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Semin Neurol. Author manuscript; available in PMC 2018 February 22.
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Published in final edited form as:

Semin Neurol. 2017 October ; 37(5): 510–537. doi:10.1055/s-0037-1608808.

Neuroimaging in Dementia
Adam M. Staffaroni, PhD1, Fanny M. Elahi, MD, PhD1, Dana McDermott, DO1, Kacey Marton,
MS1, Elissaios Karageorgiou, MD, PhD1,2, Simone Sacco, MD1,3, Matteo Paoletti, MD1,3,
Eduardo Caverzasi, MD1,4, Christopher P. Hess, MD, PhD5, Howard J. Rosen, MD1, and
Michael D. Geschwind, MD, PhD1
1Department of Neurology, Memory and Aging Center, University of California, San Francisco
(UCSF), San Francisco, California
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2Neurological Institute of Athens, Athens, Greece

3Instituteof Radiology, Department of Clinical Surgical Diagnostic and Pediatric Sciences,
University of Pavia, Pavia, Italy
4Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
5Division
of Neuroradiology, Department of Radiology, University of California, San Francisco
(UCSF), California

Abstract
Although the diagnosis of dementia still is primarily based on clinical criteria, neuroimaging is
playing an increasingly important role. This is in large part due to advances in techniques that can
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assist with discriminating between different syndromes. Magnetic resonance imaging remains at
the core of differential diagnosis, with specific patterns of cortical and subcortical changes having
diagnostic significance. Recent developments in molecular PET imaging techniques have opened
the door for not only antemortem but early, even preclinical, diagnosis of underlying pathology.
This is vital, as treatment trials are underway for pharmacological agents with specific molecular
targets, and numerous failed trials suggest that earlier treatment is needed. This article provides an
overview of classic neuroimaging findings as well as new and cutting-edge research techniques
that assist with clinical diagnosis of a range of dementia syndromes, with an emphasis on studies
using pathologically proven cases.

Keywords
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magnetic resonance imaging (MRI); positron emission tomography (PET); diffusion tensor
imaging (DTI); neurodegenerative disease

The diagnosis of dementia is becoming increasingly reliant on a broad range of

neuroimaging techniques, and this is reflected in several updated diagnostic criteria.1,2
Neuroimaging enhances the accuracy of diagnoses for distinct dementia subtypes. The
recent failures of treatment trials for Alzheimer’s disease (AD)3 indicate that earlier

Address for correspondence: Michael D. Geschwind, MD, PhD, Department of Neurology, Memory and Aging Center, University of
California San Francisco (UCSF), Box 1207, San Francisco, CA 94143-1207 ([email protected]).
 Staffaroni et al. Page 2

intervention, and therefore earlier diagnosis, may be critical to treatment success. Early
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diagnosis can be facilitated by neuroimaging techniques that can detect the earliest
pathological and metabolic alterations that occur in neurodegenerative disease.

In this review, we discuss clinically relevant neuroimaging findings in a wide range of

dementia syndromes, as well as cutting-edge techniques that are gaining traction in research.
As we move toward the age of treatments designed for specific molecular targets (e.g., tau
and amyloid), there is a growing need to move beyond simply classifying syndromes based
entirely on clinical phenotypes to predicting underlying pathologies with greater precision
using imaging, genetic, cerebrospinal fluid (CSF), and other objective markers of disease. In
this review, we try to distinguish between imaging findings in pathologically proven versus
clinically based diagnoses, placing particular emphasis on neuroimaging in pathologically
confirmed cases as well as longitudinal neuroimaging studies. Dementia and related
syndromes discussed in this review include AD, the frontotemporal dementia (FTD)
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spectrum, primary progressive aphasias (PPA), vascular dementia (VaD), Lewy body disease
(LBD) and Parkinson’s disease dementia (PDD), rapidly progressing dementias (RPD),
normal pressure hydrocephalus (NPH), and cerebellar disorders. Other dementing
conditions, including neurodegeneration with brain iron accumulation (NBIA) and chronic
traumatic encephalopathy (CTE), are not covered here to allow for a greater depth of
coverage of the more common and established causes of dementia. We conclude with a
review of neuroimaging biomarkers of neurodegenerative diseases that are being developed
in research, with a focus on structural and functional connectivity.

Alzheimer’s Disease
Introduction
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AD is a pathologic entity characterized by the aberrant aggregation of amyloid-β and tau

proteins, which form neuritic plaques and neurofibrillary tangles (NFTs), respectively. These
changes lead to neuronal dysfunction and death, with subsequent atrophy of selectively
vulnerable brain networks and emergent clinical features, including cognitive impairment.4
Depending on the brain regions and networks that are affected, AD can present with a
multitude of clinical syndromes, including, but not limited to, the classic amnestic
syndrome, posterior cortical atrophy (PCA), a frontal/dysexecutive syndrome, and the
logopenic variant of primary progressive aphasia (discussed in the Primary Progressive
Aphasia section). Substantial research efforts aimed at studying biomarkers of AD,
including the large-scale Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the
Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) studies, have shown that
neuroimaging biomarkers improve clinical diagnosis in AD. In fact, current AD diagnostic
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criteria incorporate neuroimaging as a biomarker because it increases the degree of

diagnostic certainty that the clinical presentation reflects underlying AD pathology (i.e.,
probable versus possible AD).2 Despite established criteria, however, AD remains a
diagnostic and therapeutic challenge for several reasons. First, the clinical expression of AD
is variable in its phenotypic (i.e., syndromic) and endophenotypic (e.g., network
vulnerability or genetic) features.5 Furthermore, the presence of AD pathