precedes confusion, a high
index of suspicion for medication eVect must be held. It may take months oV an
anticholinergic medication to be certain that it is not clearly part of the dementia
presentation in such patients.

II. Physical Examination

Two of the three cardinal features of classic normal pressure hydrocephalus,

mental status and gait, are amenable to examination and therefore are the most
important to be assessed, though the rest of the examination, particularly the
neurological examination, can not be neglected as it may point to mimics of
normal pressure hydrocephalus. Beyond the neurological examination, a muscu-
loskeletal examination looking for mechanical hindrances to movement is the
most important part of the non-neurological examination.
Cranial nerve examination should assess for possible mimics of normal pressure
hydrocephalus. Funduscopic examination of the optic nerves may reveal papille-
dema which can point to other forms of hydrocephalus or other causes of raised
intracranial pressure. Constriction of peripheral vision can be seen in such entities
 NORMAL PRESSURE HYDROCEPHALUS 267

and can raise the concern of the possibility of intracranial venous sinus thrombosis.
Beyond the optic nerve, any other cranial nerve abnormality brings the diagnosis of
an idiopathic normal pressure hydrocephalus into question as this can be an
additional sign of significant raised intracranial pressures as in the false localizing
signs of sixth nerve palsies, or sign of structural abnormalities in the posterior fossa
such as in basilar meningitis, which might be an underlying etiology for a secondary
normal pressure hydrocephalus. Ophthalmoplegia can indicate any number of
other etiologies that may share some features with normal pressure hydrocephalus,
including Wernicke-KorsakoV Syndrome, central nervous system Whipple’s
disease, and especially Progressive Supranuclear Palsy (particularly if there is
restriction of down-gaze) which presents early with gait instability and may have
cognitive impairment quite similar to that seen in normal pressure hydrocephalus.
Motor examination should demonstrate normal motor strength with no focal
deficits. Focal weakness might point one away from normal pressure hydroceph-
alus and toward a more focal or multifocal etiologies like vascular damage. Tone
may be normal or increased in normal pressure hydrocephalus, though asymmetric
increased tone should bring up the possibility of Parkinson’s disease, especially if
accompanied by an asymmetric resting tremor.
Reflexes should be normal to mildly increased, again in a nonfocal pattern.
Focal asymmetries in reflexes suggest the possibility of a diVerent etiology. One
may see frontal release signs (i.e., release of primitive developmental reflexes) such
as a glabellar reflex, a rooting or suck reflex, a grasp reflex, facillatory paratonia
(Mitgehen), and even bilateral Babinski signs can be found in some patients.
Sensory examination can be diYcult to reliably obtain in this patient population,
and many patients in the age group most susceptible to normal pressure hydroceph-
alus also suVer from a multifactorial vibratory sensory loss. Again, we cannot
emphasize enough the importance of asymmetric sensory loss as indicating the
possibility of a diVerent or additional diagnosis than normal pressure hydrocephalus.
There should be no Romberg sign (falling to one side when eyes are closed), otherwise
a unilateral vestibular system abnormality may be contributing to gait disturbance.
Coordination examination may show truncal ataxia and abnormalities of fine
motor activity that resemble ataxia or apraxia, particularly in the lower extremities.
Frank tremor on examination can be seen but it is typically symmetric.
Gait examination, of course, is the most important portion of the examination
in the case of normal pressure hydrocephalus. The most classic finding in idiopathic
normal pressure hydrocephalus is a magnetic apraxia of gait, where the patient has
diYculty with initiation and changes in trajectory of gait, and appears to be literally
‘‘stuck’’ to the floor. The degree of severity of magnetic apraxia can vary, with some
patients only having subtle findings particularly on turns or transfers, whereas
others may be so severe that they cannot even obtain the upright position. Unfor-
tunately, it is not always the classic magnetic apraxia that is the form of gait
disturbance that is manifest in the patient. A significant number of patients can
268 GLEN R. FINNEY

have a mixed magnetic/parkinsonian gait and in some individuals the gait can
appear quite parkinsonian with no clear apraxia. Other forms of gait disturbances
must be assessed for and ruled out. While gross testing of proprioception may be
normal, many elderly patients even without normal pressure hydrocephalus or
overt neurological impairment will have an unsteady gait due to diminution of
multiple sensory modalities (e.g., vision, vestibular, vibratory) as well as general
deconditioning of accessory musculature with decreased activity often seen in the
elderly, particularly seen in deficits in righting reflex when patients get slightly oV
balance. A wide-based gait in frank loss of lower extremity sensation either due to a
peripheral neuropathy or myelopathy impacting posterior columns also should
raise doubts about the diagnosis of normal pressure hydrocephalus.

III. Laboratory Serologies

There is no specific blood test for normal pressure hydrocephalus and any
laboratory serology work-up should be driven by history or examination findings
suggestive of other possible etiologies. It is beyond the scope of this chapter to go
into the laboratory work-up for these alternative etiologies in the diVerential
diagnosis and direct the reader to the chapters on other forms of dementia,
particularly reversible dementias, for further information.

IV. Neuroimaging

Imaging of the brain is absolutely necessary in the evaluation of the possibility

of the diagnosis of normal pressure hydrocephalus. Finding signs of normal
pressure hydrocephalus in the brain is often a subtle and diYcult task, and for
this reason we recommend against a computed tomography image of the brain for
diagnosis as being to coarse grained and lacking in other qualities that are present
in magnetic resonance imaging.
Where computed tomography of the brain can be useful is as a quick and
inexpensive option in evaluation of already diagnosed and shunted normal pressure
hydrocephalus patients in evaluating gross shunt failure and signs of increasing
ventricular size. Radiography in the terms of a shunt series to establish position and
patency of the shunt is also required, and ideally should be reviewed by a physician
familiar with the evaluation of shunt patency. In more diYcult cases repeat
magnetic resonance imagery of the brain may also add useful information.
 NORMAL PRESSURE HYDROCEPHALUS 269

V. Modern Diagnostic Criteria

Relkin et al. (2005) criteria for probable and possible normal pressure
hydrocephalus

A. PROBABLE IDIOPATHIC NORMAL PRESSURE HYDROCEPHALUS

Diagnosis of probable idiopathic normal pressure hydrocephalus is based on:

1. Clinical history
2. Brain imaging
3. Physical findings
4. Physiologic criteria
1. Clinical history (corroborated by an informant)
! Insidious onset
! Onset after 40 years old
! Minimum duration of 3 months
! No secondary causes (e.g., head trauma, intracerebral hemorrhage,
meningitis, etc.)
! Progresses over time
! No other neurological, psychiatric, or medical condition suYcient to
explain the presenting symptoms

2. Brain imaging
Brain imaging study (CT or MRI) must be after onset and must show
evidence of:
! Ventricular enlargement out of proportion to cerebral atrophy or not
entirely attributable to congenital enlargement (Evans index >0.3 or
comparable measure)
! No macroscopic obstruction of cerebrospinal fluid flow
! At least one of the following supportive features:
– Enlargement of the temporal horns of the lateral ventricles not
attributable to hippocampal atrophy
– Callosal angle of 40" or more
– Evidence of altered brain water content, including periventricular
signal changes on CT and MRI not attributable to microvascular
ischemic changes or demyelination
– Aqueductal or fourth ventricular flow void on T2 MRI
270 GLEN R. FINNEY

! Other brain imaging findings:

– Brain imaging study performed before onset of symptoms showing
smaller ventricular size or without evidence of hydrocephalus
– 48–72 h radionucleotide cisternogram showing delayed clearance of
radiotracer over the cerebral convexities
– Cine-MRI study or other technique showing increased ventricular
flow rate
– A single photon emission CT-acetazolamide challenge showing
decreased periventricular perfusion that is not altered by acetazolamide

3. Clinical
By classic definition:
Findings of gait or balance disturbance must be present plus impairment in
! Cognition
! Urinary incontinence
! Or both
With respect to gait and balance, at least two of the following should be
present and not entirely attributable to other conditions:
! Decreased step height
! Decreases step length
! Decreased cadence
! Increased trunk sway
! Widened standing base
! Toes turned outward on walking
! Retropulsion (spontaneous or provoked)
! En bloc turning (turning requires three or more steps for 180" )
With respect to cognition, there must be documented impairment (adjusted for
age and education) or decrease in performance on a cognitive screening instrument
(such as the Mini-Mental State Examination) or evidence of at least two of the
following on examination that is not fully attributable to other conditions:
! Psychomotor slowing
! Decreased fine motor speed
! DiYculty dividing or maintaining attention
! Impaired recall, especially for recent events
! Executive dysfunction, such as impairment in multistep procedures,
working memory, formulation of abstract/similarities, insight
! Behavioral or personality change
 NORMAL PRESSURE HYDROCEPHALUS 271

To document symptoms in the domains of urinary continence, either one of

the following should be present:
! Episodic or persistent urinary incontinence and not attributable to
urologic disorders
! Persistence of urinary incontinence
! Persistence of fecal incontinence
Or any two of the following be present:
! Urinary urgency as defined by perception of a pressing need to void
! Urinary frequency as defined by more than six episodes in an average
12-h period despite normal fluid intake
! Nocturia as defined by need to urinate more that two times in an
average night
4. Physiologic
Cerebrospinal fluid opening pressure in the range of 5–18 mm Hg or 70–245 mm
H2O as determined by a lumbar puncture or other comparable procedure.
Appropriately measured pressures that are significantly higher or lower are not
consistent with a probable normal pressure hydrocephalus diagnosis.

B. POSSIBLE IDIOPATHIC NORMAL PRESSURE HYDROCEPHALUS

1. History
Reported symptoms may
! Have a subacute or indeterminate mode of onset
! Begin at any age after childhood
! May have less than 3 months of indeterminate duration
! May follow events, such as mild head trauma, remote history of intrace-
rebral hemorrhage, or childhood and adolescent meningitis, or other
conditions that in the judgment of the clinician are not likely to be
casually related
! Coexist with other neurological, psychiatric, or general medical disor-
ders but in the judgment of a clinician not be entirely attributed to these
conditions
! Be nonprogressive or not clearly progressive
2. Brain imaging
Ventricular enlargement consistent with hydrocephalus but associated with
either of the following (Figs. 1 and 2):
! Evidence of cerebral atrophy of suYcient severity to potentially explain
ventricular size
! Structural lesions that may influence ventricular size
272 GLEN R. FINNEY

FIG. 1. Disproportionate enlargement of the ventricles.

3. Clinical
Symptoms of either
! Incontinence or cognitive impairment in the absence of an observable
gait or balance disturbance
! Gait disturbance or dementia alone
4. Physiologic
Opening pressure not available or pressure outside the range of required for
probable idiopathic normal pressure hydrocephalus.

C. UNLIKELY IDIOPATHIC NORMAL PRESSURE HYDROCEPHALUS

! No evidence of ventriculomegaly
! Signs of increased intracranial pressure, such as papilledema
! No component of the clinical triad of idiopathic normal pressure
hydrocephalus
! Symptoms explained by other causes (e.g., spinal stenosis)
 NORMAL PRESSURE HYDROCEPHALUS 273

FIG. 2. Crowding of sulci at the calvarium.

Demographics:
Estimates of prevalence in small studies hover around 0.5% (Casmiro et al.,
1989; Trenkwalder et al., 1995).

VI. Treatment

Treatment for normal pressure hydrocephalus is to establish a new route

of drainage of cerebrospinal fluid from the central nervous system via a ventricu-
loperitoneal shunt. This invasive neurosurgical procedure has in the past had a high
rate of complication, which in recent years has been somewhat ameliorated by the
advent of rate-adjustable shunts. Complications of shunt surgery, other than the
typical postoperative complications of any major surgery, include abdominal organ
damage, intracerebral hemorrhage, subdural hematoma/hygroma, headache,
hearing loss, oculomotor palsy, shunt infection, seizure, tinnitus. In addition,
there can be shunt malfunction over time (Bergsneider et al., 2005).
274 GLEN R. FINNEY

FIG. 3. Loss of curvature at the head of the caudate nuclei.

VII. Predictors of Response to Shunting in Normal Pressure Hydrocephalus

In his 2007 review of normal pressure hydrocephalus, Neill R. GraV-Radford of

Mayo Clinic Jacksonville listed several positive and negative predictors for response
to shunting in normal pressure hydrocephalus (GraV-Radford, 2007). Factors that
favored clinical improvement included the form of normal pressure hydrocephalus
being secondary to another etiology, if the gait disturbance appeared before the
dementia portion of the syndrome, also if the deficit in cognition is modest. Lumbar
procedure results that favored better outcomes were; a demonstrable clinical
improvement, typically after removal of cerebrospinal fluid through a lumbar
puncture or continuous lumbar drainage, Rcsf outflow of 18 mm Hg/mL/min or
greater during continuous lumbar cerebrospinal infusion testing, and presence of B
waves for 50% or greater of the time during continuous lumbar cerebrospinal fluid
monitoring. Factors noted as negative predictors of response to shunting included
moderate to severe dementia, dementia of duration greater than 2 years, if the
cognitive impairment came before the gait abnormality, the presence of aphasia
 NORMAL PRESSURE HYDROCEPHALUS 275

FIG. 4. Transependymal extravasation.

signs on examination, a history of alcohol abuse, significant white matter involve-

ment on MRI, and diVuse cerebral atrophy.
Patients who have had symptoms of dementia greater than 2 years in duration
are less likely to respond to shunting than those with a shorter course of dementia
(GraV-Radford et al., 1989; Petersen et al., 1985). Duration of gait and urinary
symptoms were not as useful (GraV-Radford et al., 1989). Interestingly, alcohol
abuse has been reported to be a poor prognostic indicator for response to shunting
(De Mol, 1985).

VIII. Recent Work

In a small Japanese study (Akiguchi et al., 2008) of patients with radiographic

signs of normal pressure hydrocephalus and parkinsonism, both the parkinsonian
symptoms and the radiographic signs, including white matter changes likely
representing cerebrospinal fluid extravisation, were found to be somewhat
276 GLEN R. FINNEY

FIG. 5. Thinning of the corpus callosum.

reversible with shunting. In another small study it was discovered that patients
with normal pressure hydrocephalus were more prone to have retrograde jugular
flow during Valsalva maneuver (Kuriyama et al., 2008). Attempts to find better
diagnostic benchmarks for treatment responsiveness in normal pressure hydro-
cephalus continues, with one modest sized study from Norway suggesting a
correlation with treatment response 1 year out from shunting for cerebrospinal
fluid pressure pulsatility after lumbar infusion (Brean et al., 2008), with cerebro-
spinal dynamics after shunting returning to a more normal nature in lumbar
infusion after shunting (Petrella et al., 2008). MRI measurement of CSF spaces at
the high convexities and midline areas of the brain has shown reasonable ability
to distinguish brains with normal pressure hydrocephalus (Sasaki et al., 2008).
Another small study identified the most common changes in gait between lumbar
drainage responders and nonresponders to be walking speed, amount of steps in
turning, and tendency toward falling (Ravdin et al., 2008). One small but sugges-
tive study that suggested the use of MRI cine (phase-contrast MRI) pre- and
postlumbar drainage (at least 50 cc removed) could reliably identify patients who
benefited from shunting from those who did not, with change in the peak flow
velocity through the cerebral aqueduct after lumbar drainage suggesting amena-
bility to shunting (Sharma et al., 2008). In another small study using [(15)O]H(2)O
 NORMAL PRESSURE HYDROCEPHALUS 277

FIG. 6. Turbulent flow void (hypointense) in the cerebral aqueduct.

positron emission tomography the pre–versus postshunting change in regional

blood flow in the mesial frontal lobes correlated with response to treatment
(Klinge et al., 2008). Perhaps one of the most important papers to come out
recently retrospectively reviewed long term outcomes over 5–7 years after shunt-
ing for normal pressure hydrocephalus, and found that sustained improvement
existed in ally symptoms, though sometimes this result had to be maintained by
multiple shunt revisions (Pujari et al., 2008). An autosomal dominant form of
heritable normal pressure hydrocephalus with earlier onset essential tremor
(essential tremor-idiopathic normal pressure hydrocephalus (ETINPH)) has
been identified (Zhang et al., 2008). The use of a spinal catheter or lumbar
shunt in lieu of large volume lumbar tap is a recent trend, the most serious
complication of which is infection, but this risk can be brought down to below
2% (1.8%) with use of proper antibiotic prophylaxis and clinical surveillance
(Greenberg and Williams, 2008). There was a recent attempt at a unified rating
tool for signs in idiopathic normal pressure hydrocephalus with relatively good
inter-rater reliability (Kubo et al., 2008). One factor not commonly taken into
278 GLEN R. FINNEY

account in shunt planning is intra-abdominal pressure which can impact shunt

performance (Sahuquillo et al., 2008). In the use of proton magnetic resonance
spectroscopy, some suggestion was made of using NAA/Cr ratios to distinguish
between idiopathic normal pressure hydrocephalus patients who have more
neuronal dysfunction than destruction, with average ratio around 1.7 in external
lumbar drainage responders compared to 1.5 in external lumbar drainage non-
responders (Lenfeldt et al., 2008). The nature of the urinary symptoms, namely
incontinence, seen in normal pressure hydrocephalus, is mostly due to detrusor
overactivity (Sakakibara et al., 2007). In functional neuroimaging with positron
emission tomography, decrease in oxygen metabolism in the basal ganglia was
noted for patients with idiopathic normal pressure hydrocephalus (Miyamoto
et al., 2007). Work to develop cerebrospinal fluid biomarkers continues, with
recent findings of utility in using neurofilament protein light (NFL), hyperpho-
sphorylated tau (P-tau), and beta-amyloid (1–42) (Abeta42) to distinguish between
idiopathic normal pressure hydrocephalus which had higher NFL, lower P-tau,
and lower Abeta42 than controls, and subcortical vascular dementia which had
higher NFL but normal P-tau and Abeta42 than controls (Agren-Wilsson et al.,
2007). Magnetic resonance imaging full-brain voxel-based morphometric analysis
was used to again verify the impact of idiopathic normal pressure hydrocephalus
on the caudate nucleus (DeVito et al., 2007). A small study found that white matter
lesions in patients believed to have normal pressure hydrocephalus correlated
negatively with a positive outcome after shunting (Bugalho and Alves, 2007). In
using functional neuroimaging to try to predict response to shunting three-
dimensional single photon emission computed tomography showed that reduced
regional cerebral blood flow in the basal frontal lobes and cingulated gyrus were
potential predictors of shunt response in a small study (Murakami et al., 2007). In a
medium sized study with long term follow-up, continuous intraventuricular moni-
toring over a 48 h period, including an intraventricular steady-state infusion test,
was used to select candidates for shunting and had a fairly high rate of improvement
for gait disturbance around 96%, cognitive improvement and urinary improvement
in the mid-70th percents, with sustainment of clinical improvement over years in all
but three of the responders (Pfisterer et al., 2007). One small study saw hypokinesia
improve more than disequilibrium after shunting (Bugalho and Guimara, 2007).
Normal pressure hydrocephalus patients display bradykinesia, increased resting
tone, and diYculty with self-initiation of tasks, though improvement in these
features after shunting is variable, but sometimes seen (Mandir et al., 2007). Another
moderate sized study compared outcomes using repeated lumbar punctures, lum-
bar drainage, or cisternography as screening procedures. Both thrice repeated high
volume (30–40 cc) and continuous lumbar drainage (150–250 cc over 3 days) had
fairly good rates of improvement in gait disturbance (88 and 91%, respectively)
whereas cisternography only had 66% responders (Kilic et al., 2007) (Figs. 3–6).
 NORMAL PRESSURE HYDROCEPHALUS 279

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 REVERSIBLE DEMENTIAS

Anahid Kabasakalian and Glen R. Finney

Memory and Cognitive Disorders Program, University of Florida
Department of Neurology, Gainesville, Florida 32610-0236, USA

I. Introduction
II. Etiologies
III. Nutritional Abnormalities
IV. Endocrine Disorders and Cognition
References

The causes of potentially reversible dementia syndromes are legion, as many

perturbations of body chemistry can lead to dysfunction of higher cortical func-
tion, including the chemical interventions we call medication. It is vital for the
cautious clinician to take a painstaking history to develop a differential diagnosis
of potential causally related reversible phenomena. This, coupled with an exten-
sive examination and a widecast net of serological, and when appropriate,
cerebrospinal, electrophysiologic, and neuroimaging studies can increase the
potential for discovering these mimics of the primary neurodegenerative demen-
tias. While some cases of reversible dementia will be obvious from history and
physical and only require a few confirmatory tests or even just a trial of treatment
(or often, discontinuation of a suspect treatment), it is worthwhile to perform more
extensive work-up in cases of dementia, as the costs to allowing our patients to
remain in an incapacitated, possibly progressive, state of disability far outweigh
the costs of ruling out reversible causes. This chapter provides a lengthy, though
by no means exhaustive, review of etiologies and work-up for the currently
recognized reversible dementias.

I. Introduction

Dementia is a loss of cognitive capacity usually associated with minimal eVect

on level of consciousness. Primary neurodegenerative dementias result from
progressive, irreversible destruction of neurons in the brain, whereas, reversible
dementias result from progressive but potentially reversible processes from a

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NEUROBIOLOGY, VOL. 84 All rights reserved.
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284 KABASAKALIAN AND FINNEY

secondary etiology. The underlying etiologies of reversible dementias may be the

same as those causing delirium except occurring over a much longer time frame
and having a more indolent course. While in some cases, correction of the
underlying etiology may reverse or halt the progression of the cognitive decline,
in others a fixed deficit may remain due to permanent damage to the brain. Often,
the degree of reversibility is unpredictable and can only be ascertained by
treatment. An additional caveat lies in the tendency to assume irreversibility in
patients who have cognitive impairments at baseline. It is important to remember
that patients with a primary neurodegenerative dementia or a static encephalop-
athy can still develop reversible cognitive impairments, and in fact, are at greater
risk for cognitive decline from systemic disturbances, infection, or medications
(Moore and O’Keefe, 1999). Dementia or a history of any other brain damage, is,
in fact, a primary risk factor for delirium. Other major risk factors for reversible
cognitive impairment are age and multiple chronic diseases (Moore and O’Keefe,
1999). Finally, due to the protean nature of many illnesses, it is critical to keep an
open mind and consider a broad diVerential when approaching the cognitively
impaired patient. Reversible cognitive impairments may closely mimic characteris-
tic features of neurodegenerative dementias, so care must be taken not to make
hasty judgments based on impression without further investigation. The potential
for treatable causes of dementia, thus places an onus on the physician to investigate
demands investigation in cases of dementia, as allowing a further or continued
deterioration of cognition when preventable is a disservice to the patient.
History: Patients with cognitive disorders are suspect historians. As such, a
friend, family member, or caretaker plays the important roles of corroborator at
minimum, though more often as surrogate historian. Dementia patients them-
selves are notorious for anosognosia (unawareness of their own deficits) and may
be quite convincing at times in their denials of significant problems. Since the
pattern of onset, progression and the circumstances surrounding cognitive decline
can give important clues to possible etiology, historical details provided by healthy
family, friends or caregivers are often invaluable. History taking should include
baseline state, character of the impairment, rate of onset of change (gradual vs
abrupt), course of the impairment since onset, for example, static, continual
decline, fluctuating, or stepwise, associated symptoms and signs; and assessment
of risk factors, for example, sick contacts, toxic exposures, recent changes in
medications roughly corresponding in time with the onset. A complete list of
medications must be obtained as iatrogenic etiologies are the most common cause
of reversible dementias. Dates of initiation or changes in dosage of medications
known to cause confusion, either primarily or secondarily may correspond with
the onset of cognitive decline. A complete past medical history may reveal chronic
diseases which if inadequately treated may lead to cognitive decline over time.
Sometimes, a history from the remote past may prove relevant to the current
complaint. A remote history of blood transfusions, unsafe sexual practices, or
 REVERSIBLE DEMENTIAS 285

intravenous drug use increases risk for blood-borne diseases, for example, HIV,
syphilis, and hepatitis. History of immunodeficiency may point to indolent infec-
tions, for example, crytococcal meningitis (CM), though lack of such a history
does not necessarily rule these opportunistic infections out. Remote history of
head trauma may point to a chronic subdural hematoma. Social history is vitally
important. Abuse of recreational substances such as alcohol, tobacco, and other
intoxicants may cause cognitive decline or predispose the patient to several
secondary etiologies. As above, IV drug use may lead to investigation of certain
blood-borne diseases. Suspicion for substance abuse should not be omitted based
on the patient’s appearance. Well-dressed and groomed patients may use sub-
stances covertly. Nutritional habits may reveal unusual or poor diets predisposing
patients to vitamin deficiencies, or more rarely, toxicities. Travel history to areas
both in and outside of the country may reveal exposure to infectious diseases
associated with a particular region to which an illness is known to be endemic,
for example, the northeastern United States for Lyme disease or to Central
America for neurocysticercosis. Family history of heritable medical conditions
(or heritable risk) that might lead to cognitive decline may be prime targets for
exploration of the patient’s own cognitive decline.
Examination: Vital signs, while normal in most cases of indolent reversible
dementias, may reveal an etiology, for example, extraordinarily high resting
blood pressure may underlie a chronic hypertensive encephalopathy. An inspec-
tion of the skin surface can discover signs of infection, neurocutaneous abnorm-
alities, signs of hepatic dysfunction, such as capet medusa, the spidery web of
blood vessels on the surface due to portal hypertension, or evidence of vitamin
deficiency, for example, pellagra. Orientation may be impaired in a myriad
etiologies reflecting alteration of consciousness, most often aVecting orientation
to time and to place. Orientation to self is typically is spared in mild to moderate
forms of altered mental status. Level of consciousness is typically normal in
patients with primary neurodegenerative disorders, though Lewy body dementia
can have a fluctuating level of consciousness. Unlike deliriums which overlap in
diVerential diagnosis with forms of reversible dementias, reversible dementias
tend to have relatively normal to slightly impaired level of consciousness, or at
worst a fluctuating level of consciousness. This is most likely due to the indolent
nature of these perturbations of consciousness which allow for a degree of
compensatory function in arousal systems not seen in acute perturbation as seen
in acute onset delirium. Attention level is often impaired in reversible forms of
dementia and is one of the most common forms of disruption of mental status.
Since higher cortical functions rely on a certain level of attention, a defect in this
portion of the examination can cause disruption in numerous cognitive responses.
Concentration is closely related to attention, but even when working memory and
attention to stimuli may be adequate, concentration requires further executive
function, a role of the frontal lobes, to keep the patient on task and tracking
286 KABASAKALIAN AND FINNEY

progression of complicated tasks. Finger agnosia, left/right confusion, calculation,

and agraphia without alexia form the elements of the Gerstmann Syndrome and
localize to the angular gyrus of the dominant parietal lobe. The presence of a full
Gerstmann Syndrome out of proportion to other cognitive impairments may
indicate a degree of focality, especially if the findings are reproducible on exam-
inations separated in time. Such focality in the examination tends to point away
from more systemic disruptions like hormonal abnormalities and toward more
direct lesions to the brain. Thought process and thought content can be a hint to
possible etiologies. Hallucinations are more often seen in acute deliriums and in
psychoses, but can be seen intermittently in any of the reversible dementias.
Hallucinations can be in any sensory modality. Cranial Nerve Examination can
include ophthalmologic examination for Keyser-Fleischer rings is particularly
important when behavioral disturbances are accompanied by movement disor-
ders, though it may require a slit lamp examination to be certain. Cranial nerve
palsies may represent a basilar process such as neurosarcoidosis, tuberculosis
meningitis, or carcinomatous meningitis, though these more often present with
an acute or subacute presentation rather than a subacute to chronic course which
is the hallmark of the reversible dementias. Patients with Whipple’s disease (WD)
can demonstrate supranuclear palsies and or an abnormal oculocephalic reflex.
Speech may be dysarthric, or if there is specific cerebellar involvement, ataxic.
Language is typically spared in systemic etiologies of reversible dementia, but can
be abnormal in etiologies that have multifocal impact directly on the central
nervous system. Motor features can include rigidity, tremors, multifocal myoclo-
nus (drug intoxication), whole body myoclonus, psychomotor slowing may be
observed in drug intoxication, hypothyroid, hyperactivity (hyperthyroid), asterixis
is present in toxic metabolic conditions like uremia or hepatic encephalopathy.
Reflexes may show delayed relaxation, as with hypothyroid, or be brisk, as with
hyperthyroid.
Laboratory studies: Nutritional: B1 (thiamine), B3 (niacin), B6, B12, vitamin E,
vitamin D, vitamin A, folate. Hematologic: blood cell count: for evidence
of anemia, elevated or decreased leukocyte count, micro- and macrocytosis.
Electrolytes: sodium, calcium, magnesium, phosphorus, 24 h excretion of sodium,
potassium, calcium, magnesium, chloride, uric acid, inorganic phosphorus, glu-
cose, creatinine. Metabolic: liver function tests (AST, ALT, Alkaline Phosphatase),
ammonia, blood urea nitrogen, creatinine, amylase, lipase. Metals: ceruloplasmin,
copper, 24 h copper excretion, arsenic, lead, iron, mercury, cadmium, aluminum,
manganese. Hormonal: antithyropyroxidase antibody, antithyroid antibodies
(Hashimoto’s encephalitis), thyropyroxidase (TPO), parathyroid hormone
(PTH), free T4, T3, thyroid stimulating hormone, cortisol (24 h), aldosterone,
ACTH, prolactin, testosterone. Infection: lyme antibody titers, Syphilis tests
(RPR, HATTS, TPPA, FTA), HIV, cryptococcus antibody, Whipple’s disease
 REVERSIBLE DEMENTIAS 287

PCR. Protein: SPEP, UPEP, albumin, Cyclic AMP (plasma, urine, CSF). Para-
neoplastic (Limbic encephalitis): anti-HU, anti-MA, anti-TA. Autoimmune: ASO
(antistreptolysin antibody), ESR, RF, ANA, lupus anticoagulant assay (tissue
thromboplastin inhibition, anticardiolipin antibody IgG, IgM), Anti-Ro(SS-A),
anti-La (SS-B), antiribosomal ab, anti-Smith ab, anti-RNP, anti-dsDNA, C3
complement, C4 complement, perinuclear antineutrophil cytoplasmic autoanti-
bodies (pANCA), cytoplasmic (cANCA).

II. Etiologies

Medications: Risk factors for cognitive impairment resulting from medications

include age, premorbid brain pathology, renal insuYciency or failure, multiple
chronic medical problems, previous adverse drug reactions, polypharmacy, and
multiple prescribers (Canto and Korek, 1991; Hajjar et al., 2003; Moore and
O’Keefe, 1999; Trimble, 1987). Specific classes of medications are known culprits
in reversible dementias; although others not typically associated with impairment
are possible causes in some cases. Drug classes causing reversible dementia include
anticholinergics, antiepileptics, tricyclic antidepressants, antihistamines, antipsy-
chotics, hypnotics and sedatives, opiods, and amphetamines (Hajjar et al., 2003;
Moore and O’Keefe, 1999). While certain drugs are marketed specifically as
anticholinergic medications (scopolamine, atropine, trihexiphenydyl, benztro-
pine), other medications, including tricyclic antidepressants (Moore and
O’Keefe, 1999), antipsychotics (Feinberg, 1993; Foy et al., 1995; Moore and
O’Keefe, 1999) and some antihistamines such as first generation H1 blockers, for
example, benadryl, H2 receptor antagonists (Das et al., 1990; Moore and O’Keefe,
1999) have significant anticholinergic properties. Valproate has been shown to
cause reversible dementia in both elderly and young patients which may be
associated with elevated ammonia levels (Beyenburg et al., 2007; Zaret and
Cohen, 1986). Reversible dementia has been reported with topiramate in an
elderly patient. Other common medications described as causing reversible cogni-
tive impairment include lithium dopaminergic, agents, opioids, especially meperi-
dine digoxin, and beta-blockers (Miller and Jick, 1978; Moore and O’Keefe, 1999;
Rogers and Bowman, 1990). Smith and Kocen (1988) describe two patients in
whom lithium toxicity presented clinically in a manner indistinguishable from
Creutzfeldt-Jakob encephalopathy, including the characteristic one-per-second
periodic complexes on EEG. Antineoplastic agents may also impair cognition.
Severe but reversible cognitive impairment has been reported with thalidomide
which is used to treat multiple myeloma (Morgan et al., 2003).
288 KABASAKALIAN AND FINNEY

III. Nutritional Abnormalities

Vitamin B1 (Thiamine): Wernicke’s encephalopathy, characterized by a triad of

opthalmoparesis, ataxia, and confusion, results from thiamine deficiency. While
most commonly associated with alcohol abuse, Wernicke’s encephalopathy may
be seen with dialysis, bariatric surgery, prolonged administration of IV glucose
alone, high caloric administration of parenteral nutrition, hyperemesis gravi-
darum, and acute lymphoblastic leukemia (Nakajima et al., 2006; Singh and
Kumar, 2007; Ueda et al., 2006). Thiamine is a water soluble vitamin which is
absorbed by intestinal epithelium and stored in liver, brain, and skeletal muscle.
Thiamine deficiency results in hemorrhagic encephalitis in the gray matter. In
addition to the classic triad of symptoms, Wernicke’s encephalopathy may present
with nystagmus, polyneuropathy, myoclonus, convulsions, hypothermia, and
shock (Ueda et al., 2006). MRI may show dilatation of the third ventricle, atrophy
of mamillary bodies, and damage to the medial thalamus (dorsal medial nucleus)
and midbrain (periaquductal gray), caudate and putamen (Singh and Kumar,
2007; Ueda et al., 2006).
Vitamin B3 (Niacin): Pellagra is characterized by dermatitis, dementia, diarrhea
and without intervention, death. This condition may be observed with malnutri-
tion, alcohol abuse, and gastric surgery. Pellagra has been observed in anorexia
nervosa, in which it primarily presents with cutaneous manifestations. It is also
observed in Hartnup disease, carcinoid syndrome, and with several medications
thought to disrupt the vitamin B6-nicotinamide pathway, including antiepileptics
(valproic acid, phenytoin, and diazepam), carbamezpine, phenbarbital, and hydan-
toins, INH, pyrazinamide, 6-mercaptopurine, 5-fluourouracil, azathioprine, chlor-
amphenicol, ethionamide, and protionamide. The rash occurs in sun-exposed areas,
consisting of round erytematous macules that evolve into blisters then become dry
and scaly. Additionally there is glossitis and stomatitis.
Vitamin B12 (Cobalamin): There is controversy about whether a causal relation-
ship exists between vitamin B12/cobalamin deficiency and cognitive impairment
(Andres et al., 2007; Chiu, 1996). However, Chiu (1996) concludes that literature
review supports such a relationship and that ‘‘clinicians should assume that
vitamin B12 deficiency can give rise to cognitive impairment ranging from
memory defects to a potentially reversible dementia.’’ Andres et al. (2007) take a
less firm position but does note a higher incidence of cobalamin deficiency in
association with several neurological impairments including dementia, Alzhei-
mer’s disease, and depression. Loikas et al. (2007) found that ‘‘undiagnosed
vitamin B12 deficiency is remarkably common in the age,’’ and others have
‘‘found a positive correlation between low levels of vitamin B12 and low
MMSE scores among older patients. The question of reversibility is somewhat
at issue and appears to be a function of the duration of the symptoms prior to
 REVERSIBLE DEMENTIAS 289

treatment. The main causes for vitamin B12 deficiency are pernicious anemia and
food-cobalamin malabsorption, a syndrome characterized by the inability to
release cobalamin from food or from its binding proteins, usually resulting from
atrophic gastritis which stresses the urgency for prompt diagnosis and treatment
(Andres et al., 2007). Other risk factors and causes include male gender, age
75 years or more, refraining from milk products (Loikas et al., 2007), blind loop
syndrome, dietary deficiency, gastrectomy, surgical resection of the ileum, defi-
ciency in the exocrine function of the pancreas in chronic gastritis, lymphomas, or
tuberculosis (intestinal), Crohn’s disease, Whipple’s disease, and celiac disease
(Andres et al., 2007). Other neurologic manifestations of cobalamin deficiency
include acroparesthesia (burning and painful sensations in the hands and feet),
sensory ataxia, visual loss (due to optic neuropathy), autonomic dysfunction (e.g.,
sphincter dysfunction, impotence and orthostatic hypotension), loss of position
and vibratory sensation, positive Romberg sign, brisk reflexes (Worrall and
Worrall, 2005). Macrocytic anemia may not be present. MRI and CT may
demonstrate white matter lesions that may be mistaken for changes due to
hypertension or other metabolic causes (Sudo and Tashiro, 1998).
Vitamin D (Calcitriol): Although there are no significant data on the relationship
between vitamin D and dementia, there are some findings supporting a positive
relationship between vitamin D levels and cognitive performance. Przybelski and
Binkley (2007) found a significant positive correlation between performance on
MMSE and serum 25(OH) D. Studies of older adults found a positive relationship
between low levels of vitamin D and poor cognition (Kipen et al., 1995). Stueren-
berg (1996) found that dementia associated with idiopathic hypoparathyroidism
may be eVectively treated with 1, 25-dihydroxy-cholecalciferol. Vitamin D home-
ostatis is also intimately related to PTH (Kipen et al., 1995), and thus to the
homeostasis of several other electrolytes known to aVect cognition, particularly
calcium (Shoback, 2008).

IV. Endocrine Disorders and Cognition

Overview: Endocrine disorders aVecting cognition may result in derangements

of other systemic parameters, for example, electrolyte or glucose homeostatis
which then become symptomatic. Additionally, endocrine disorders may result
from immune-mediated processes. Finally, endocrine related disorders of cogni-
tion may masquerade as other disorders. As such, we reiterate the need to search
for reversible causes before arriving at a final diagnosis.
Thyroid: There is controversy regarding the eVects of thyroid function on
cognition (Dugbartey, 1998). The degree of reversibility of thyroid-related cogni-
tive impairment varies, likely depending on underlying etiology and duration
290 KABASAKALIAN AND FINNEY

before treatment. Hogervorst et al. (2008) found high TSH, as seen in those with
hypothyroidism, was associated with low cognition, and normal TSH but high
normal free T4 also is associated with poor cognition at baseline and clinically
significant decrease at 2 year follow-up. With regard to etiology and reversibility,
Whalund et al., 2002 found ‘‘little evidence that hypothyroidism causes dementia,
either reversibly or irreversibly.’’ However, there are several cases in which
treatment of both hypothyroid and hyperthyroid function (Fukui et al., 2001)
have restored cognitive function to diVerent degrees (Bono et al., 2004;
Dugbartey, 1998; Mennemeier et al., 1993). Etiologies for derangements in thy-
roid function may be clear, for example, thyroid cancer or treatment with
radiation, or may require more investigation. Anti-thyroid receptor antibodies
and antithyroid stimulating antibodies are found with Grave’s disease, anti-TPO
and antimicrosomal antibodies may be found in Hashimoto’s encephalopathy.
TSH, Free T4, T3 may all be normal in cases of autoimmune thyroid disease,
particularly in Hashimoto’s encephalopathy. Therefore, thorough investigation
demands assessment for antimicrosomal and TPO in conjunction with the
standard thyroid function tests (TFTs).
Hypercortisolemia: Selective memory impairment is seen in Cushing’s syndrome.
Results following surgery are equivocal with some studies demonstrating
improvement in cognitive function and others not (Mauri et al., 1993).
Parathyroid: PTH regulates the homeostatis of calcium, phosphate and vitamin D
activation (Shoback, 2008). PTH released into the blood acts distally at the bone to
increase release of calcium and phosphate into the blood and at the kidney to
promote calcium resorption into the blood and phosphate excretion in the urine. In
the kidney, PTH also facilitates the conversion of inactive vitamin D (25-hydro-
xycalciferol) to active vitamin D (1, 25-dihydroxycalciferol) which subsequently
facilitates increased intestinal absorption of both phosphate and calcium.
Cognitive disturbances are seen in both hypo- and hyperparathyroidism
(Adorni et al., 2005; Chadenat et al., 2008). Cognitive impairment associated
with PTH is most often associated with derangements in free calcium (Shoback
et al., 2008), however, in at least one case of idiopathic hypoparathyroidism and
normal calcium, dementia reversed following treatment with 1,25-dihydroxycal-
ciferol (Stuerenburg et al., 1996). In that same case, MRI had diVuse signal
enhancement of the periventricular frontal and parietal white matter on T2
suggestive of edema that also resolved after treatment with vitamin D. In addition,
magnesium depletion or excess may cause functional hypoparathyroidism
(Shoback, 2008). Hypercalcemia may also result from activity of a PTH-like
substance which may be produced ectopically by several tumor types. The most
common cause of hyperparathyroidism is parathyroid adenoma. Additionally,
hyperparathyroidism and Creutzfeldt-Jakob disease may be mistaken for each
other (Chadenat et al., 2008; Goto et al., 2000). CT in hypoparathyroid will
demonstrate intra parenchymal calcifications (Adorni et al., 2005), and some
 REVERSIBLE DEMENTIAS 291

have noted, a positive correlation between the degree of calcification and the
degree of cognitive loss and motor symptoms.
Electrolyte abnormalities: Alterations in mental status resembling dementia may
result from electrolyte abnormalities, particularly sodium, calcium, and
magnesium.
Disorders of calcium homeostasis: Hypocalcemia, in addition to presenting with
cognitive dysfunction, may present with seizures, extrapyramidal signs, papille-
dema and elevated intracranial pressure, neuromuscular hyperreactivity, and
cataracts (Stuerenburg et al., 1996). Hypercalcemia may occur as a paraneoplastic
condition, most often with lung and breast cancer, osteolytic metastases to bone,
as well as in association with hyperparathyroidism. Activated vitamin D, 1,25
(OH)2D3 is normally suppressed when serum calcium levels are high. Elevated
1,25(OH)2D3 in association with hypercalcemia may be seen with granulomatous
disease, non-Hodgkin’s lymphoma, and other hematologic malignancies due to
extrarenal production of 1,25(OH)2D3 (Clines and Guise, 2005). Increased
suspicion for malignancy should be raised in patients greater than 50 years of
age, or progressive pain for greater than 1 month with no relief with bed rest.
Solid tumors may produce other humoral factors resulting in hypercalcemia, for
example, IL-1, IL-6, TGF-alpha, TNF, and granulocyte-CSF (Clines and Guise,
2005).
Disorders of sodium homeostasis: In hypernatremia older patients are at increased
risk of hyperosmolar states. One documented etiology for this is decreased fluid
intake. Decreased thirst has been demonstrated in normal elderly adults. Elderly
patients may be limited in their abilities to act on thirst due medical conditions
limiting their mobility and making them dependent on others to bring them fluids.
In hyponatremia, patients demonstrate lethargy, fatigue, sleep disturbance, mus-
cle cramps, and headaches. Worsening of the condition may result in nausea,
vomiting, confusion, seizures, coma, and death (Flicker and Ames, 2005).
Hepatic encephalopathy: A linear progression of cognitive decline is associated
with severity hepatic dysfunction.
Chronic obstructive pulmonary disease (COPD): COPD complicated by hypoxemia
is associated with cognitive impairments, and patients with COPD are shown to
demonstrate anterior cerebral hypoperfusion and directly correlated with impair-
ments on neuropsychological assessment (Incalzi et al., 2003). In a recent literature
review, Kozora et al. (2008) documented some improvement with traditional
therapies, for example, continuous and intermittent oxygen therapy and compre-
hensive pulmonary rehabilitation. Even greater improvement was demonstrated
following lung volume reduction surgery.
Renal failure: Patients with renal failure may develop dialysis encephalopathy
syndrome post-dialysis, which had been proposed to result from aluminum
toxicity (Flicker and Ames, 2005). Pre-dialysis, uremia may result in cognitive
compromise. Neurologic exam may demonstrate asterixis.
292 KABASAKALIAN AND FINNEY

Infectious causes of dementia: If there are rules about manifestations of reversible

infectious causes of dementia, the first is that there are no rules. Most of
these infections are protean, occur infrequently, are insidious in onset, and
therefore, not the first things to come to mind in the face of progressive cognitive
decline. Additionally, all can be lethal. Therefore, the diagnostician’s rule must
be to consider all the zebras until a definitive cause has been clarified.
Whipple’s disease: Whipple’s disease is a rare systemic disease caused by infec-
tion by Tropheryma whippelii in which any organ system may be aVected, including
the brain which may include alterations in cognition or behavior (Rossi et al.,
2004). The central nervous system may demonstrate infection in 50% cases at
postmortem; however, neurological symptoms are observed in only 10–20% of
cases. Due to the insidious nature of onset and protean manifestations of infection,
diagnosis is often elusive. Whipple’s disease has presented with symptoms asso-
ciated with several neurodegenerative conditions, including progressive supra-
nuclear palsy, hypersomnia, and frontotemporal dementia (Rossi et al., 2004).
Other neurologic symptoms may occur, including, but not restricted to a stroke-
like syndrome, ophthalmoplegia, mystagmus, myoclonus, disturbed sleep pattern,
ataxia, seizure, or symptoms of elevated intracranial pressure secondary to hy-
drocephalus (Marth and Raoult, 2003). In some cases, the impairment is revers-
ible (Rossi et al., 2004). Early suspicion and aggressive diagnostic work-up may
identify cases earlier when treatment may be more eVective. Nonneurologic
symptoms which should raise suspicion for WD include gastrointestinal symp-
toms, especially weight loss and diarrhea suggestive of malabsorption. Other
symptoms may include arthropathy and myalgias (Marth and Raoult, 2003).
Labs abnormalities may suggest malabsorption with low albumin, elevated
serum cholesterol, steatorrhea, vitamin deficiencies of B12, D, K, folic acid and
beta-carotene. Acute phase reactants, for example, erythrocyte sedimentation
rate (ESR) and C-reactive protein (CRP) may be elevated. Additionally there
may be lymphocytopenia, throumbocytosis, and hypochronic anemia (Marth and
Raoult, 2003). Diagnosis of WD may be performed by PCR amplification of TW
16S rRNA in biological fluids and staining of CSF may demonstrate PAS staining
of cellular material (Rossi et al., 2004). Treatment may be with ceftriaxone,
sulfamethoxazole, and trimethoprim, though streptomycin and rifampicin have
also been used with success (Gerard et al., 2002; Rossi et al., 2004). For treatment
of the CNS, antibiotics must cross the blood-brain barrier. Panegyres et al. (2006)
suggest penicillin/streptomycin or cotrimoxazole over tetracycline as well as
penicillin, cetriaxone, chloramphenicol, and quinolones. Extended treatment is
the rule, though the disease can have a chronic relapsing course and the organism
can remain in many tissues even with extended therapy (Marth and Raoult,
2003). In cases of CNS involvement, treatment should be discontinued only
when results of the PCR of the CSF are negative (Gerard et al., 2002). Imaging
 REVERSIBLE DEMENTIAS 293

of the brain in primary WD of the CNS may show single or multiple enhancing
lesions (Panegyres et al., 2006).
Crytococcal meningitis and meningoencephalitis: Crytococcal meningitis, usually
thought of as an opportunistic infection in immunocompromised patients
(Mitchell and Perfect, 1995) may occur in immunocompetent patients in whom
diagnosis may be delayed or missed due to similarity of presentation to other
dementias, the insidious nature of onset, lack of risk factors for opportunistic
disease, and the lack of specific symptoms (Butler et al., 2000; Lewis and
Rabinovich, 1972; Vella Zahra et al., 2004). The presence of focal symptoms
which may occur from infarct (Luse, 1967) need not concur with the cognitive
changes. Diagnosis of in immunocompromised patients presents further compli-
cation as immunocompromised patients may not have an inflammatory response
in the spinal fluid. PCR is useful for identification. Imaging studies for CNS
cryptococcal infection have shown deep white matter and basal ganglia lesions
typically interpreted as lacunes, dilated Virchow-Robin spaces, pseudocysts,
masses, hydrocephalus, and radiological meningitis, multiple ring enhancing
lesions, brain edema, hydrocephalus, leptomeningeal enhancement, subdural
eVusions, basal ganglia infarcts, and leukoencephalopathy. Of note, imaging
findings may persist long after eVective treatment and should not be mistaken
for active Cryptococcus (Hospenthal and Bennet, 2000).
Lyme disease: Infection of the brain by Borrelia burgdorferi (neuroborreliosis) may
result in reversible cognitive impairment. However, cognitive impairments may
persist despite treatment and in some cases progress to death. Lyme disease usually
begins with a rash which is usually, but not always, consistent with erythema
migrans. This may be accompanied by fatigue, headache, mild stiV neck, joint
and muscle aches, and fever. Disseminated disease may follow weeks or months
after initial exposure primarily involving neurologic, cardiac, or joint disease.
Neuroborreliosis has a protean presentation and has been reported as presenting
with a frontotemporal dementia syndrome associated with severe associated sub-
cortical atrophy (Waniek et al., 1995), normal pressure hydrocephalus (NPH)
(Danek et al., 1996), and nigrostriatal degeneration (Cassarino et al., 2003) as well
as a ‘‘Lyme encephalopathy,’’ mild to moderate in severity aVecting memory and
learning, sometimes with subtle psychiatric symptoms or somnolence, but usually
without focal neurological signs or abnormalities on MRI (Logigian et al., 1997).
Chronic cognitive deficits may persist posttreatment. Encephalomyelitis and en-
cephalopathy are most often been seen as late manifestations of infection (Wormser
et al., 2006), with rare exceptions (Danek et al., 1996). In untreated patients,
encephalomyelitis is most often monophasic, slowly progressive, and primarily
aVecting white matter and may be confused clinically with an initial manifestation
of multiple sclerosis (Wormser et al., 2006). There is no ‘‘gold standard’’ method to
accurately determine neuroborreliosis. CSF shows a lymphocytic pleocytosis, mod-
erately elevated protein and normal glucose. Serology is performed first by ELISA or
294 KABASAKALIAN AND FINNEY

immunofluorescence antibody, and when positive followed by a Western blot (Roos

and Berger, 2007). Serologic tests may be negative during early infection (Roos and
Berger, 2007). In the United States, the presence of anti- B. burgdorferi antibodies in
the CSF has been suYcient for diagnosis; however, as antibodies can passively
transfer from serum to CSF, some argue that this is inadequate proof of CNS
infection (Roos and Berger, 2007). In patients with focal neurological deficits from
Lyme infection, MRI may demonstrate white matter abnormalities visible on T2
imaging similar to those seen in multiple sclerosis, while patients without focal
symptoms may show no abnormalities. Some cases have demonstrated findings
consistent with NPH (Danek et al.,1996). Reversible hypoperfusion of frontal
subcortical and cortical structures has been shown on SPECT (Logigian et al.,
1997). Alteration of white matter blood flow has been demonstrated in brains of
patients with chronic Lyme disease who complain of cognitive problems.
In adults, early infection may be preferentially treated with oral antibiotics,
for example, doxycycline, amoxicillin, or cefuroxime for 14–21 days, with
selected macrolides used as alternatives when preferred medications are not
tolerated. Late infection in adults requires treatment preferentially with paren-
teral ceftriazone, or alternately with cefotaxime or penicillin (Wormser et al.,
2006). Antibodies may remain elevated in the CSF after treatment (Wormser
et al., 2006).
Syphilis: Neurosyphilis results from infection of the nervous system by the
spirochete Treponema pallidum. As with other indolent infections in the nervous
system, its manifestations are protean. Some propose that presentations of neu-
rosyphilis have changed since the development antibiotics and the spread of HIV
infection with more than half of the cases late presenting with ‘‘dementia or
psychiatric/behavioral syndromes.’’ Others found a similar proportion of demen-
tia, delirium, and other neuropsychiatric manifestations, but also noted the typical
pre-antibiotic presentations of stroke, spinal cord disease, and seizures. Authors
caution against neglecting to test for syphilis even in cases where there is low
suspicion. RPR may be falsely negative, especially in secondary and tertiary
syphilis. The T. pallidum particle agglutination test (TP-PA) is a more sensitive
serum test of exposure than RPR in syphilis. CSF VDRL is specific for neurosy-
philis but not very sensitive (Timmermans and Carr, 2004). In the case of a
negative VDRL, a negative result in a treponeme-specific FTA-Abs in the CSF,
which is sensitive but not specific for neurosyphilis, may support a negative
diagnosis (Timmermans and Carr, 2004). In patients with HIV, CSF analysis is
recommended when the serum RPR is greater than or equal to 1/32 (Libois et al.,
2007), and CSF-FTA and %CSF B cells may be used for diagnosis when the
CSF-VDRL is nonreactive.
HIV: While HIV dementia is typically irreversible, in the earlier phases of the
disease, HIV-related neurocognitive impairment can be reversed by highly active
antiretroviral therapy (HAART), though some degree of neuropsychological
 REVERSIBLE DEMENTIAS 295

deficit may persist even after HAART treatment. The most important predictor
of response to treatment was the degree of neurocognitive impairment prior to
initiation of treatment (Tozzi et al., 2007). Therefore, it is important to have a low
threshold of suspicion for possible HIV infection and to screen for it on a regular
basis in subacute dementias. In one study, HIV cognitive impairment patients
were found to have reduced markers of mature neurons and increased markers of
gliosis in the basal ganglia and frontal white matter (Paul et al., 2007), which
correlates with the frontal subcortical dysfunction seen in HIV cases.
Cerebral manifestations of systemic inflammatory disorders: This category includes
such diverse entities as Behcet’s disease, hypereosinophilic syndrome, celiac
sprue CNS vasculitis, Susac’s syndrome, Lupus cerebritis, Sjogren’s syndrome,
Antiphospholipid antibody syndrome, and Neurosarcoidosis. A number of these
inflammatory conditions are associated with vasculopathy of the CNS, by either
inflammatory or coagulopathic mechanisms. In some cases, both of these
mechanisms are observed. A number of mechanisms may be involved in CNS
damage. In SLE, for example, CNS damage may ‘‘fibrinoid necrosis of small
vessels, embolic large- and small-vessel infarction, coagulopathy, vasculitis, anti-
neuronal antibodies and the eVects of cytokines (Ovsiew and Utset, 2002). Anti-
phospholipid antibodies (aPLs) have been associated with hypercoagulability,
recurrent thromboses, transient ischemic attacks and chorea. Some lupus anti-
DNA antibodies may cross-react with NMDA receptor subunits and cause apo-
ptotic cell death. These findings suggest that the integrity of the blood-brain
barrier may be crucial in protecting against the development of cognitive
impairment due to NMDA-binding anti-DNA antibodies in patients with lupus.
Vasculitis may be limited to the CNS or may have associated systemic symptoms
including fever, fatigue, weight loss, rash, neuropathy, or other organ involve-
ment. Workup for vasculitis includes ESR, CRP, C3, C4, Ch-50, ANA, RF, anti-
SSA, anti-SSB, p-ANCA, c-ANCA. Urine evaluation may demonstrate a hemo-
lytic anemia. Lupus anticoagulant may occur independently of SLE and may
present with progressive intellectual decline and has been shown to be reversible
with immune-suppressive therapy. Labs may clarify the diagnosis. Sjogren’s syn-
drome will usually be positive for ANA, SS-A (Anti-Ro), SS-B (Anti-La), though
rarely both SS-A and SS-B may be negative. SLE may demonstrate a positive
ANA, double-stranded DNA, Anti-Smith antibody. Celiac sprue may be diagnosed
with positive antigliaden antibodies. SLE-cerebritis may demonstrate positive anti-
ribosomal and antineuronal antibodies. MRI may show cerebral atrophy, gadolini-
um enhancing T2 hyperintiensities in gray or white matter which are more often
subcortical than periventricular. All may demonstrate elevated ESR and CRP.
In Sjogren’s syndrome, MRI may demonstrate nonenhancing densities on T2
in periventricular and subcortical areas. Reversibility of cognitive impairment in
inflammatory conditions is highly variable (Caselli et al., 1991). Hypercoagulable
states may result from antiphospholipid antibodies. Hyperviscosity syndromes
296 KABASAKALIAN AND FINNEY

resulting from polycythemia or gammopathies, for example, Waldenstrom’s mac-

roglobulinemia may cause a rapidly progressive dementia due to cerebral ischemia
(Schofield, 2005).
Toxic conditions: Lead exposure may occur via oral ingestion, skin or lungs. Risk
factors include battery production, brass, bronze, or glass works, ammunition
production, paint and pigment production, pottery making and other industrial
exposures. Lead encephalopathy can cause seizures and coma. Mercury in the
brain is associated with erythrism (aka Mad Hatter’s Disease) presenting with
nervousness and timidity, irritability, labile mood, ataxia, and some cognitive
changes. Aluminum toxicity is associated with dysarthria, dysphagia, dyspraxia,
and personality change. Cases of manganese, tin, and arsenic are also reported as
causes of neurocognitive impairment. Lead, arsenic, and mercury also result in
peripheral neuropathy. MRI may show calcification and increased signal on
T2 weighted imaging in the periventricular white matter, basal ganglia, hypothal-
amus, and pons with lead poisoning. 24 h urine heavy metal for lead, arsenic, and
mercury, bismuth, aluminum, lithium. 24 h urine for copper. Treatment is by
chelation. Ethylendiamineteraacetic acid (EDTA) or dimercaptosuccinic acid is
used to lower lead levels. Dimercaprol, or British Anti-Lewisite (BAL) and peni-
cillamine are used for treatment of elemental and inorganic mercury, but not
methylmercury. History taking should include questions industrial contact or
symptoms which might reveal exposure to carbon monoxide or solvents. Though
changes are most often not reversible per se, identification of the oVending agent
may prevent further decline (Schofield, 2005).
Paraneoplastic limbic encephalitis (PLE): PLE is an immune-mediated neurological
complication of malignancy characterized by triad of short term memory
impairment, complex-partial temporal lobe seizures, and psychiatric symptoms
(depression, psychosis, or change in personality). They are most often associated
with specific cancer types, which produce correspondingly specific autoantibodies,
for example, small cell lung cancer (anti-HU, anti-MA 1, 2, CRMP/anti-CV2,
N-type VGKC antibodies), testicular cancer (anti-MA 2 antibodies), thymoma
(antivoltage-gated potassium channel (anti-VGKC) antibodies and breast cancer
(N-type VGCC). PLE has a heterogeneous presentation mimicking many other
neurologic or psychiatric conditions, and onset may be acute or insidious. Most
often, PLE precedes the diagnosis of cancer; however, constitutional symptoms of
weight loss, night sweats, or lab findings of elevated ESR may suggest the presence of
cancer. PLE typically involves the anteromedial temporal cortex, hippocampus and
amygdale, and may also include nearby limbic structures, that is, hypothalamus and
insular cortex. MRI may show nonenhancing signal changes in the mesial temporal
lobes. PLE may improve with treatment of the underlying cancer and some may
respond to steroids. Some patients also respond to plasmapheresis or IVIG (Vernino
et al., 2007).
 REVERSIBLE DEMENTIAS 297

Autoimmune disease and the thyroid: Grave’s disease and Hashimoto’s thyroiditis
are autoimmune-mediated conditions of the thyroid. Grave’s disease often pre-
sents with neuropsychiatric and systemic symptoms. Labs demonstrate low TSH,
elevated thyroid hormone levels and demonstration of anti-TSH receptor anti-
body (TSHR). While, memory and cognitive complaints are common in acute
onset Grave’s disease, they do not manifest on formal neurocognitive assessment
and are believed to be manifestations of mood and somatic symptoms experi-
enced by patients with Grave’s, and symptoms resolve with treatment. Hashimo-
to’s thyroiditis (aka corticosteroid-responsive encephalopath associated with
evidence of thyroid autoimmunity (SREAT) is one of several conditions charac-
terized by encephalopathy which responds to treatment with steroids (nonvascu-
litic autoimmune meningoencephalitis (NAIM), has a broad range of clinical
presentations. Onset may be acute or insidious with measurable multiple neuro-
cognitive and neuropsychiatric impairments sometimes accompanied by tremor,
seizures, stroke-like events and systemic symptoms of fatigue, general malaise,
reduced appetite and weight loss (Mocellin et al., 2006; Vernino et al., 2007).
History may include generalized seizures, and neurologic exam may reveal
frontal release signs, brisk reflexes, myoclonus, tremor, and ataxia. Lab evaluation
for Hashimoto’s thyroiditis includes anti-TPO antiobody and antithyroglubulin
antibody (TG). Antimicrosomal antibodies may also be positive. Thyroid hor-
mones may be normal and inflammatory markers, for example, CRP and ESR
may be elevated and some patients may show elevated liver aminotranferase
levels. CSF may show elevated protein with mild lymphocytic pleocytosis.
Neuroimaging is usually normal, however some may show increased white matter
signal and T2-weighted and FLAIR sequences and less commonly dural enhance-
ment. Treatment is with steroids. Of note, though anti-TPO and anti-TG anti-
bodies may be found in Grave’s disease, anti-TSHR antibodies are not observed
in Hashimoto’s thyroiditis. In general, steroid-responsiveness may be the only
diagnostic clue for an autoimmune encephalopathy when serologic work-up is not
revealing. Leger et al. (2004) reported on a woman who presented with changes in
personality and attention with minor associated involuntary movements. In this
patient a PET scan was diagnostic, demonstrating hypermetabolism in the striatum
and CSF exam demonstrated antistriatal antibodies. Steroid nonresponsiveness in
cases suggests a paraneoplastic or neurodegenerative disease (Mocellin et al., 2006).
Wilson’s disease (aka hepatolenticular degeneration): An autosomal recessive disorder
of copper metabolism, resulting in copper toxicity, primarily in the liver and
brain. This presents with psychiatric and movement abnormalities including
personality changes, depression, hyperactivity, dystonia, incoordination, and
tremor. Laboratory assessment should include ceruloplasmin, serum copper,
and liver function tests. Slit lamp exam should be performed to evaluate for
Kayser-Fleisher rings in Descemet’s membrane. Treatment is through chelation
with trientine and supplementation of zinc. In cognitive assessment of treated
298 KABASAKALIAN AND FINNEY

patients with Wilson’s found a presentation is consistent with subcortical demen-

tia, with increased reaction times, impairments in short term memory, selective
attention and executive functions and suggested that cognitive impairments result
from disturbances in the frontal-subcortical circuits (Flicker and Ames, 2005).
Dural arteriovenous fistula (DAVF): A reported structural abnormality associated with
progressive cognitive decline is DAVF (Bernstein et al., 2003; Hirono et al., 1993).
These lesions may present with severe and slowly progressive global cognitive
impairment as the main derangement, though they may also occur in association
with transient or focal neurological deficits or symptoms (Bernstein et al., 2003;
Hirono et al., 1993). However, there may be essentially no focal signs or symp-
toms. Associated signs and symptoms may include pulsatile tinnitus which may be
transient, headache, papilledema, gait disturbance, parkinsonism. Examination
may also reveal a bruit over the skull, most often the mastoid. MRI may
demonstrate diVuse white matter changes with high signal intensity on FLAIR,
and DWI. MRA and conventional angiography may show flow reversal in the
venous system in association with venous thrombosis and decreased perfusion of
the associated parenchyma. The symptoms and imaging findings are thought to
result from venous hypertension. In all cases reported here, selective embolization
resulted in complete or near complete resolution of function (Bernstein et al., 2003;
Hirono et al., 1993).
Normal pressure hydrocephalus: NPH may present with progressive impairment of
gait, cognition in association with urinary incontinence. However, not all cases
may have reversible findings. See the separate chapter on ‘‘Normal Pressure
Hydrocephalus’’ for more details.
Psychiatric causes: Depression and dementia are frequently comorbid. However,
nondemented patients with depression may demonstrate or complain of impair-
ments in cognition, giving the impression of dementia, a condition termed ‘‘pseu-
dodementia.’’ Neuropsychological testing is considered the gold standard in
distinguishing between the two, as patterns in demented versus nondemented
depressed normal are identifiable. However, because dementia and depression
may be comorbid, addressing the treatable depression component is crucial for a
patient’s maintaining the highest level of functioning. The reverse is also true,
however. Pseudodementia in the elderly is identified as a risk factor for progression
to dementia. Therefore, older patients presenting with depression should be fully
evaluated for dementia. In addition to standard labs for screening of reversible
dementias, a cortisol level should be assessed, as hypercortisolemia may be asso-
ciated with depression in the elderly. Imaging studies may show white matter and
subcortical gray matter hyperintensities in elderly patients with depression. Catato-
nia is characterized by three cardinal features; little or no spontaneous movement,
mutism, and refusal to eat or drink. Catatonia is observed with many brain
disorders, including depression, dementia, head trauma, encephalitis, focal brain
lesions, and in response to psychotropic medications. Catatonia may be mistaken
 REVERSIBLE DEMENTIAS 299

for severe, end-stage dementia. When associated with medications, particularly

neuroleptics, vital signs demonstrating elevated body temperature and tachycardia
are clues to the diagnosis. In those cases, medications should be stopped and the
patient may require dopamine agonists to reverse the eVects of the original oVend-
ing agents. Benzodiazepines may be needed. Monitoring of vital signs, renal
function, and supportive care is indicated. In other cases, patients may respond to
benzodiazepines. Refractory cases may respond to electroconvulsive therapy
(Wright and Persad, 2007).

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 INDEX

A Amnestic MCI, 83–84, 106. See also Mild

cognitive impairment
A!42 (A!) degradation, 152 clinical trials, 94
A!42/A!40 ratio, 159 1
H MRS findings, 113–115
Acetylcholinesterase inhibitors, 238 Amygdala atrophy, 200
Activities of daily living (ADLs), 5, 87 Amyloid !, 155
AD. See Alzheimer’s disease Amyloid precursor protein (APP), 152, 155–156,
Addenbrooke’s cognitive assessment, 247 168. See also Dementia of the Alzheimer’s
Aerobic exercise, 11 type (DAT)
Age-specific traits, 3 Angiotensin converting enzyme (ACE), 160, 177
Aging: Anterior pharynx defective-1, 156
epidemiology, 2–5 Anticholinergic medications, 287
actual and projected growth, 3 Antimicrosomal antibodies, 290
age-adjusted and age-specific mortality, 4 Antineoplastic agents, 287
states, deranging brain neurons, 36 Antioxidant agents, 28
imaging studies, 11–14 Antiparkinsonian anticholinergic drugs, 226
neuropsychology, 9–11 Antiphospholipid antibodies (aPLs), 295
Aluminum toxicity, 291 Antiphospholipid antibody syndrome, 295
AlzGene approach, strengths and Antipsychotic drugs, 225
limitations, 175–176 Antispasmodics, for bladder, 226
AlzGene database, 172–174 Anti-TPO antiobody, 297
AlzGene Web site, 175–176 Anxiety, 3, 73, 220, 225, 234, 260
Alzheimer’s dementia, 258 APOE-e4 allele, 94, 172
Alzheimer’s disease, 24, 36 Apolipoprotein E gene, 169
cardiac disease and, 42 Apomorphine, 158
epidemiology, 134–135 Apparent diffusion coeYcient (ADC), 51–52
family datasets, 178 APP gene, 154, 156, 159
FDG-PET, 139 Arteriopathies, 61
genome-wide association studies, 169–171 Astrocyte plaques, 188
1
H MRS findings, 108–113 Atrial fibrillation, 23–24, 28
microbleeds (MB), 65 Atrophy, 53, 90, 116, 188, 199–200. See also
neurobiology, 134 Brain atrophy; Cerebral atrophy; Cortical
neuropathology, 153 atrophy; Hippocampal atrophy; Pick’s disease
preclinical detection, 42–44 Auditory verbal learning (AVLT), 115
risk factors, 37–41 Autoimmune disease, 297. See also Grave’s
susceptibility genes and potential disease; Hashimoto’s thyroiditis
pathogenetic roles, 180
treatment, 44–45 B
vascular-related risk factors, 38
Alzheimer’s type dementia, 28 Babinski signs, 267
Alzhemed, drug, 157 BACE1 inhibitors, 157

303
304 INDEX

Bayesian calculations, 143–144 Cerebral autosomal dominant arteriopathy with

Behcet’s disease, 295 subcortical infarcts and
Benzodiazepine, 299 leucoencephalopathy, 63, 65, 69–70, 252
Beta-amyloid (1–42) (Abeta42), 278 Cerebral blood flow (CBF), 37
Beta-amyloid (A!) peptide, 134 Cerebral blood volume (rCBV), 54
Blood oxygen level dependent (BOLD), 92 Cerebral energy, 35
Borrelia burgdorferi, 255, 293 role on AD, 36
Bradykinesia, 216, 219 Cerebral hypoperfusion, 36, 42–43, 291
Bradyphrenia, 220, 247 Cerebral ischemia, 28, 296
Brain aging, 1. See also Aging Cerebrospinal fluid, 50, 139, 158, 249, 263–264,
Brain atrophy, 12, 52, 61, 70 269, 271, 275–276, 278
measurement, 52–54 Cerebrovascular disease (CVD), 49, 58–59,
Brain hypoperfusion, 38 62–63, 6–7, 73
Brain imaging, 60, 200, 249, 251–252, 256, Cho/Cr levels, in MCI patients, 115
269–270 Choline (Cho), 57, 107
British Anti-Lewisite (BAL), 296 levels in AD, 110
!site APP cleaving enzyme-1 Cholinesterase inhibitors, 27, 66, 225, 237–238
(BACE1), 156 CHRNB2 gene, 160–161
Chronic health conditions, 3
C Chronicobstructive pulmonarydisease(COPD),291
Chronologic age, 3
CADASIL. See Cerebral autosomal dominant Clozapine, 220, 238
arteriopathy with subcortical infarcts and Cobalamin, 288–289
leucoencephalopathy Cognition and aging, 23–24
Calcitriol, 289 Cognitive decline, 5, 9, 11, 25, 43, 62, 65, 86, 92,
Calcium activated neural proteinases 97, 117, 138, 159, 216, 247, 253–254, 256,
(CANPs), 155 258, 261, 284–285, 291
Calcium-channel blocking agent, 28 Cognitive impairment, 22. See also Alzheimer’s
Cancer, 3, 157, 257, 290–291, 296 disease
Cardiac pathology, 44 pathophysiology in subcortical vascular
Cardiovascular disease, 42 lesions, 26–28
Carotid artery ultrasound and subcortical strokes and, 24–25
echocardiography (CAUSE), 43 in subcortical vascular lesions,
Catatonia, 298 pathophysiology, 26–28
Catechol-O-methyl transferase Cognitive performance, 2, 11, 13, 68, 70, 86, 289
(COMT), 238 Co-morbidities, 1–2, 246
Caudate atrophy, 260 Computed tomography (CT), 50, 268, 278
CD28þCD8þ T-cells, 8 Conventional MRI techniques, 50–51
CD4þ T-cells, 8 Copper and Zinc ions, 158
CD8þ T-cells in elderly, 7–8 Coronary artery disease, 3
Celiac sprue, 295 Corpus callosum, 70, 276
Cell biology, use of chemical energy, 39 Cortical atrophy, 21, 73, 255–256, 260
Celocoxib, 158 Corticobasal degeneration (CBD), 249, 259
Centenarians, 6–7 COX 2 inhibitor, 95, 158
Central nervous system (CNS), 57, Cranial nerve examination, 266
177, 222, 264, 266, 273, 286, 292 C-reactive protein (CRP), 292
proteins, 223–224 Creatinine (Cr), 57, 107
vasculitis, 257 Creutzfeldt-Jakob disease (CJD), 247, 254, 290
Cerebral aqueduct, 277 Critically attained threshold of cerebral
Cerebral atrophy, 201, 269, 275, 295 hypoperfusion (CATCH), 37
 INDEX 305

Crytococcal meningitis (CM), 285, 293 Diagnostic workup

Curcumin, 159 of dementia in primary care, 138–139
Cystatin-C amyloid angiopathy, 61 of dementia in specialty care settings, 139
Cysticercosis, 255 Diffuse cerebral atrophy, 275
Cytomegalovirus (CMV), 7, 252 Diffusion tensor imaging (DTI), 12, 53, 70, 90
Diffusion-weighted imaging (DWI), 51–52, 70
Dimercaptosuccinic acid, 296
D
DLB. See Dementia with Lewy bodies
Daily function questionnaire (DFQ), 89 Donepezil, 28, 44, 237–238
Delirium, 249–250, 285, 294 Dopamine, 118, 222
Delusions, 216, 220, 234 Dopamine agonists, 238, 299
Dementia, 22. See also Mild cognitive Dopaminergic therapy, 225
impairment; Vascular dementia Drug NC-531, 157
caused by specific arteriopathies, 61 Dural arteriovenous fistula (DAVF), 298
comparison, of most common forms, 217 Dysarthria, 234
defined, 216, 246
FDG-PET, 136 E
1
H MRS, 119–121
infectious causes, 292 Early-onset dementia, 245
with Lewy bodies, 258 diagnostic process, 246–247, 249
psychiatric causes, 298 differential diagnosis, 249–250
risk factors for development, 230 immune-mediated disorders, 256–257
Dementia lacking distinctive histology infectious diseases, 252–256
(DLDH), 188 neoplastic/metastatic disorders, 257–258
Dementia of the Alzheimer’s type (DAT), 151. neurodegenerative disorders, 258–261
See also Dementia toxic-metabolic disorders, 256
accumulation of amyloid !oligomers and, 153 vascular diseases, 250–252
A! deposition, 152 miscellaneous causes of, 261
A! production, 155–156 neurological signs, 248
cellular pathogenesis and investigational non-neurological signs, 249
strategies, 152–155 Early-onset familial AD (EOFAD), 168
defects in axonal transport and, 153 Echocardiography image, 43–44
glutaminergic neurotransmission and, 154 Electrolyte abnormalities, 291
mouse model, 153 Endocrine disorders and cognition, 289–299
therapeutic strategies, 155–161 EOD. See Early-onset dementia
transgenic mouse model, 158 Erythrocyte sedimentation rate (ESR), 292
Dementia rating scale (DRS), 113, 237 Essential tremor-idiopathic normal pressure
Dementia with Lewy bodies, 215 hydrocephalus (ETINPH), 277
biomarkers, 224 Ethylendiamineteraacetic acid (EDTA), 296
clinical features, 218–220 European Concerted Action on Pick’s disease
consortium, 218 (ECAPD), 188
genetics, 223–224 Extracranial vessel disease, 44
1
H MRS findings, 117–118
pathology, 221–223
F
and PD-D, 221
syndrome, 216 Fatal familial insomnia, 254
treatment and management, 225–226 [18F]2-Fluoro-2-deoxy-D-glucose, 135–136
Depression, 3, 45, 87, 120, 190, 199, 215, 220, Fluorodeoxyglucose (FDG), 42
225, 234, 249, 261, 288, 296–298 Fractional anisotropy (FA), 12
Diabetes mellitus, 21, 28, 41, 246 Frontal variant FTD (fv-FTD), 259
306 INDEX

Frontotemporal atrophy, 252 GRB2-associated binding protein 2

Frontotemporal dementia (FTD), 106, 116, 186, (GAB2), 160, 171, 179
192, 197 GTPases, 154
1
H MRS findings, 116
vs PPA, 196
H
vs SD, 196
Frontotemporal lobar degeneration Hallucinations, 87, 117, 215–216, 219–220, 225,
(FTLD), 185–186, 258–259 234, 258, 286
classification of subtypes and features, 190 Hashimoto’s encephalopathy, 257, 290
frontotemporal degeneration, 190 Hashimoto’s thyroiditis, 297
primary progressive aphasia, 191 Health status, in elderly, 2
progressive nonfluent aphasia, 191 Healthy and functional neurons, 36
semantic dementia, 191–192 Hemorrhagic dementia, 60–61
clinical criteria, 187–188 Hepatic encephalopathy, 291
diagnosis, 187 Hepatitis, 285
genetics, 189–190 Hereditary vascular cognitive impairment, 63
histopathology, 188–189 Highly active antiretroviral therapy
neurobehavioral assessment, 197–199 (HAART), 294
neuroimaging, 199–200 Hippocampal atrophy, 200, 236, 269
differentiation of subtypes, of FTLD, HIV-associated dementia (HAD), 252–253
203–207 HIV-related neurocognitive impairment, 294
differentiation of FTLD, from AD, H2 receptor antagonists, 287
200–203 Human prion diseases, 254
neuropsychological assessment, 192 Huntington’s disease (HD), 249, 260
distinguishing FTLD, from AD, 192–195 Hypercholesterolemia, 40
distinguishing FTLD subtypes, 196–197 Hypercortisolemia, 290
Functional and pathological states, deranging Hyperglycemia, 3
brain neurons, 36 Hyperlipidemia, 21, 28
Functional imaging, 2, 13, 54, 72, 74, 139, 200 Hypernatremia, 291
Functional magnetic resonance imaging Hyperphosphorylated tau (P-tau), 278
(fMRI), 13, 90, 249 Hypertension, 12, 21, 24, 64, 66, 86, 251,
285, 289
chronic health conditions, 3
G
in geriatric patients, 41
Gadolinium, 54, 252, 295 hemorrhagic dementia, 60
Gait examination, 267 prevention and treatment, 28
Galantamine, 28, 44, 95, 237 Hypocalcemia, 291
Galantamine hydrobromide, 44 Hypoperfusion dementia, 62
Gamma secretase, 156–157 Hypothyroidism, 290
General Electric (GE) scanner, 115
Genomewide association studies (GWAS),
167, 171–172 I
Gerstmann–Strussler–Scheinker disease, 254 Idiopathic normal pressure hydrocephalus.
Gerstmann syndrome, 286 See also Normal pressure hydrocephalus
Glucose hypometabolism, 135 possible, 271–272
Glx/Cr ratios, 117 probable, 269–271
Glycogen synthase kinase 3! (GSK-3!), 159 unlikely, 272–273
Grave’s disease, 296 Idiopathic Parkinson’s disease (IPD),
Gray matter (GM), 12, 27, 52, 203–204, 252, 260–261
288, 298 Immune-mediated disorders, 256
 INDEX 307

Infectious diseases, 252–256 Metabolic syndrome (MeS), 41

Inhibitors of A! fibrillization, 157 Microbleeds (MBs), 65, 69
Instrumental activities of daily living (IADLs), 5, Microscopic infarcts, 65, 69
88–89 mI/Cr ratios, 114–115, 117, 120
Interferon-gamma (IFN-"), 8 Mild cognitive impairment, 81–82
Italian Multicenter Study on Centenarians APOE e4 allele and, 84
(IMUSCE), 7 conversion to dementia, 85–86
daily functioning and, 88–89
K FDG-PET/PiB-PET, 144
and health variables, 86–87
1
Kinesin-I, 154 HMRS and neurocognitive measures, 115
1
Kuru disease, 254 HMRS predictors of dementia, 115
multi-domain MCI and amnestic MCI
(aMCI), subtypes, 83
L
neuroimaging
Lactate, 57 diffusion tensor imaging, 91
Lacunar infarcts, 64–65 functional MRI, 91–93
Laminins, 161 structural MRI, 89–90
Late-onset AD (LOAD), 168 neuropsychological presentation, 83–85
Lateralization of brain activity, 2 stability of diagnosis, 85
Lead encephalopathy, 296 treatment, 93–95
Left prefrontal cortical (PFC), 13 Miliary bodies (plaques), 151
Lewy bodies (LB), 215–216, 236, 258, 285. Mini-mental status examination (MMSE),
See also Dementia with Lewy bodies 138, 270
Lewy body dementia (LBD), 106 Mitofusin 2, 154
Lewy neurites, 223 Mixed dementia, 62, 65
Limbic encephalitis, 287 MMSE score, 154, 192, 230, 247
Linkage disequilibrium (LD), 169 MNDI patients, 189
Lipase A (LIPA), 160 Monoamine oxidase B (MAO-B) inhibitors, 238
Liver function tests, 286 MR diffusion-weighted imaging, 12
LMNA gene, 161 MRI diffusion tensor imaging, 204
Lupus cerebritis, 295 MR spectroscopy, 206
Lyme disease, 255, 293 Multidetector computer tomography
(MDCT), 56
Multi-infarct dementia, 21, 59
M
Multiple sclerosis (MS), 53, 107, 256–257, 293
Macroscopic infarcts, 64 Multi-voxel sMR, 58
Macrotubule-associated protein tau Musculoskeletal disorders, 3
(MAPT), 161 Myoclonus, 216
Magnetic resonance imaging (MRI), 13, 50, Myoinositol, 57, 107, 201, 252
236, 268, 278
Magnetic resonance spectroscopy (MRS), 56–58 N
Magnetization transfer imaging (MTI),
51–52, 71 NAA/Cr ratio, 72, 113, 115, 119–120, 278
Magnetization transfer ratio (MTR), 51 NAA/mI ratio, 112, 120
MCI. See Mild cognitive impairment N-acetyl aspartate (NAA), 57, 106–107, 109,
Memantine, 45, 154, 237 112, 115, 117–118, 206
Memory impairment, 231, 233 Neoplastic/metastatic disorders, 257–258
Meningoencephalitis, 293 Neurocysticercosis (NCC), 255
Metabolic imaging, 56, 71 Neurodegenerative disorders, 258
308 INDEX

Neuronal loss, 222 visuospatial abnormalities, 232

Neuropsychological function, in normal Wisconsin card sorting task, 231
aging, 10–11 Parkinson’s disease with dementia (PDD), 106,
Neurosarcoidosis, 294 220, 229
Niacin, 288 clinical features, 233–234
Nicastrin, 156 diagnosis, 237
Nimodipine, 28 early cognitive changes, 231–233
NMDA receptor, 154, 158, 295 epidemiology, 230–231
[N-methyl-11C]–2-(40 -methylaminophenyl)–6- 1
H MRS findings, 118–119
hydroxybenzothiazole, 137 neuroimaging, 236
N-methyl-Daspartate receptors, 45 pathology, 235–236
Nonconventional MRI techniques, 51 treatment, 237–239
Nonsteroidal anti-inflammatory agents Pellagra, 288
(NSAIDs), 45, 158 Perfusion-weighted imaging (PWI), 54–55, 72
Normal aging and functional performance, 5–6 Perisylvian atrophy, 259
Normal pressure hydrocephalus, 247, PET tracer 11C-PIB, 202
261, 263, 298 Phosphocreatinine (PCr), 57
history of present illness, 265 Pick’s bodies, 18–19
laboratory serologies, 268 Pick’s disease (PD), 186, 259
medications, 266 Pittsburgh compound B-PET, 137–138
modern diagnostic criteria, 269–273 PLE. See Paraneoplastic limbic encephalitis
neuroimaging, 268 Positron emission tomography (PET), 13, 42, 72,
past medical history, 266 133–134, 138, 206
physical examination, 266–268 appropriate uses, 140–141
predictors of response to shunting, 274–275 a likelihood ratio ‘‘mnemonic’’, 143
treatment, 273 Bayesian calculations, 143–144
Notch 3 gene, 252 likelihood ratios for PET AND AD, 144
Nuclear medical imaging, 55–56 likelihood ratio tables, 141–143
Post-stroke dementia ( PSD), 59
O Presenilin enhancer 2, 156
Presenilin 1 (PS1), 152, 156
Obesity, 41 Primary progressive aphasia (PPA), 186,
Olanzapine, 220 191–192, 194, 198
Ophthalmoplegia, 267. See also Whipple’s Prion diseases, 254
disease (WD) Prion protein (PRP), 161, 254
Optic atrophy 1, 154 Programmed aging, 2. See also Aging
Orthostatic hypotension, 225 Progressive nonfluent aphasia (PNFA), 186,
191, 259
Progressive supranuclear palsy, 259–260
P
Pronounced subcortical hyperintensities, in
Paraneoplastic limbic encephalitis (PLE), 296 subcortical white matter, 26
Parasomnias, 219 Protective factors, 6
Parathyroid, 290 Proton MR spectroscopy (1HMRS), 105
Parkinsonian motor, 216 findings in dementias
Parkinson’s disease (PD), 224 in Alzheimer’s disease, 108–113
cognitive changes, 231 in amnestic mild cognitive
Brown-Peterson distractor task, 231 impairment, 113–115
disease duration and, 232 in dementia with Lewy bodies, 117–118
executive dysfunction leading to, 231–232 for discriminating among
language deficits, 232 dementias, 119–120
 INDEX 309

in frontotemporal dementia, 116 Sortilin related receptor (SorLA), 154

for monitoring treatment effects in SPECT. See Single-photon emission computed
dementias, 120–121 tomography
in Parkinson’s disease dementia, 118–119 Sporadic vascular cognitive impairment, 59
in vascular dementia, 116–117 Strategic-infarct dementia, 61
metabolites, 106–108 Structural brain imaging, 50. See also
Psychosis in PDD, treatment, 238 Brain imaging
Subacute sclerosing panencephalitis
(SSPE), 253–254
Q
Subcortical ischemic cerebrovascular
Quetiapine, 226, 238 dementia, 22, 28
Subcortical ischemic vascular dementia
R (SIVD), 25, 60, 65, 73
Subcortical vascular lesions, 22
Rate-of-change traits, 3 Subdural hemorrhage, 61
Reactive nitrogen species (RNS), 159 Survival traits, 3
Reactive oxygen species (ROS), 154, 179 Syphilis, 294
Refecoxib, 158 Syphilitic dementia, 253
Reflexes, 267
REM behavioral disorder (RBD), 219 T
Renal failure, 291
Reversible cognitive impairments, 284 Tacrine, 44
Reversible dementias, 284. See also Dementia T-and B-Lymphocyte, 7–9
etiologies, 287 Tau aggregates, 222
examination, 285 Tau protein, 160
history, 284 T-cells, 7, 9, 157
laboratory studies, 286–287 Thiamine, 288
nutritional abnormalities, 288–289 Thyroid function tests (TFTs), 289–290
Rigidity symptom, 117, 187, 216, 219, 229, Thyropyroxidase (TPO), 286
258–259, 261, 286 Tissue atrophy, 42
Rivastigmine, 28, 237–239 Toxic-metabolic disorders, 256
Rivastigmine tartrate, 44 Tramiprosate, 157
Rofecoxib, 95, 158 Transcranial Doppler (TCD), 42
Transependymal extravasation, 275
Transferrin (TF), 154
S Traumatic brain injury, 261
Scyllo-inositol, 107 Treponema pallidum, 253, 294
# Secretase, 156 Tricyclic antidepressants, 226
! Secretase, 156–157 Trisomy 21, 153
Semantic dementia (SD), 186, 195–197, 199, Tropheryma whippelii, 292
259. See also Dementia T2-weighted imaging (WI), 50–51
Signal-to-noise-ratio (SNR), 54 T2-weighted MRI images, 13
Single nucleotide polymorphisms (SNPs), 160, 169
Single-photon emission computed
V
tomography, 42, 54, 72, 203, 206–207,
236, 249 VaD. See Vascular dementia
Sjogren’s syndrome, 295 Variant Creutzfeldt-Jakob disease (vCJD), 254
SLE-cerebritis, 295 Vascular cognitive impairment, 21, 49, 58.
Sleep anomalies, 216 See also Cognitive impairment
Smoking, 21 classification, 59
310 INDEX

Vascular cognitive impairment, 21, 49, 58. Vascular mild cognitive impairment
See also Cognitive impairment (cont.) (VaMCI), 59, 62–63
diagnostic neuroimaging criteria, 65–66 VCI. See Vascular cognitive impairment
hereditary, 69–70 Visual hallucinations, 216, 219, 221
histopathology, 64 Visuospatial abnormalities, 232
imaging findings and pathology, 73 Visuospatial deficits, 234
neuroimaging techniques, 67 Vitamin B12, 138, 247, 249, 288
conventional structural MRI, 67–70 Vitamin E, 286
functional imaging, 72–73
metabolic imaging, 71–72
nonconventional techniques, 70–71 W
primary prevention, 66
Vascular dementia, 43, 59, 65, 106, 116 Wernicke-Korsakoff syndrome, 267
cholinesterase inhibitors for, 66 Whipple’s disease (WD), 255, 286, 292
classification, 22 White matter atrophy, 205
diagnostic criteria, 66 White matter hyperintensities (WMH),
1
H MRS findings, 116–117 64, 67–68
NINDS-AIREN criteria, 24 White matter ischemia, 24
treatment, 66 Wilson’s disease, 297
Vascular diseases, 23, 250–252
 CONTENTS OF RECENT VOLUMES

Volume 37 Memory and Forgetting: Long-Term and

Gradual Changes in Memory Storage
Section I: Selectionist Ideas and Neurobiology Larry R. Squire

Selectionist and Instructionist Ideas in Implicit Knowledge: New Perspectives on

Neuroscience Unconscious Processes
Olaf Sporns Daniel L. Schacter

Population Thinking and Neuronal Selection: Section V: Psychophysics, Psychoanalysis, and

Metaphors or Concepts? Neuropsychology
Ernst Mayr Phantom Limbs, Neglect Syndromes, Repressed
Selection and the Origin of Information Memories, and Freudian Psychology
Manfred Eigen V. S. Ramachandran
Neural Darwinism and a Conceptual Crisis in
Section II: Development and Neuronal Psychoanalysis
Populations Arnold H. Modell
Morphoregulatory Molecules and Selectional A New Vision of the Mind
Dynamics during Development Oliver Sacks
Kathryn L. Crossin
Exploration and Selection in the Early Acquisi- index
tion of Skill
Esther Thelen and Daniela Corbetta
Population Activity in the Control of Movement Volume 38
Apostolos P. Georgopoulos
Regulation of GABAA Receptor Function and
Section III: Functional Segregation and Gene Expression in the Central Nervous System
Integration in the Brain A. Leslie Morrow
Reentry and the Problem of Cortical Integration Genetics and the Organization of the Basal
Giulio Tononi Ganglia
Coherence as an Organizing Principle of Robert Hitzemann, Yeang Olan,
Cortical Functions Stephen Kanes, Katherine Dains,
Wolf Singerl and Barbara Hitzemann
Temporal Mechanisms in Perception Structure and Pharmacology of Vertebrate
Ernst Pöppel GABAA Receptor Subtypes
Paul J. Whiting, Ruth M. McKernan,
Section IV: Memory and Models and Keith A. Wafford
Selection versus Instruction: Use of Computer Neurotransmitter Transporters: Molecular
Models to Compare Brain Theories Biology, Function, and Regulation
George N. Reeke, Jr. Beth Borowsky and Beth J. Hoffman

311
312 CONTENTS OF RECENT VOLUMES

Presynaptic Excitability Volume 40

Meyer B. Jackson
Monoamine Neurotransmitters in Invertebrates Mechanisms of Nerve Cell Death: Apoptosis or
and Vertebrates: An Examination of the Diverse Necrosis after Cerebral Ischemia
Enzymatic Pathways Utilized to Synthesize and R. M. E. Chalmers-Redman, A. D. Fraser,
Inactivate Biogenic Amines W. Y. H. Ju, J. Wadia, N. A. Tatton, and
B. D. Sloley and A. V. Juorio W. G. Tatton
Neurotransmitter Systems in Schizophrenia Changes in Ionic Fluxes during Cerebral Ische-
Gavin P. Reynolds mia
Physiology of Bergmann Glial Cells Tibor Kristian and Bo K. Siesjo
Thomas Müller and Helmut Kettenmann Techniques for Examining Neuroprotective
Drugs in Vitro
index
A. Richard Green and Alan J. Cross
Techniques for Examining Neuroprotective
Volume 39 Drugs in Vivo
Mark P. Goldberg, Uta Strasser, and Laura L. Dugan

Modulation of Amino Acid-Gated Ion Channels Calcium Antagonists: Their Role in Neuro-
by Protein Phosphorylation protection
Stephen J. Moss and Trevor G. Smart A. Jacqueline Hunter
Use-Dependent Regulation of GABAA Sodium and Potassium Channel Modulators:
Receptors Their Role in Neuroprotection
Eugene M. Barnes, Jr. Tihomir P. Obrenovich

Synaptic Transmission and Modulation in the NMDA Antagonists: Their Role in Neuroprotection
Neostriatum Danial L. Small
David M. Lovinger and Elizabeth Tyler Development of the NMDA Ion-Channel
The Cytoskeleton and Neurotransmitter Blocker, Aptiganel Hydrochloride, as a Neuro-
Receptors protective Agent for Acute CNS Injury
Valerie J. Whatley and R. Adron Harris Robert N. McBurney

Endogenous Opioid Regulation of Hippocampal The Pharmacology of AMPA Antagonists and

Function Their Role in Neuroprotection
Michele L. Simmons and Charles Chavkin Rammy Gill and David Lodge
Molecular Neurobiology of the Cannabinoid GABA and Neuroprotection
Receptor Patrick D. Lyden
Mary E. Abood and Billy R. Martin Adenosine and Neuroprotection
Genetic Models in the Study of Anesthetic Drug Bertil B. Fredholm
Action Interleukins and Cerebral Ischemia
Victoria J. Simpson and Thomas E. Johnson Nancy J. Rothwell, Sarah A. Loddick,
Neurochemical Bases of Locomotion and and Paul Stroemer
Ethanol Stimulant Effects
Tamara J. Phillips and Elaine H. Shen Nitrone-Based Free Radical Traps as Neuropro-
tective Agents in Cerebral Ischemia and Other
Effects of Ethanol on Ion Channels Pathologies
Fulton T. Crews, A. Leslie Morrow, Kenneth Hensley, John M. Carney,
Hugh Criswell, and George Breese Charles A. Stewart, Tahera Tabatabaie,
index Quentin Pye, and Robert A. Floyd
 CONTENTS OF RECENT VOLUMES 313

Neurotoxic and Neuroprotective Roles of Nitric Sensory and Cognitive Functions

Oxide in Cerebral Ischemia Lawrence M. Parsons and
Turgay Dalkara and Michael A. Moskowitz Peter T. Fox
A Review of Earlier Clinical Studies on Neuro- Skill Learning
protective Agents and Current Approaches Julien Doyon
Nils-Gunnar Wahlgren
Section V: Clinical and Neuropsychological
index Observations
Executive Function and Motor Skill Learning
Mark Hallett and Jordon Grafman
Volume 41
Verbal Fluency and Agrammatism
Marco Molinari, Maria G. Leggio, and
Section I: Historical Overview Maria C. Silveri
Rediscovery of an Early Concept Classical Conditioning
Jeremy D. Schmahmann Diana S. Woodruff-Pak
Section II: Anatomic Substrates Early Infantile Autism
Margaret L. Bauman, Pauline A. Filipek, and
The Cerebrocerebellar System
Thomas L. Kemper
Jeremy D. Schmahmann and Deepak N. Pandya
Olivopontocerebellar Atrophy and Fried-
Cerebellar Output Channels
reich’s Ataxia: Neuropsychological Conse-
Frank A. Middleton and Peter L. Strick
quences of Bilateral versus Unilateral Cerebellar
Cerebellar-Hypothalamic Axis: Basic Circuits Lesions
and Clinical Observations Thérèse Botez-Marquard and
Duane E. Haines, Espen Dietrichs, Mihai I. Botez
Gregory A. Mihailoff, and
Posterior Fossa Syndrome
E. Frank McDonald
Ian F. Pollack
Section III. Physiological Observations
Cerebellar Cognitive Affective Syndrome
Amelioration of Aggression: Response to Select- Jeremy D. Schmahmann and Janet C. Sherman
ive Cerebellar Lesions in the Rhesus Monkey
Inherited Cerebellar Diseases
Aaron J. Berman
Claus W. Wallesch and Claudius Bartels
Autonomic and Vasomotor Regulation
Neuropsychological Abnormalities in Cerebellar
Donald J. Reis and Eugene V. Golanov
Syndromes—Fact or Fiction?
Associative Learning Irene Daum and Hermann Ackermann
Richard F. Thompson, Shaowen Bao, Lu Chen,
Benjamin D. Cipriano, Jeffrey S. Grethe, Section VI: Theoretical Considerations
Jeansok J. Kim, Judith K. Thompson, Jo Anne Tracy, Cerebellar Microcomplexes
Martha S. Weninger, and David J. Krupa Masao Ito
Visuospatial Abilities Control of Sensory Data Acquisition
Robert Lalonde James M. Bower
Spatial Event Processing Neural Representations of Moving Systems
Marco Molinari, Laura Petrosini, Michael Paulin
and Liliana G. Grammaldo
How Fibers Subserve Computing Capabilities:
Section IV: Functional Neuroimaging Studies
Similarities between Brains and Machines
Linguistic Processing Henrietta C. Leiner and
Julie A. Fiez and Marcus E. Raichle Alan L. Leiner
314 CONTENTS OF RECENT VOLUMES

Cerebellar Timing Systems Volume 43

Richard Ivry
Attention Coordination and Anticipatory Early Development of the Drosophila Neuromus-
Control cular Junction: A Model for Studying Neuronal
Natacha A. Akshoomoff, Eric Courchesne, and Networks in Development
Jeanne Townsend Akira Chiba
Context-Response Linkage Development of Larval Body Wall Muscles
W. Thomas Thach Michael Bate, Matthias Landgraf,
and Mar Ruiz Gmez Bate
Duality of Cerebellar Motor and Cognitive
Functions Development of Electrical Properties and Synap-
James R. Bloedel and Vlastislav Bracha tic Transmission at the Embryonic Neuro-
muscular Junction
Section VII: Future Directions
Kendal S. Broadie
Therapeutic and Research Implications
Ultrastructural Correlates of Neuromuscular
Jeremy D. Schmahmann Junction Development
Mary B. Rheuben, Motojiro Yoshihara,
and Yoshiaki Kidokoro
Assembly and Maturation of the Drosophila
Volume 42 Larval Neuromuscular Junction
L. Sian Gramates and Vivian Budnik
Alzheimer Disease Second Messenger Systems Underlying Plasticity
Mark A. Smith at the Neuromuscular Junction
Neurobiology of Stroke Frances Hannan and Yi Zhong
W. Dalton Dietrich Mechanisms of Neurotransmitter Release
Free Radicals, Calcium, and the Synaptic J. Troy Littleton, Leo Pallanck, and
Plasticity-Cell Death Continuum: Emerging Barry Ganetzky
Roles of the Trascription Factor NF!B Vesicle Recycling at the Drosophila Neuromuscu-
Mark P. Mattson lar Junction
AP-I Transcription Factors: Short- and Long- Daniel T. Stimson and Mani Ramaswami
Term Modulators of Gene Expression in the Ionic Currents in Larval Muscles of Drosophila
Brain Satpal Singh and Chun-Fang Wu
Keith Pennypacker
Development of the Adult Neuromuscular
Ion Channels in Epilepsy System
Istvan Mody Joyce J. Fernandes and Haig Keshishian
Posttranslational Regulation of Ionotropic Glu- Controlling the Motor Neuron
tamate Receptors and Synaptic Plasticity James R. Trimarchi, Ping Jin, and
Xiaoning Bi, Steve Standley, and Rodney K. Murphey
Michel Baudry
Heritable Mutations in the Glycine, GABAA, Volume 44
and Nicotinic Acetylcholine Receptors Provide
New Insights into the Ligand-Gated Ion Chan-
Human Ego-Motion Perception
nel Receptor Superfamily
A. V. van den Berg
Behnaz Vafa and Peter R. Schofield
Optic Flow and Eye Movements
index M. Lappe and K.-P. Hoffman
 CONTENTS OF RECENT VOLUMES 315

The Role of MST Neurons during Ocular Brain Development and Generation of Brain
Tracking in 3D Space Pathologies
K. Kawano, U. Inoue, A. Takemura, Gregory L. Holmes and Bridget McCabe
Y. Kodaka, and F. A. Miles
Maturation of Channels and Receptors: Conse-
Visual Navigation in Flying Insects quences for Excitability
M. V. Srinivasan and S.-W. Zhang David F. Owens and Arnold R. Kriegstein
Neuronal Matched Filters for Optic Flow Neuronal Activity and the Establishment of
Processing in Flying Insects Normal and Epileptic Circuits during Brain
H. G. Krapp Development
A Common Frame of Reference for the Analysis John W. Swann, Karen L. Smith, and Chong L. Lee
of Optic Flow and Vestibular Information The Effects of Seizures of the Hippocampus of
B. J. Frost and D. R. W. Wylie the Immature Brain
Optic Flow and the Visual Guidance of Ellen F. Sperber and Solomon L. Moshe
Locomotion in the Cat Abnormal Development and Catastrophic
H. Sherk and G. A. Fowler Epilepsies: The Clinical Picture and Relation to
Stages of Self-Motion Processing in Primate Neuroimaging
Posterior Parietal Cortex Harry T. Chugani and Diane C. Chugani
F. Bremmer, J.-R. Duhamel, S. B. Hamed, and Cortical Reorganization and Seizure Generation
W. Graf in Dysplastic Cortex
Optic Flow Analysis for Self-Movement G. Avanzini, R. Preafico, S. Franceschetti,
Perception G. Sancini, G. Battaglia, and V. Scaioli
C. J. Duffy Rasmussen’s Syndrome with Particular Refer-
Neural Mechanisms for Self-Motion Perception ence to Cerebral Plasticity: A Tribute to Frank
in Area MST Morrell
R. A. Andersen, K. V. Shenoy, J. A. Crowell, Fredrick Andermann and Yuonne Hart
and D. C. Bradley Structural Reorganization of Hippocampal
Computational Mechanisms for Optic Flow Networks Caused by Seizure Activity
Analysis in Primate Cortex Daniel H. Lowenstein
M. Lappe Epilepsy-Associated Plasticity in gamma-
Human Cortical Areas Underlying the Percep- Amniobutyric Acid Receptor Expression,
tion of Optic Flow: Brain Imaging Studies Function and Inhibitory Synaptic Properties
M. W. Greenlee Douglas A. Coulter

What Neurological Patients Tell Us about the Synaptic Plasticity and Secondary Epilepto-
Use of Optic Flow genesis
L. M. Vaina and S. K. Rushton Timothy J. Teyler, Steven L. Morgan,
Rebecca N. Russell, and Brian L. Woodside
index Synaptic Plasticity in Epileptogenesis: Cel-
lular Mechanisms Underlying Long-Lasting
Synaptic Modifications that Require New Gene
Expression
Volume 45 Oswald Steward, Christopher S. Wallace, and
Paul F. Worley
Mechanisms of Brain Plasticity: From Normal Cellular Correlates of Behavior
Brain Function to Pathology Emma R. Wood, Paul A. Dudchenko, and
Philip. A. Schwartzkroin Howard Eichenbaum
316 CONTENTS OF RECENT VOLUMES

Mechanisms of Neuronal Conditioning Biosynthesis of Neurosteroids and Regulation of

David A. T. King, David J. Krupa, Their Synthesis
Michael R. Foy, and Richard F. Thompson Synthia H. Mellon and Hubert Vaudry
Plasticity in the Aging Central Nervous System Neurosteroid 7-Hydroxylation Products in the
C. A. Barnes Brain
Secondary Epileptogenesis, Kindling, and Robert Morfin and Luboslav Stárka
Intractable Epilepsy: A Reappraisal from the
Neurosteroid Analysis
Perspective of Neuronal Plasticity
Ahmed A. Alomary, Robert L. Fitzgerald, and
Thomas P. Sutula
Robert H. Purdy
Kindling and the Mirror Focus
Dan C. McIntyre and Michael O. Poulter Role of the Peripheral-Type Benzodiazepine
Receptor in Adrenal and Brain Steroidogenesis
Partial Kindling and Behavioral Pathologies Rachel C. Brown and Vassilios Papadopoulos
Robert E. Adamec
Formation and Effects of Neuroactive
The Mirror Focus and Secondary Epileptogenesis
Steroids in the Central and Peripheral Nervous
B. J. Wilder
System
Hippocampal Lesions in Epilepsy: A Historical Roberto Cosimo Melcangi, Valerio Magnaghi,
Review Mariarita Galbiati, and Luciano Martini
Robert Naquet
Neurosteroid Modulation of Recombinant and
Clinical Evidence for Secondary Epileptogensis Synaptic GABAA Receptors
Hans O. Luders Jeremy J. Lambert, Sarah C. Harney,
Epilepsy as a Progressive (or Nonprogressive Delia Belelli, and John A. Peters
‘‘Benign’’) Disorder GABAA-Receptor Plasticity during Long-
John A. Wada Term Exposure to and Withdrawal from
Pathophysiological Aspects of Landau-Kleffner Progesterone
Syndrome: From the Active Epileptic Phase to Giovanni Biggio, Paolo Follesa,
Recovery Enrico Sanna, Robert H. Purdy, and
Marie-Noelle Metz-Lutz, Pierre Maquet, Alessandra Concas
Annd De Saint Martin, Gabrielle Rudolf, Stress and Neuroactive Steroids
Norma Wioland, Edouard Hirsch, Maria Luisa Barbaccia, Mariangela Serra,
and Chriatian Marescaux Robert H. Purdy, and Giovanni Biggio
Local Pathways of Seizure Propagation in Neurosteroids in Learning and Memory
Neocortex Processes
Barry W. Connors, David J. Pinto, and Monique Vallée, Willy Mayo,
Albert E. Telefeian George F. Koob, and Michel Le Moal
Multiple Subpial Transection: A Clinical Neurosteroids and Behavior
Assessment Sharon R. Engel and Kathleen A. Grant
C. E. Polkey
Ethanol and Neurosteroid Interactions in the
The Legacy of Frank Morrell Brain
Jerome Engel, Jr. A. Leslie Morrow, Margaret J. VanDoren,
Rebekah Fleming, and Shannon Penland
Volume 46 Preclinical Development of Neurosteroids as
Neuroprotective Agents for the Treatment of
Neurosteroids: Beginning of the Story Neurodegenerative Diseases
Etienne E. Baulieu, P. Robel, and M. Schumacher Paul A. Lapchak and Dalia M. Araujo
 CONTENTS OF RECENT VOLUMES 317

Clinical Implications of Circulating Neuroster- Processing Human Brain Tissue for in Situ
oids Hybridization with Radiolabelled Oligonucleo-
Andrea R. Genazzani, Patrizia Monteleone, tides
Massimo Stomati, Francesca Bernardi, Louise F. B. Nicholson
Luigi Cobellis, Elena Casarosa, Michele Luisi,
In Situ Hybridization of Astrocytes and Neurons
Stefano Luisi, and Felice Petraglia
Cultured in Vitro
Neuroactive Steroids and Central Nervous L. A. Arizza-McNaughton, C. De Felipe,
System Disorders and S. P. Hunt
Mingde Wang, Torbjörn Bäckström,
In Situ Hybridization on Organotypic Slice
Inger Sundström, Göran Wahlström,
Cultures
Tommy Olsson, Di Zhu, Inga-Maj Johansson,
A. Gerfin-Moser and H. Monyer
Inger Björn, and Marie Bixo
Quantitative Analysis of in Situ Hybridization
Neuroactive Steroids in Neuropsychopharma-
Histochemistry
cology
Andrew L. Gundlach and Ross D. O’Shea
Rainer Rupprecht and Florian Holsboer
Current Perspectives on the Role of Neuroster- Part II: Nonradioactive in Situ hybridization
oids in PMS and Depression Nonradioactive in Situ Hybridization Using Alka-
Lisa D. Griffin, Susan C. Conrad, and line Phosphatase-Labelled Oligonucleotides
Synthia H. Mellon S. J. Augood, E. M. McGowan, B. R. Finsen,
B. Heppelmann, and P. C. Emson
index
Combining Nonradioactive in Situ Hybridization
with Immunohistological and Anatomical
Techniques
Volume 47 Petra Wahle
Nonradioactive in Situ Hybridization: Simplified
Introduction: Studying Gene Expression in Procedures for Use in Whole Mounts of Mouse
Neural Tissues by in Situ Hybridization and Chick Embryos
W. Wisden and B. J. Morris Linda Ariza-McNaughton and Robb Krumlauf
Part I: In Situ Hybridization with Radiolabelled
index
Oligonucleotides
In Situ Hybridization with Oligonucleotide
Probes
Wl. Wisden and B. J. Morris
Cryostat Sectioning of Brains Volume 48
Victoria Revilla and Alison Jones
Processing Rodent Embryonic and Early Post- Assembly and Intracellular Trafficking of
natal Tissue for in Situ Hybridization with GABAA Receptors Eugene
Radiolabelled Oligonucleotides Barnes
David J. Laurie, Petra C. U. Schrotz, Subcellular Localization and Regulation of
Hannah Monyer, and Ulla Amtmann
GABAA Receptors and Associated Proteins
Processing of Retinal Tissue for in Situ Hybrid- Bernhard Lüscher and Jean-Marc Fritschy D1
ization Dopamine Receptors
Frank Müller Richard Mailman
Processing the Spinal Cord for in Situ Hybridiza- Molecular Modeling of Ligand-Gated Ion
tion with Radiolabelled Oligonucleotides Channels: Progress and Challenges
A. Berthele and T. R. Tölle Ed Bertaccini and James R. Trudel
318 CONTENTS OF RECENT VOLUMES

Alzheimer’s Disease: Its Diagnosis and Patho- The Treatment of Infantile Spasms: An
genesis Evidence-Based Approach
Jillian J. Kril and Glenda M. Halliday Mark Mackay, Shelly Weiss, and
DNA Arrays and Functional Genomics in O. Carter Snead III
Neurobiology ACTH Treatment of Infantile Spasms: Mechan-
Christelle Thibault, Long Wang, Li Zhang, and isms of Its Effects in Modulation of Neuronal
Michael F. Miles Excitability
K. L. Brunson, S. Avishai-Eliner, and
index T. Z. Baram
Neurosteroids and Infantile Spasms: The Deox-
ycorticosterone Hypothesis
Volume 49 Michael A. Rogawski and Doodipala S. Reddy
Are there Specific Anatomical and/or Transmit-
What Is West Syndrome? ter Systems (Cortical or Subcortical) That
Olivier Dulac, Christine Soufflet, Should Be Targeted?
Catherine Chiron, and Anna Kaminski Phillip C. Jobe
The Relationship between encephalopathy and Medical versus Surgical Treatment: Which
Abnormal Neuronal Activity in the Developing Treatment When
Brain W. Donald Shields
Frances E. Jensen
Developmental Outcome with and without
Hypotheses from Functional Neuroimaging Successful Intervention
Studies Rochelle Caplan, Prabha Siddarth,
Csaba Juhász, Harry T. Chugani, Gary Mathern, Harry Vinters, Susan Curtiss,
Ouo Muzik, and Diane C. Chugani Jennifer Levitt, Robert Asarnow, and
Infantile Spasms: Unique Sydrome or General W. Donald Shields
Age-Dependent Manifestation of a Diffuse Infantile Spasms versus Myoclonus: Is There a
Encephalopathy? Connection?
M. A. Koehn and M. Duchowny Michael R. Pranzatelli
Histopathology of Brain Tissue from Patients Tuberous Sclerosis as an Underlying Basis for
with Infantile Spasms Infantile Spasm
Harry V. Vinters Raymond S. Yeung
Generators of Ictal and Interictal Electroenceph- Brain Malformation, Epilepsy, and Infantile
alograms Associated with Infantile Spasms: Spasms
Intracellular Studies of Cortical and Thalamic M. Elizabeth Ross
Neurons
M. Steriade and I. Timofeev Brain Maturational Aspects Relevant to Patho-
physiology of Infantile Spasms
Cortical and Subcortical Generators of Normal G. Auanzini, F. Panzica, and
and Abnormal Rhythmicity S. Franceschetti
David A. McCormick
Gene Expression Analysis as a Strategy to
Role of Subcortical Structures in the Patho- Understand the Molecular Pathogenesis of
genesis of Infantile Spasms: What Are Possible Infantile Spasms
Subcortical Mediators? Peter B. Crino
F. A. Lado and S. L. Moshé
Infantile Spasms: Criteria for an Animal Model
What Must We Know to Develop Better Carl E. Stafstrom and Gregory L. Holmes
Therapies?
Jean Aicardi index
 CONTENTS OF RECENT VOLUMES 319

Volume 50 Nerve Growth Factor for the Treatment of

Diabetic Neuropathy: What Went Wrong, What
Part I: Primary Mechanisms Went Right, and What Does the Future Hold?
Stuart C. Apfel
How Does Glucose Generate Oxidative Stress In
Peripheral Nerve? Angiotensin-Converting Enzyme Inhibitors: Are
Irina G. Obrosova there Credible Mechanisms for Beneficial Effects
in Diabetic Neuropathy?
Glycation in Diabetic Neuropathy: Characteris- Rayaz A. Malik and
tics, Consequences, Causes, and Therapeutic David R. Tomlinson
Options
Paul J. Thornalley Clinical Trials for Drugs Against Diabetic Neu-
ropathy: Can We Combine Scientific Needs
Part II: Secondary Changes With Clinical Practicalities?
Dan Ziegler and Dieter Luft
Protein Kinase C Changes in Diabetes: Is the
Concept Relevant to Neuropathy? index
Joseph Eichberg
Are Mitogen-Activated Protein Kinases
Glucose Transducers for Diabetic Neuropathies? Volume 51
Tertia D. Purves and David R. Tomlinson
Neurofilaments in Diabetic Neuropathy
Paul Fernyhough and Robert E. Schmidt Energy Metabolism in the Brain
Apoptosis in Diabetic Neuropathy Leif Hertz and Gerald A. Dienel
Aviva Tolkovsky
The Cerebral Glucose-Fatty Acid Cycle: Evolu-
Nerve and Ganglion Blood Flow in Diabetes: An tionary Roots, Regulation, and (Patho) physio-
Appraisal logical Importance
Douglas W. Zochodne Kurt Heininger
Expression, Regulation, and Functional Role of
Part III: Manifestations
Glucose Transporters (GLUTs) in Brain
Potential Mechanisms of Neuropathic Pain in Donard S. Dwyer, Susan J. Vannucci, and
Diabetes Ian A. Simpson
Nigel A. Calcutt
Insulin-Like Growth Factor-1 Promotes Neu-
Electrophysiologic Measures of Diabetic Neu- ronal Glucose Utilization During Brain Devel-
ropathy: Mechanism and Meaning opment and Repair Processes
Joseph C. Arezzo and Elena Zotova Carolyn A. Bondy and Clara M. Cheng
Neuropathology and Pathogenesis of Diabetic CNS Sensing and Regulation of Peripheral
Autonomic Neuropathy Glucose Levels
Robert E. Schmidt Barry E. Levin, Ambrose A. Dunn-Meynell, and
Vanessa H. Routh
Role of the Schwann Cell in Diabetic Neu-
ropathy Glucose Transporter Protein Syndromes
Luke Eckersley Darryl C. De Vivo, Dong Wang,
Juan M. Pascual, and
Part IV: Potential Treatment Yuan Yuan Ho
Polyol Pathway and Diabetic Peripheral Neu- Glucose, Stress, and Hippocampal Neuronal
ropathy Vulnerability
Peter J. Oates Lawrence P. Reagan
320 CONTENTS OF RECENT VOLUMES

Glucose/Mitochondria in Neurological Condi- Stress and Secretory Immunity

tions Jos A. Bosch, Christopher Ring,
John P. Blass Eco J. C. de Geus, Enno C. I. Veerman, and
Energy Utilization in the Ischemic/Reperfused Arie V. Nieuw Amerongen
Brain Cytokines and Depression
John W. Phillis and Michael H. O’Regan Angela Clow
Diabetes Mellitus and the Central Nervous Immunity and Schizophrenia: Autoimmunity,
System Cytokines, and Immune Responses
Anthony L. McCall Fiona Gaughran
Diabetes, the Brain, and Behavior: Is There a Cerebral Lateralization and the Immune System
Biological Mechanism Underlying the Associ- Pierre J. Neveu
ation between Diabetes and Depression?
Behavioral Conditioning of the Immune System
A. M. Jacobson, J. A. Samson,
Frank Hucklebridge
K. Weinger, and C. M. Ryan
Psychological and Neuroendocrine Correlates of
Schizophrenia and Diabetes
Disease Progression
David C. Henderson and Elissa R. Ettinger
Julie M. Turner-Cobb
Psychoactive Drugs Affect Glucose Transport
The Role of Psychological Intervention in
and the Regulation of Glucose Metabolism
Modulating Aspects of Immune Function in
Donard S. Dwyer, Timothy D. Ardizzone, and
Relation to Health and Well-Being
Ronald J. Bradley
J. H. Gruzelier
index
index

Volume 52
Volume 53
Neuroimmune Relationships in Perspective
Frank Hucklebridge and Angela Clow Section I: Mitochondrial Structure and Function
Sympathetic Nervous System Interaction with Mitochondrial DNA Structure and Function
the Immune System Carlos T. Moraes, Sarika Srivastava,
Virginia M. Sanders and Adam P. Kohm Ilias Kirkinezos, Jose Oca-Cossio,
Mechanisms by Which Cytokines Signal the Brain Corina van Waveren, Markus Woischnick,
Adrian J. Dunn and Francisca Diaz

Neuropeptides: Modulators of Immune Oxidative Phosphorylation: Structure, Function,

Responses in Health and Disease and Intermediary Metabolism
David S. Jessop Simon J. R. Heales, Matthew E. Gegg, and
John B. Clark
Brain–Immune Interactions in Sleep
Import of Mitochondrial Proteins
Lisa Marshall and Jan Born
Matthias F. Bauer, Sabine Hofmann, and
Neuroendocrinology of Autoimmunity Walter Neupert
Michael Harbuz
Section II: Primary Respiratory Chain
Systemic Stress-Induced Th2 Shift and Its Disorders
Clinical Implications Mitochondrial Disorders of the Nervous System:
Ibia J. Elenkov Clinical, Biochemical, and Molecular Genetic
Neural Control of Salivary S-IgA Secretion Features
Gordon B. Proctor and Guy H. Carpenter Dominic Thyagarajan and Edward Byrne
 CONTENTS OF RECENT VOLUMES 321

Section III: Secondary Respiratory Chain The Mitochondrial Theory of Aging: Involve-
Disorders ment of Mitochondrial DNA Damage and
Friedreich’s Ataxia Repair
J. M. Cooper and J. L. Bradley Nadja C. de Souza-Pinto and
Vilhelm A. Bohr
Wilson Disease
C. A. Davie and A. H. V. Schapira index
Hereditary Spastic Paraplegia
Christopher J. McDermott and Pamela J. Shaw
Cytochrome c Oxidase Deficiency Volume 54
Giacomo P. Comi, Sandra Strazzer,
Sara Galbiati, and Nereo Bresolin Unique General Anesthetic Binding Sites Within
Distinct Conformational States of the Nicotinic
Section IV: Toxin Induced Mitochondrial
Acetylcholine Receptor
Dysfunction
Hugo R. Ariaas, William, R. Kem,
Toxin-Induced Mitochondrial Dysfunction James R. Truddell, and Michael P. Blanton
Susan E. Browne and M. Flint Beal
Signaling Molecules and Receptor Transduction
Cascades That Regulate NMDA Receptor-
Section V: Neurodegenerative Disorders
Mediated Synaptic Transmission
Parkinson’s Disease Suhas. A. Kotecha and John F. MacDonald
L. V. P. Korlipara and A. H. V. Schapira
Behavioral Measures of Alcohol Self-Administra-
Huntington’s Disease: The Mystery Unfolds? tion and Intake Control: Rodent Models
Åsa Petersén and Patrik Brundin Herman H. Samson and Cristine L. Czachowski
Mitochondria in Alzheimer’s Disease Dopaminergic Mouse Mutants: Investigating
Russell H. Swerdlow and Stephen J. Kish the Roles of the Different Dopamine Receptor
Contributions of Mitochondrial Alterations, Subtypes and the Dopamine Transporter
Resulting from Bad Genes and a Hostile Envi- Shirlee Tan, Bettina Hermann, and
ronment, to the Pathogenesis of Alzheimer’s Emiliana Borrelli
Disease Drosophila melanogaster, A Genetic Model System
Mark P. Mattson for Alcohol Research
Mitochondria and Amyotrophic Lateral Douglas J. Guarnieri and Ulrike Heberlein
Sclerosis
index
Richard W. Orrell and Anthony H. V. Schapira

Section VI: Models of Mitochondrial Disease

Models of Mitochondrial Disease
Volume 55
Danae Liolitsa and Michael G. Hanna

Section VII: Defects of " Oxidation Including Section I: Virsu Vectors For Use in the Nervous
Carnitine Deficiency System

Defects of " Oxidation Including Carnitine Non-Neurotropic Adenovirus: a Vector for Gene
Deficiency Transfer to the Brain and Gene Therapy of
K. Bartlett and M. Pourfarzam Neurological Disorders
P. R. Lowenstein, D. Suwelack, J. Hu,
Section VIII: Mitochondrial Involvement in X. Yuan, M. Jimenez-Dalmaroni,
Aging S. Goverdhama, and M.G. Castro
322 CONTENTS OF RECENT VOLUMES

Adeno-Associated Virus Vectors Processing and Representation of Species-

E. Lehtonen and Specific Communication Calls in the Audi-
L. Tenenbaum tory System of Bats
Problems in the Use of Herpes Simplex Virus as George D. Pollak, Achim Klug, and
a Vector Eric E. Bauer
L. T. Feldman Central Nervous System Control of Micturition
Lentiviral Vectors Gert Holstege and Leonora J. Mouton
J. Jakobsson, C. Ericson, The Structure and Physiology of the Rat
N. Rosenquist, and C. Lundberg Auditory System: An Overview
Retroviral Vectors for Gene Delivery to Neural Manuel Malmierca
Precursor Cells Neurobiology of Cat and Human Sexual
K. Kageyama, H. Hirata, and J. Hatakeyama Behavior
Gert Holstege and J. R. Georgiadis
Section II: Gene Therapy with Virus Vectors for
Specific Disease of the Nervous System index
The Principles of Molecular Therapies for
Glioblastoma
G. Karpati and J. Nalbatonglu Volume 57
Oncolytic Herpes Simplex Virus
J. C. C. Hu and R. S. Coffin Cumulative Subject Index of Volumes 1–25
Recombinant Retrovirus Vectors for Treatment
of Brain Tumors
N. G. Rainov and C. M. Kramm Volume 58
Adeno-Associated Viral Vectors for Parkinson’s
Disease Cumulative Subject Index of Volumes 26–50
I. Muramatsu, L. Wang, K. Ikeguchi, K-i Fujimoto,
T. Okada, H. Mizukami, Y. Hanazono, A. Kume,
I. Nakano, and K. Ozawa Volume 59
HSV Vectors for Parkinson’s Disease
D. S. Latchman Loss of Spines and Neuropil
Gene Therapy for Stroke Liesl B. Jones
K. Abe and W. R. Zhang Schizophrenia as a Disorder of Neuroplasticity
Gene Therapy for Mucopolysaccharidosis Robert E. McCullumsmith, Sarah M. Clinton, and
A. Bosch and J. M. Heard James H. Meador-Woodruff
The Synaptic Pathology of Schizophrenia: Is
index
Aberrant Neurodevelopment and Plasticity to
Blame?
Sharon L. Eastwood
Volume 56
Neurochemical Basis for an Epigenetic Vision of
Synaptic Organization
Behavioral Mechanisms and the Neurobiology of E. Costa, D. R. Grayson, M. Veldic,
Conditioned Sexual Responding and A. Guidotti
Mark Krause
Muscarinic Receptors in Schizophrenia: Is
NMDA Receptors in Alcoholism There a Role for Synaptic Plasticity?
Paula L. Hoffman Thomas J. Raedler
 CONTENTS OF RECENT VOLUMES 323

Serotonin and Brain Development Volume 60

Monsheel S. K. Sodhi and Elaine Sanders-Bush
Presynaptic Proteins and Schizophrenia Microarray Platforms: Introduction and Appli-
William G. Honer and Clint E. Young cation to Neurobiology
Mitogen-Activated Protein Kinase Signaling Stanislav L. Karsten, Lili C. Kudo, and
Svetlana V. Kyosseva Daniel H. Geschwind

Postsynaptic Density Scaffolding Proteins at Experimental Design and Low-Level Analysis of

Excitatory Synapse and Disorders of Synaptic Microarray Data
Plasticity: Implications for Human Behavior B. M. Bolstad, F. Collin, K. M. Simpson,
Pathologies R. A. Irizarry, and T. P. Speed
Andrea de Bartolomeis and Germano Fiore Brain Gene Expression: Genomics and Genetics
Prostaglandin-Mediated Signaling in Schizo- Elissa J. Chesler and Robert W. Williams
phrenia DNA Microarrays and Animal Models of Learn-
S. Smesny ing and Memory
Mitochondria, Synaptic Plasticity, and Schizo- Sebastiano Cavallaro
phrenia Microarray Analysis of Human Nervous System
Dorit Ben-Shachar and Daphna Laifenfeld Gene Expression in Neurological Disease
Membrane Phospholipids and Cytokine Inter- Steven A. Greenberg
action in Schizophrenia DNA Microarray Analysis of Postmortem Brain
Jeffrey K. Yao and Daniel P. van Kammen Tissue
Neurotensin, Schizophrenia, and Antipsychotic Károly Mirnics, Pat Levitt, and David A. Lewis
Drug Action
Becky Kinkead and Charles B. Nemeroff index
Schizophrenia, Vitamin D, and Brain Develop-
ment Volume 61
Alan Mackay-Sim, François Féron, Darryl Eyles,
Thomas Burne, and John McGrath
Section I: High-Throughput Technologies
Possible Contributions of Myelin and Oligo-
dendrocyte Dysfunction to Schizophrenia Biomarker Discovery Using Molecular Profiling
Daniel G. Stewart and Kenneth L. Davis Approaches
Brain-Derived Neurotrophic Factor and the Stephen J. Walker and Arron Xu
Plasticity of the Mesolimbic Dopamine Pathway Proteomic Analysis of Mitochondrial Proteins
Oliver Guillin, Nathalie Griffon, Jorge Diaz, Mary F. Lopez, Simon Melov, Felicity Johnson,
Bernard Le Foll, Erwan Bezard, Christian Gross, Nicole Nagulko, Eva Golenko, Scott Kuzdzal,
Chris Lammers, Holger Stark, Patrick Carroll, Suzanne Ackloo, and Alvydas Mikulskis
Jean-Charles Schwartz, and Pierre Sokoloff
S100B in Schizophrenic Psychosis Section II: Proteomic Applications
Matthias Rothermundt, Gerald Ponath, and NMDA Receptors, Neural Pathways, and
Volker Arolt Protein Interaction Databases
Oct-6 Transcription Factor Holger Husi
Maria Ilia
Dopamine Transporter Network and Pathways
NMDA Receptor Function, Neuroplasticity, and
Rajani Maiya and R. Dayne Mayfield
the Pathophysiology of Schizophrenia
Joseph T. Coyle and Guochuan Tsai Proteomic Approaches in Drug Discovery and
Development
index Holly D. Soares, Stephen A. Williams,
324 CONTENTS OF RECENT VOLUMES

Peter J. Snyder, Feng Gao, Tom Stiger, Rene L. Olvera, David C. Glahn, Sheila C. Caetano,
Christian Rohlff, Athula Herath, Trey Sunderland, Steven R. Pliszka, and Jair C. Soares
Karen Putnam, and W. Frost White
Chemosensory G-Protein-Coupled Receptor
Section III: Informatics Signaling in the Brain
Geoffrey E. Woodard
Proteomic Informatics
Steven Russell, William Old, Katheryn Resing, and Disturbances of Emotion Regulation after Focal
Lawrence Hunter Brain Lesions
Antoine Bechara
Section IV: Changes in the Proteome by
The Use of Caenorhabditis elegans in Molecular
Disease Neuropharmacology
Proteomics Analysis in Alzheimer’s Disease: New Jill C. Bettinger, Lucinda Carnell, Andrew G. Davies,
Insights into Mechanisms of Neurodegeneration and Steven L. McIntire
D. Allan Butterfield and Debra Boyd-Kimball
index
Proteomics and Alcoholism
Frank A. Witzmann and Wendy N. Strother
Proteomics Studies of Traumatic Brain Injury Volume 63
Kevin K. W. Wang, Andrew Ottens,
William Haskins, Ming Cheng Liu, Mapping Neuroreceptors at work: On the Def-
Firas Kobeissy, Nancy Denslow, inition and Interpretation of Binding Potentials
SuShing Chen, and Ronald L. Hayes after 20 years of Progress
Influence of Huntington’s Disease on the Human Albert Gjedde, Dean F. Wong, Pedro Rosa-Neto, and
and Mouse Proteome Paul Cumming
Claus Zabel and Joachim Klose Mitochondrial Dysfunction in Bipolar Disorder:
From 31P-Magnetic Resonance Spectroscopic
Section V: Overview of the Neuroproteome Findings to Their Molecular Mechanisms
Proteomics—Application to the Brain Tadafumi Kato
Katrin Marcus, Oliver Schmidt, Heike Schaefer, Large-Scale Microarray Studies of Gene Expres-
Michael Hamacher, AndrÅ van Hall, and Helmut sion in Multiple Regions of the Brain in Schizo-
E. Meyer phrenia and Alzeimer’s Disease
Pavel L. Katsel, Kenneth L. Davis, and Vahram
index Haroutunian
Regulation of Serotonin 2C Receptor PRE-
Volume 62 mRNA Editing By Serotonin
Claudia Schmauss

GABAA Receptor Structure–Function Studies: A The Dopamine Hypothesis of Drug Addiction:

Reexamination in Light of New Acetylcholine Hypodopaminergic State
Receptor Structures Miriam Melis, Saturnino Spiga, and Marco Diana
Myles H. Akabas Human and Animal Spongiform Encephalopa-
Dopamine Mechanisms and Cocaine Reward thies are Autoimmune Diseases: A Novel Theory
Aiko Ikegami and Christine L. Duvauchelle and Its supporting Evidence
Bao Ting Zhu
Proteolytic Dysfunction in Neurodegenerative
Disorders Adenosine and Brain Function
Kevin St. P. McNaught Bertil B. Fredholm, Jiang-Fan Chen, Rodrigo A.
Cunha, Per Svenningsson, and Jean-Marie Vaugeois
Neuroimaging Studies in Bipolar Children and
Adolescents index
 CONTENTS OF RECENT VOLUMES 325

Volume 64 G-Protein–Coupled Receptor Deorphanizations

Yumiko Saito and Olivier Civelli
Section I. The Cholinergic System Mechanistic Connections Between Glucose/
John Smythies Lipid Disturbances and Weight Gain Induced
Section II. The Dopamine System by Antipsychotic Drugs
John Symythies Donard S. Dwyer, Dallas Donohoe, Xiao-Hong Lu,
and Eric J. Aamodt
Section III. The Norepinephrine System
John Smythies Serotonin Firing Activity as a Marker for Mood
Disorders: Lessons from Knockout Mice
Section IV. The Adrenaline System Gabriella Gobbi
John Smythies
Section V. Serotonin System index
John Smythies

index Volume 66

Brain Atlases of Normal and Diseased Popula-

Volume 65 tions
Arthur W. Toga and Paul M. Thompson
Neuroimaging Databases as a Resource for
Scientific Discovery
Insulin Resistance: Causes and Consequences
John Darrell Van Horn, John Wolfe, Autumn Agnoli,
Zachary T. Bloomgarden
Jeffrey Woodward, Michael Schmitt, James Dobson,
Antidepressant-Induced Manic Conversion: A Sarene Schumacher, and Bennet Vance
Developmentally Informed Synthesis of the
Modeling Brain Responses
Literature
Karl J. Friston, William Penny, and Olivier David
Christine J. Lim, James F. Leckman,
Christopher Young, and Andrés Martin Voxel-Based Morphometric Analysis Using
Shape Transformations
Sites of Alcohol and Volatile Anesthetic Action
Christos Davatzikos
on Glycine Receptors
Ingrid A. Lobo and R. Adron Harris The Cutting Edge of f MRI and High-Field
f MRI
Role of the Orbitofrontal Cortex in Reinforce-
Dae-Shik Kim
ment Processing and Inhibitory Control: Evi-
dence from Functional Magnetic Resonance Quantification of White Matter Using Diffusion-
Imaging Studies in Healthy Human Subjects Tensor Imaging
Rebecca Elliott and Bill Deakin Hae-Jeong Park

Common Substrates of Dysphoria in Stimulant Perfusion f MRI for Functional Neuroimaging

Drug Abuse and Primary Depression: Thera- Geoffrey K. Aguirre, John A. Detre, and
peutic Targets Jiongjiong Wang
Kate Baicy, Carrie E. Bearden, John Monterosso, Functional Near-Infrared Spectroscopy: Poten-
Arthur L. Brody, Andrew J. Isaacson, and tial and Limitations in Neuroimaging Studies
Edythe D. London Yoko Hoshi
The Role of cAMP Response Element–Binding Neural Modeling and Functional Brain Imaging:
Proteins in Mediating Stress-Induced Vulner- The Interplay Between the Data-Fitting and
ability to Drug Abuse Simulation Approaches
Arati Sadalge Kreibich and Julie A. Blendy Barry Horwitz and Michael F. Glabus
326 CONTENTS OF RECENT VOLUMES

Combined EEG and fMRI Studies of Human W. Gordon Frankle, Mark Slifstein, Peter S. Talbot,
Brain Function and Marc Laruelle
V. Menon and S. Crottaz-Herbette
index
index

Volume 68
Volume 67
Fetal Magnetoencephalography: Viewing the
Distinguishing Neural Substrates of Heterogen- Developing Brain In Utero
eity Among Anxiety Disorders Hubert Preissl, Curtis L. Lowery, and Hari Eswaran
Jack B. Nitschke and Wendy Heller Magnetoencephalography in Studies of Infants
Neuroimaging in Dementia and Children
K. P. Ebmeier, C. Donaghey, and Minna Huotilainen
N. J. Dougall Let’s Talk Together: Memory Traces Revealed
Prefrontal and Anterior Cingulate Contributions by Cooperative Activation in the Cerebral
to Volition in Depression Cortex
Jack B. Nitschke and Kristen L. Mackiewicz Jochen Kaiser, Susanne Leiberg, and Werner
Lutzenberger
Functional Imaging Research in Schizophrenia
H. Tost, G. Ende, M. Ruf, F. A. Henn, and Human Communication Investigated With
A. Meyer-Lindenberg Magnetoencephalography: Speech, Music, and
Gestures
Neuroimaging in Functional Somatic Syn-
Thomas R. Knösche, Burkhard Maess, Akinori
dromes
Nakamura, and Angela D. Friederici
Patrick B. Wood
Combining Magnetoencephalography and
Neuroimaging in Multiple Sclerosis
Functional Magnetic Resonance Imaging
Alireza Minagar, Eduardo Gonzalez-Toledo,
Klaus Mathiak and Andreas J. Fallgatter
James Pinkston, and Stephen L. Jaffe
Beamformer Analysis of MEG Data
Stroke
Arjan Hillebrand and Gareth R. Barnes
Roger E. Kelley and Eduardo Gonzalez-Toledo
Functional Connectivity Analysis in Magnetoen-
Functional MRI in Pediatric Neurobehavioral
cephalography
Disorders
Alfons Schnitzler and Joachim Gross
Michael Seyffert and F. Xavier Castellanos
Human Visual Processing as Revealed by Mag-
Structural MRI and Brain Development
netoencephalographys
Paul M. Thompson, Elizabeth R. Sowell,
Yoshiki Kaneoke, Shoko Watanabe, and Ryusuke
Nitin Gogtay, Jay N. Giedd, Christine N. Vidal,
Kakigi
Kiralee M. Hayashi, Alex Leow, Rob Nicolson,
Judith L. Rapoport, and Arthur W. Toga A Review of Clinical Applications of Magne-
toencephalography
Neuroimaging and Human Genetics
Andrew C. Papanicolaou, Eduardo M. Castillo,
Georg Winterer, Ahmad R. Hariri, David Goldman,
Rebecca Billingsley-Marshall, Ekaterina Pataraia,
and Daniel R. Weinberger
and Panagiotis G. Simos
Neuroreceptor Imaging in Psychiatry: Theory
and Applications index
 CONTENTS OF RECENT VOLUMES 327

Volume 69 Spectral Processing in the Auditory Cortex

Mitchell L. Sutter
Nematode Neurons: Anatomy and Anatomical Processing of Dynamic Spectral Properties of
Methods in Caenorhabditis elegans Sounds
David H. Hall, Robyn Lints, and Zeynep Altun Adrian Rees and Manuel S. Malmierca
Investigations of Learning and Memory in Representations of Spectral Coding in the
Caenorhabditis elegans Human Brain
Andrew C. Giles, Jacqueline K. Rose, and Catharine Deborah A. Hall, PhD
H. Rankin
Spectral Processing and Sound Source Deter-
Neural Specification and Differentiation mination
Eric Aamodt and Stephanie Aamodt Donal G. Sinex
Sexual Behavior of the Caenorhabditis elegans Spectral Information in Sound Localization
Male Simon Carlile, Russell Martin, and Ken McAnally
Scott W. Emmons
Plasticity of Spectral Processing
The Motor Circuit Dexter R. F. Irvine and Beverly A. Wright
Stephen E. Von Stetina, Millet Treinin, and David M.
Spectral Processing In Cochlear Implants
Miller III
Colette M. McKay
Mechanosensation in Caenorhabditis elegans
Robert O’Hagan and Martin Chalfie index

Volume 71
Volume 70

Autism: Neuropathology, Alterations of the GA-

Spectral Processing by the Peripheral Auditory
BAergic System, and Animal Models
System Facts and Models
Christoph Schmitz, Imke A. J. van Kooten,
Enrique A. Lopez-Poveda
Patrick R. Hof, Herman van Engeland,
Basic Psychophysics of Human Spectral Pro- Paul H. Patterson, and Harry W. M. Steinbusch
cessing
The Role of GABA in the Early Neuronal
Brian C. J. Moore
Development
Across-Channel Spectral Processing Marta Jelitai and Emı´lia Madarasz
John H. Grose, Joseph W. Hall III, and
GABAergic Signaling in the Developing Cere-
Emily Buss
bellum
Speech and Music Have Different Requirements Chitoshi Takayama
for Spectral Resolution
Insights into GABA Functions in the Developing
Robert V. Shannon
Cerebellum
Non-Linearities and the Representation of Audi- Mo´nica L. Fiszman
tory Spectra
Role of GABA in the Mechanism of the Onset of
Eric D. Young, Jane J. Yu, and Lina A. J. Reiss
Puberty in Non-Human Primates
Spectral Processing in the Inferior Colliculus Ei Terasawa
Kevin A. Davis
Rett Syndrome: A Rosetta Stone for Under-
Neural Mechanisms for Spectral Analysis in the standing the Molecular Pathogenesis of Autism
Auditory Midbrain, Thalamus, and Cortex Janine M. LaSalle, Amber Hogart, and Karen N.
Monty A. Escab and Heather L. Read Thatcher
328 CONTENTS OF RECENT VOLUMES

GABAergic Cerebellar System in Autism: A Neu- A Systematic Examination of Catatonia-Like

ropathological and Developmental Perspective Clinical Pictures in Autism Spectrum Disorders
Gene J. Blatt Lorna Wing and Amitta Shah
Reelin Glycoprotein in Autism and Schizophrenia Catatonia in Individuals with Autism Spectrum
S. Hossein Fatemi Disorders in Adolescence and Early Adulthood:
Is There A Connection Between Autism, A Long-Term Prospective Study
Prader-Willi Syndrome, Catatonia, and GABA? Masataka Ohta, Yukiko Kano, and Yoko Nagai
Dirk M. Dhossche, Yaru Song, and Yiming Liu Are Autistic and Catatonic Regression Related?
Alcohol, GABA Receptors, and Neurodevelop- A Few Working Hypotheses Involving GABA,
mental Disorders Purkinje Cell Survival, Neurogenesis, and ECT
Ujjwal K. Rout Dirk Marcel Dhossche and Ujjwal Rout

Effects of Secretin on Extracellular GABA and Psychomotor Development and Psychopath-

Other Amino Acid Concentrations in the Rat ology in Childhood
Hippocampus Dirk M. J. De Raeymaecker
Hans-Willi Clement, Alexander Pschibul, and The Importance of Catatonia and Stereotypies
Eberhard Schulz in Autistic Spectrum Disorders
Predicted Role of Secretin and Oxytocin in the Laura Stoppelbein, Leilani Greening, and
Treatment of Behavioral and Developmental Angelina Kakooza
Disorders: Implications for Autism Prader–Willi Syndrome: Atypical Psychoses and
Martha G. Welch and David A. Ruggiero Motor Dysfunctions
Immunological Findings in Autism Willem M. A. Verhoeven and Siegfried Tuinier
Hari Har Parshad Cohly and Asit Panja Towards a Valid Nosography and Psychopath-
Correlates of Psychomotor Symptoms in Autism ology of Catatonia in Children and Adolescents
Laura Stoppelbein, Sara Sytsma-Jordan, and David Cohen
Leilani Greening Is There a Common Neuronal Basis for Autism
and Catatonia?
GABRB3 Gene Deficient Mice: A Potential
Model of Autism Spectrum Disorder Dirk Marcel Dhossche, Brendan T. Carroll, and
Timothy M. DeLorey Tressa D. Carroll

The Reeler Mouse: Anatomy of a Mutant Shared Susceptibility Region on Chromosome

Gabriella D’Arcangelo 15 Between Autism and Catatonia
Yvon C. Chagnon
Shared Chromosomal Susceptibility Regions
Between Autism and Other Mental Disorders Current Trends in Behavioral Interventions for
Yvon C. Chagnon index Children with Autism
Dorothy Scattone and Kimberly R. Knight
index Case Reports with a Child Psychiatric Explor-
ation of Catatonia, Autism, and Delirium
Jan N. M. Schieveld
Volume 72 ECT and the Youth: Catatonia in Context
Frank K. M. Zaw
Classification Matters for Catatonia and Autism Catatonia in Autistic Spectrum Disorders: A
in Children Medical Treatment Algorithm
Klaus-Jürgen Neumärker Max Fink, Michael A. Taylor, and Neera Ghaziuddin
 CONTENTS OF RECENT VOLUMES 329

Psychological Approaches to Chronic Volume 74

Catatonia-Like Deterioration in Autism
Spectrum Disorders Evolutionary Neurobiology and Art
Amitta Shah and Lorna Wing C. U. M. Smith
Section V: Blueprints Section I: Visual Aspects
Blueprints for the Assessment, Treatment, and
Future Study of Catatonia in Autism Spectrum Perceptual Portraits
Disorders Nicholas Wade
Dirk Marcel, Dhossche, Amitta Shah, and Lorna Wing
The Neuropsychology of Visual Art: Conferring
index Capacity
Anjan Chatterjee
Vision, Illusions, and Reality
Volume 73 Christopher Kennard
Localization in the Visual Brain
Chromosome 22 Deletion Syndrome and George K. York
Schizophrenia Section II: Episodic Disorders
Nigel M. Williams, Michael C. O’Donovan, and
Michael J. Owen Neurology, Synaesthesia, and Painting
Amy Ione
Characterization of Proteome of Human Cere-
brospinal Fluid Fainting in Classical Art
Jing Xu, Jinzhi Chen, Elaine R. Peskind, Philip Smith
Jinghua Jin, Jimmy Eng, Catherine Pan, Migraine Art in the Internet: A Study of 450
Thomas J. Montine, David R. Goodlett, and Contemporary Artists
Jing Zhang Klaus Podoll
Hormonal Pathways Regulating Intermale and Sarah Raphael’s Migraine with Aura as Inspir-
Interfemale Aggression ation for the Foray of Her Work into Abstraction
Neal G. Simon, Qianxing Mo, Shan Hu, Klaus Podoll and Debbie Ayles
Carrie Garippa, and Shi-Fang Lu
The Visual Art of Contemporary Artists with
Neuronal GAP Junctions: Expression, Function, Epilepsy
and Implications for Behavior Steven C. Schachter
Clinton B. McCracken and David C. S. Roberts
Section III: Brain Damage
Effects of Genes and Stress on the Neurobiology
Creativity in Painting and Style in Brain-
of Depression
Damaged Artists
J. John Mann and Dianne Currier
Julien Bogousslavsky
Quantitative Imaging with the Micropet Small-
Artistic Changes in Alzheimer’s Disease
Animal Pet Tomograph
Sebastian J. Crutch and Martin N. Rossor
Paul Vaska, Daniel J. Rubins, David L. Alexoff, and
Wynne K. Schiffer Section IV: Cerebrovascular Disease
Understanding Myelination through Studying its Stroke in Painters
Evolution H. Bäzner and M. Hennerici
Rüdiger Schweigreiter, Betty I. Roots, Visuospatial Neglect in Lovis Corinth’s Self-
Christine Bandtlow, and Robert M. Gould Portraits
index Olaf Blanke
330 CONTENTS OF RECENT VOLUMES

Art, Constructional Apraxia, and the Brain Transmitter Release at the Neuromuscular
Louis Caplan Junction
Section V: Genetic Diseases Thomas L. Schwarz

Neurogenetics in Art Vesicle Trafficking and Recycling at the Neuro-

Alan E. H. Emery muscular Junction: Two Pathways for Endocytosis
Yoshiaki Kidokoro
A Naı̈ve Artist of St Ives
F. Clifford Rose Glutamate Receptors at the Drosophila Neuro-
muscular Junction
Van Gogh’s Madness Aaron DiAntonio
F. Clifford Rose
Scaffolding Proteins at the Drosophila Neuromus-
Absinthe, The Nervous System and Painting cular Junction
Tiina Rekand Bulent Ataman, Vivian Budnik, and Ulrich Thomas
Section VI: Neurologists as Artists Synaptic Cytoskeleton at the Neuromuscular
Sir Charles Bell, KGH, FRS, FRSE (1774–1842) Junction
Christopher Gardner-Thorpe Catalina Ruiz-Cañada and Vivian Budnik

Section VII: Miscellaneous Plasticity and Second Messengers During Synapse

Development
Peg Leg Frieda
Leslie C. Griffith and Vivian Budnik
Espen Dietrichs
The Deafness of Goya (1746–1828) Retrograde Signaling that Regulates Synaptic
F. Clifford Rose Development and Function at the Drosophila
Neuromuscular Junction
Guillermo Marqués and Bing Zhang
index
Activity-Dependent Regulation of Transcription
During Development of Synapses
Volume 75 Subhabrata Sanyal and Mani Ramaswami
Experience-Dependent Potentiation of Larval
Introduction on the Use of the Drosophila Embry-
Neuromuscular Synapses
onic/Larval Neuromuscular Junction as a Model
Christoph M. Schuster
System to Study Synapse Development and
Function, and a Brief Summary of Pathfinding Selected Methods for the Anatomical Study of
and Target Recognition Drosophila Embryonic and Larval Neuromuscular
Junctions
Catalina Ruiz-Cañada and Vivian Budnik
Vivian Budnik, Michael Gorczyca, and
Development and Structure of Motoneurons Andreas Prokop
Matthias Landgraf and Stefan Thor
index
The Development of the Drosophila Larval
Body Wall Muscles
Karen Beckett and Mary K. Baylies
Volume 76
Organization of the Efferent System and Struc-
ture of Neuromuscular Junctions in Drosophila
Andreas Prokop Section I: Physiological Correlates of Freud’s
Development of Motoneuron Electrical Proper- Theories
ties and Motor Output The ID, the Ego, and the Temporal Lobe
Richard A. Baines Shirley M. Ferguson and Mark Rayport
 CONTENTS OF RECENT VOLUMES 331

ID, Ego, and Temporal Lobe Revisited Evidence for Neuroprotective Effects of Antipsy-
Shirley M. Ferguson and chotic Drugs: Implications for the Pathophysiology
Mark Rayport and Treatment of Schizophrenia
Xin-Min Li and Haiyun Xu
Section II: Stereotaxic Studies
Neurogenesis and Neuroenhancement in the
Olfactory Gustatory Responses Evoked by Elec-
Pathophysiology and Treatment of Bipolar
trical Stimulation of Amygdalar Region in Man
Disorder
Are Qualitatively Modifiable by Interview Con-
Robert J. Schloesser, Guang Chen, and
tent: Case Report and Review
Husseini K. Manji
Mark Rayport, Sepehr Sani, and Shirley M. Ferguson
Neuroreplacement, Growth Factor, and Small
Section III: Controversy in Definition of Behavioral
Molecule Neurotrophic Approaches for Treating
Disturbance
Parkinson’s Disease
Pathogenesis of Psychosis in Epilepsy. The ‘‘See- Michael J. O’Neill, Marcus J. Messenger,
saw’’ Theory: Myth or Reality? Viktor Lakics, Tracey K. Murray, Eric H. Karran,
Shirley M. Ferguson and Mark Rayport Philip G. Szekeres, Eric S. Nisenbaum, and
Kalpana M. Merchant
Section IV: Outcome of Temporal Lobectomy
Using Caenorhabditis elegans Models of Neuro-
Memory Function After Temporal Lobectomy
degenerative Disease to Identify Neuroprotective
for Seizure Control: A Comparative Neuropsy
Strategies
chiatric and Neuropsychological Study
Brian Kraemer and Gerard D. Schellenberg
Shirley M. Ferguson, A. John McSweeny, and
Mark Rayport Neuroprotection and Enhancement of Neurite
Life After Surgery for Temporolimbic Seizures Outgrowth With Small Molecular Weight Com-
Shirley M. Ferguson, Mark Rayport, and pounds From Screens of Chemical Libraries
Carolyn A. Schell Donard S. Dwyer and Addie Dickson
index
Appendix I
Mark Rayport
Appendix II: Conceptual Foundations of Studies Volume 78
of Patients Undergoing Temporal Lobe Surgery
for Seizure Control
Neurobiology of Dopamine in Schizophrenia
Mark Rayport
Olivier Guillin, Anissa Abi-Dargham, and
index Marc Laruelle

The Dopamine System and the Pathophysiology

Volume 77 of Schizophrenia: A Basic Science Perspective
Yukiori Goto and Anthony A. Grace

Regenerating the Brain Glutamate and Schizophrenia: Phencyclidine,

David A. Greenberg and Kunlin Jin N-methyl-D-aspartate Receptors, and
Dopamine–Glutamate Interactions
Serotonin and Brain: Evolution, Neuroplasticity,
Daniel C. Javitt
and Homeostasis
Efrain C. Azmitia Deciphering the Disease Process of Schizophrenia:
The Contribution of Cortical GABA Neurons
Therapeutic Approaches to Promoting Axonal
David A. Lewis and Takanori Hashimoto
Regeneration in the Adult Mammalian Spinal
Cord Alterations of Serotonin Transmission in
Sari S. Hannila, Mustafa M. Siddiq, and Schizophrenia
Marie T. Filbin Anissa Abi-Dargham
332 CONTENTS OF RECENT VOLUMES

Serotonin and Dopamine Interactions in The CD8 T Cell in Multiple Sclerosis: Suppressor
Rodents and Primates: Implications for Psych- Cell or Mediator of Neuropathology?
osis and Antipsychotic Drug Development Aaron J. Johnson, Georgette L. Suidan,
Gerard J. Marek Jeremiah McDole, and Istvan Pirko
Cholinergic Circuits and Signaling in the Patho- Immunopathogenesis of Multiple Sclerosis
physiology of Schizophrenia Smriti M. Agrawal and V. Wee Yong
Joshua A. Berman, David A. Talmage, and
Lorna W. Role Molecular Mimicry in Multiple Sclerosis
Jane E. Libbey, Lori L. McCoy, and
Schizophrenia and the #7 Nicotinic Acetylchol- Robert S. Fujinami
ine Receptor
Laura F. Martin and Robert Freedman Molecular ‘‘Negativity’’ May Underlie Multiple
Sclerosis: Role of the Myelin Basic Protein
Histamine and Schizophrenia Family in the Pathogenesis of MS
Jean-Michel Arrang Abdiwahab A. Musse and George Harauz
Microchimerism and Stem Cell Transplantation
Cannabinoids and Psychosis
in Multiple Sclerosis
Deepak Cyril D’Souza
Behrouz Nikbin, Mandana Mohyeddin Bonab, and
Involvement of Neuropeptide Systems in Schizo- Fatemeh Talebian
phrenia: Human Studies
The Insulin-Like Growth Factor System in
Ricardo Cáceda, Becky Kinkead, and
Multiple Sclerosis
Charles B. Nemeroff
Daniel Chesik, Nadine Wilczak, and
Brain-Derived Neurotrophic Factor in Schizo- Jacques De Keyser
phrenia and Its Relation with Dopamine
Cell-Derived Microparticles and Exosomes in
Olivier Guillin, Caroline Demily, and
Neuroinflammatory Disorders
Florence Thibaut
Lawrence L. Horstman, Wenche Jy, Alireza Minagar,
Schizophrenia Susceptibility Genes: In Search of Carlos J. Bidot, Joaquin J. Jimenez,
a Molecular Logic and Novel Drug Targets for a J. Steven Alexander, and Yeon S. Ahn
Devastating Disorder
Joseph A. Gogos Multiple Sclerosis in Children: Clinical, Diagnostic,
and Therapeutic Aspects
index Kevin Rostásy

Migraine in Multiple Sclerosis

Volume 79 Debra G. Elliott

Multiple Sclerosis as a Painful Disease

The Destructive Alliance: Interactions of Leuko- Meghan Kenner, Uma Menon, and Debra Elliott
cytes, Cerebral Endothelial Cells, and the Immune
Cascade in Pathogenesis of Multiple Sclerosis Multiple Sclerosis and Behavior
Alireza Minagar, April Carpenter, and James B. Pinkston, Anita Kablinger, and
J. Steven Alexander Nadejda Alekseeva

Role of B Cells in Pathogenesis of Multiple Cerebrospinal Fluid Analysis in Multiple Sclerosis

Sclerosis Francisco A. Luque and Stephen L. Jaffe
Behrouz Nikbin, Mandana Mohyeddin Bonab, Multiple Sclerosis in Isfahan, Iran
Farideh Khosravi, and Fatemeh Talebian Mohammad Saadatnia, Masoud Etemadifar, and
The Role of CD4 T Cells in the Pathogenesis of Amir Hadi Maghzi
Multiple Sclerosis Gender Issues in Multiple Sclerosis
Tanuja Chitnis Robert N. Schwendimann and Nadejda Alekseeva
 CONTENTS OF RECENT VOLUMES 333

Differential Diagnosis of Multiple Sclerosis Optic Neuritis and the Neuro-Ophthalmology of

Halim Fadil, Roger E. Kelley, and Multiple Sclerosis
Eduardo Gonzalez-Toledo Paramjit Kaur and Jeffrey L. Bennett
Prognostic Factors in Multiple Sclerosis Neuromyelitis Optica: New Findings on
Roberto Bergamaschi Pathogenesis
Neuroimaging in Multiple Sclerosis Dean M. Wingerchuk
Robert Zivadinov and Jennifer L. Cox index
Detection of Cortical Lesions Is Dependent on
Choice of Slice Thickness in Patients with
Multiple Sclerosis Volume 79
Ondrej Dolezal, Michael G. Dwyer, Dana Horakova,
Eva Havrdova, Alireza Minagar, Epilepsy in the Elderly: Scope of the Problem
Srivats Balachandran, Niels Bergsland, Zdenek Seidl, Ilo E. Leppik
Manuela Vaneckova, David Fritz, Jan Krasensky,
and Robert Zivadinov Animal Models in Gerontology Research
Nancy L. Nadon
The Role of Quantitative Neuroimaging Indices in
the Differentiation of Ischemia from Demyelina- Animal Models of Geriatric Epilepsy
tion: An Analytical Study with Case Presentation Lauren J. Murphree, Lynn M. Rundhaugen, and
Romy Hoque, Christina Ledbetter, Eduardo Gonzalez- Kevin M. Kelly
Toledo, Vivek Misra, Uma Menon, Meghan Kenner, Life and Death of Neurons in the Aging
Alejandro A. Rabinstein, Roger E. Kelley, Cerebral Cortex
Robert Zivadinov, and Alireza Minagar John H. Morrison and Patrick R. Hof

HLA-DRB1*1501, -DQB1*0301, -DQB1*0302, An In Vitro Model of Stroke-Induced Epilepsy:

-DQB1*0602, and -DQB1*0603 Alleles Are Elucidation of the Roles of Glutamate and Cal-
Associated with More Severe Disease Outcome cium in the Induction and Maintenance of
on MRI in Patients with Multiple Sclerosis Stroke-Induced Epileptogenesis
Robert Zivadinov, Laura Uxa, Alessio Bratina, Robert J. DeLorenzo, David A. Sun, Robert E. Blair,
Antonio Bosco, Bhooma Srinivasaraghavan, and Sompong Sambati
Alireza Minagar, Maja Ukmar, Su yen Benedetto, Mechanisms of Action of Antiepileptic Drugs
and Marino Zorzon H. Steve White, Misty D. Smith, and Karen S. Wilcox

Glatiramer Acetate: Mechanisms of Action in Epidemiology and Outcomes of Status Epilepti-

Multiple Sclerosis cus in the Elderly
Tjalf Ziemssen and Wiebke Schrempf Alan R. Towne

Evolving Therapies for Multiple Sclerosis Diagnosing Epilepsy in the Elderly

Elena Korniychuk, John M. Dempster, R. Eugene Ramsay, Flavia M. Macias, and A. James
Eileen O’Connor, J. Steven Alexander, Rowan
Roger E. Kelley, Meghan Kenner, Uma Menon,
Vivek Misra, Romy Hoque, Eduardo C. Gonzalez- Pharmacoepidemiology in Community-Dwelling
Toledo, Robert N. Schwendimann, Stacy Smith, and Elderly Taking Antiepileptic Drugs
Alireza Minagar Dan R. Berlowitz and Mary Jo V. Pugh

Remyelination in Multiple Sclerosis Use of Antiepileptic Medications in Nursing

Divya M. Chari Homes
Judith Garrard, Susan L. Harms, Lynn E. Eberly,
Trigeminal Neuralgia: A Modern-Day Review
and Ilo E. Leppik
Kelly Hunt and Ravish Patwardhan
334 CONTENTS OF RECENT VOLUMES

Differential Diagnosis of Multiple Sclerosis Optic Neuritis and the Neuro-Ophthalmology of

Halim Fadil, Roger E. Kelley, and Eduardo Multiple Sclerosis
Gonzalez-Toledo Paramjit Kaur and Jeffrey L. Bennett
Prognostic Factors in Multiple Sclerosis Neuromyelitis Optica: New Findings on
Roberto Bergamaschi Pathogenesis
Neuroimaging in Multiple Sclerosis Dean M. Wingerchuk
Robert Zivadinov and Jennifer L. Cox index
Detection of Cortical Lesions Is Dependent
on Choice of Slice Thickness in Patients with
Multiple Sclerosis Volume 81
Ondrej Dolezal, Michael G. Dwyer, Dana Horakova,
Eva Havrdova, Alireza Minagar, Epilepsy in the Elderly: Scope of the Problem
Srivats Balachandran, Niels Bergsland, Zdenek Seidl, Ilo E. Leppik
Manuela Vaneckova, David Fritz, Jan Krasensky,
and Robert Zivadinov Animal Models in Gerontology Research
Nancy L. Nadon
TheRole ofQuantitativeNeuroimaging Indices in
the Differentiation of Ischemia from Demyelina- Animal Models of Geriatric Epilepsy
tion: An Analytical Study with Case Presentation Lauren J. Murphree, Lynn M. Rundhaugen,
Romy Hoque, Christina Ledbetter, Eduardo Gonzalez- and Kevin M. Kelly
Toledo, Vivek Misra, Uma Menon, Meghan Kenner, Life and Death of Neurons in the Aging
Alejandro A. Rabinstein, Roger E. Kelley, Cerebral Cortex
Robert Zivadinov, and Alireza Minagar John H. Morrison and Patrick R. Hof
HLA-DRB1*1501, -DQB1*0301,-DQB1*0302,-
An In Vitro Model of Stroke-Induced Epilepsy:
DQB1*0602, and -DQB1*0603 Alleles Are
Elucidation of the Roles of Glutamate and
Associated with More Severe Disease Outcome
Calcium in the Induction and Maintenance of
on MRI in Patients with Multiple Sclerosis
Stroke-Induced Epileptogenesis
Robert Zivadinov, Laura Uxa, Alessio Bratina,
Robert J. DeLorenzo, David A. Sun, Robert E. Blair,
Antonio Bosco, Bhooma Srinivasaraghavan,
and Sompong Sambati
Alireza Minagar, Maja Ukmar, Su yen Benedetto,
and Marino Zorzon Mechanisms of Action of Antiepileptic Drugs
H. Steve White, Misty D. Smith, and Karen S. Wilcox
Glatiramer Acetate: Mechanisms of Action in
Multiple Sclerosis Epidemiology and Outcomes of Status Epilepti-
Tjalf Ziemssen and Wiebke Schrempf cus in the Elderly
Alan R. Towne
Evolving Therapies for Multiple Sclerosis
Elena Korniychuk, John M. Dempster, Diagnosing Epilepsy in the Elderly
Eileen O’Connor, J. Steven Alexander, R. Eugene Ramsay, Flavia M. Macias,
Roger E. Kelley, Meghan Kenner, Uma Menon, and A. James Rowan
Vivek Misra, Romy Hoque, Eduardo C. Gonzalez-
Pharmacoepidemiology in Community-Dwelling
Toledo, Robert N. Schwendimann, Stacy Smith,
Elderly Taking Antiepileptic Drugs
and Alireza Minagar
Dan R. Berlowitz and Mary Jo V. Pugh
Remyelination in Multiple Sclerosis
Use of Antiepileptic Medications in Nursing
Divya M. Chari
Homes
Trigeminal Neuralgia: A Modern-Day Review Judith Garrard, Susan L. Harms, Lynn E. Eberly,
Kelly Hunt and Ravish Patwardhan and Ilo E. Leppik
 CONTENTS OF RECENT VOLUMES 335

Age-Related Changes in Pharmacokinetics: Glutamate Release from Astrocytes in Physio-

Predictability and Assessment Methods logical Conditions and in Neurodegenerative
Emilio Perucca Disorders Characterized by Neuroinflammation
Sabino Vesce, Daniela Rossi, Liliana Brambilla, and
Factors Affecting Antiepileptic Drug Pharmaco-
Andrea Volterra
kinetics in Community-Dwelling Elderly
James C. Cloyd, Susan Marino, The High-Mobility Group Box 1 Cytokine Induces
and Angela K. Birnbaum Transporter-Mediated Release of Glutamate from
Glial Subcellular Particles (Gliosomes) Prepared
Pharmacokinetics of Antiepileptic Drugs in
from In Situ-Matured Astrocytes
Elderly Nursing Home Residents
Giambattista Bonanno, Luca Raiteri, Marco
Angela K. Birnbaum Milanese, Simona Zappettini, Edon Melloni, Marco
The Impact of Epilepsy on Older Veterans Pedrazzi, Mario Passalacqua, Carlo Tacchetti, Cesare
Mary Jo V. Pugh, Dan R. Berlowitz, and Lewis Kazis Usai, and Bianca Sparatore

Risk and Predictability of Drug Interactions in The Role of Astrocytes and Complement System
the Elderly in Neural Plasticity
Milos Pekny, Ulrika Wilhelmsson, Yalda Rahpeymai
René H. Levy and Carol Collins
Bogestål, and Marcela Pekna
Outcomes in Elderly Patients With Newly
New Insights into the Roles of Metalloprotei-
Diagnosed and Treated Epilepsy
nases in Neurodegeneration and Neuroprotec-
Martin J. Brodie and Linda J. Stephen tion
Recruitment and Retention in Clinical Trials of A. J. Turner and N. N. Nalivaeva
the Elderly
Relevance of High-Mobility Group Protein
Flavia M. Macias, R. Eugene Ramsay, and A. James
Box 1 to Neurodegeneration
Rowan
Silvia Fossati and Alberto Chiarugi
Treatment of Convulsive Status Epilepticus
Early Upregulation of Matrix Metalloproteinases
David M. Treiman
Following Reperfusion Triggers Neuroinflam-
Treatment of Nonconvulsive Status Epilepticus matory Mediators in Brain Ischemia in Rat
Matthew C. Walker Diana Amantea, Rossella Russo, Micaela Gliozzi,
Vincenza Fratto, Laura Berliocchi, G. Bagetta,
Antiepileptic Drug Formulation and Treatment
G. Bernardi, and M. Tiziana Corasaniti
in the Elderly: Biopharmaceutical Consider-
ations The (Endo)Cannabinoid System in Multiple
Barry E. Gidal Sclerosis and Amyotrophic Lateral Sclerosis
Diego Centonze, Silvia Rossi, Alessandro Finazzi-
index Agrò, Giorgio Bernardi, and Mauro Maccarrone
Chemokines and Chemokine Receptors: Multi-
Volume 82 purpose Players in Neuroinflammation
Richard M. Ransohoff, LiPing Liu, and Astrid E.
Inflammatory Mediators Leading to Protein Cardona
Misfolding and Uncompetitive/Fast Off-Rate Systemic and Acquired Immune Responses in
Drug Therapy for Neurodegenerative Disorders Alzheimer’s Disease
Stuart A. Lipton, Zezong Gu, and Tomohiro Markus Britschgi and Tony Wyss-Coray
Nakamura
Neuroinflammation in Alzheimer’s Disease and
Innate Immunity and Protective Neuroinflam-
Parkinson’s Disease: Are Microglia Pathogenic in
mation: New Emphasis on the Role of Neuroim-
Either Disorder?
mune Regulatory Proteins
Joseph Rogers, Diego Mastroeni, Brian Leonard,
M. Griffiths, J. W. Neal, and P. Gasque
Jeffrey Joyce, and Andrew Grover
336 CONTENTS OF RECENT VOLUMES

Cytokines and Neuronal Ion Channels in Health Retinal Damage Caused by High Intraocular
and Disease Pressure-Induced Transient Ischemia is Pre-
Barbara Viviani, Fabrizio Gardoni, and Marina vented by Coenzyme Q10 in Rat
Marinovich Carlo Nucci, Rosanna Tartaglione, Angelica Cerulli,
Cyclooxygenase-2, Prostaglandin E2, and Micro- R. Mancino, A. Spanò, Federica Cavaliere, Laura
glial Activation in Prion Diseases Rombol, G. Bagetta, M. Tiziana Corasaniti, and
Luigi A. Morrone
Luisa Minghetti and Maurizio Pocchiari
Evidence Implicating Matrix Metalloproteinases
Glia Proinflammatory Cytokine Upregulation as in the Mechanism Underlying Accumulation of
a Therapeutic Target for Neurodegenerative IL-1" and Neuronal Apoptosis in the Neocortex
Diseases: Function-Based and Target-Based
of HIV/gp120-Exposed Rats
Discovery Approaches Rossella Russo, Elisa Siviglia, Micaela Gliozzi,
Linda J. Van Eldik, Wendy L. Thompson, Diana Amantea, Annamaria Paoletti,
Hantamalala Ralay Ranaivo, Heather A. Behanna,
Laura Berliocchi, G. Bagetta, and M.
and D. Martin Watterson
Tiziana Corasaniti
Oxidative Stress and the Pathogenesis of Neuro-
Neuroprotective Effect of Nitroglycerin in a
degenerative Disorders Rodent Model of Ischemic Stroke: Evaluation
Ashley Reynolds, Chad Laurie, R. Lee Mosley, and of Bcl-2 Expression
Howard E. Gendelman
Rosaria Greco, Diana Amantea, Fabio Blandini,
Differential Modulation of Type 1 and Type 2 Giuseppe Nappi, Giacinto Bagetta, M. Tiziana
Cannabinoid Receptors Along the Neuro- Corasaniti, and Cristina Tassorelli
immune Axis
Sergio Oddi, Paola Spagnuolo, Monica Bari, Antonella index
D’Agostino, and Mauro Maccarrone
Effects of the HIV-1 Viral Protein Tat on Cen- Volume 83
tral Neurotransmission: Role of Group I Meta-
botropic Glutamate Receptors Gender Differences in Pharmacological
Elisa Neri, Veronica Musante, and Anna Pittaluga Response
Gail D. Anderson
Evidence to Implicate Early Modulation of Inter-
leukin-1" Expression in the Neuroprotection Epidemiology and Classification of Epilepsy:
Afforded by 17"-Estradiol in Male Rats Under- Gender Comparisons
gone Transient Middle Cerebral Artery Occlusion John C. McHugh and Norman Delanty
Olga Chiappetta, Micaela Gliozzi, Elisa Siviglia, Hormonal Influences on Seizures:
Diana Amantea, Luigi A. Morrone, Laura Berliocchi, Basic Neurobiology
G. Bagetta, and M. Tiziana Corasaniti Cheryl A. Frye
A Role for Brain Cyclooxygenase-2 and Prosta- Catamenial Epilepsy
glandin-E2 in Migraine: Effects of Nitroglycerin Patricia E. Penovich and Sandra Helmers
Cristina Tassorelli, Rosaria Greco, Marie Therèse
Armentero, Fabio Blandini, Giorgio Sandrini, and Epilepsy in Women: Special Considerations
Giuseppe Nappi for Adolescents
Mary L. Zupanc and Sheryl Haut
The Blockade of K+-ATP Channels has Neuro-
protective Effects in an In Vitro Model of Brain Contraception in Women with Epilepsy:
Ischemia Pharmacokinetic Interactions, Contraceptive
Robert Nisticò, Silvia Piccirilli, L. Sebastianelli, Options, and Management
Giuseppe Nisticò, G. Bernardi, and N. B. Mercuri Caryn Dutton and Nancy Foldvary-Schaefer
 CONTENTS OF RECENT VOLUMES 337

Reproductive Dysfunction in Women with Seizures in Pregnancy: Diagnosis and

Epilepsy: Menstrual Cycle Abnormalities, Management
Fertility, and Polycystic Ovary Robert L. Beach and Peter W. Kaplan
Syndrome
Management of Epilepsy and Pregnancy:
Jürgen Bauer and Déirdre Cooper-Mahkorn
An Obstetrical Perspective
Sexual Dysfunction in Women with Epilepsy: Julian N. Robinson and Jane Cleary-Goldman
Role of Antiepileptic Drugs and Psychotropic
Pregnancy Registries: Strengths, Weaknesses,
Medications
and Bias Interpretation of Pregnancy Registry
Mary A. Gutierrez, Romila Mushtaq, and
Data
Glen Stimmel
Marianne Cunnington and John Messenheimer
Pregnancy in Epilepsy: Issues of Concern
Bone Health in Women With Epilepsy: Clinical
John DeToledo
Features and Potential Mechanisms
Teratogenicity and Antiepileptic Drugs: Alison M. Pack and Thaddeus S. Walczak
Potential Mechanisms Metabolic Effects of AEDs: Impact on Body
Mark S. Yerby Weight, Lipids and Glucose Metabolism
Raj D. Sheth and Georgia Montouris
Antiepileptic Drug Teratogenesis:
What are the Risks for Congenital Psychiatric Comorbidities in Epilepsy
Malformations and Adverse Cognitive W. Curt Lafrance, Jr., Andres M. Kanner, and
Outcomes? Bruce Hermann
Cynthia L. Harden
Issues for Mature Women with Epilepsy
Teratogenicity of Antiepileptic Drugs: Role of Cynthia L. Harden
Pharmacogenomics
Pharmacodynamic and Pharmacokinetic
Raman Sankar and Jason T. Lerner Interactions of Psychotropic Drugs with
Antiepileptic Drugs
Antiepileptic Drug Therapy in Pregnancy I:
Gestation-Induced Effects on AED Andres M. Kanner and Barry E. Gidal
Pharmacokinetics Health Disparities in Epilepsy: How
Page B. Pennell and Collin A. Hovinga Patient-Oriented Outcomes in Women Differ
from Men
Antiepileptic Drug Therapy in Pregnancy II:
Fetal and Neonatal Exposure Frank Gilliam
Collin A. Hovinga and Page B. Pennell index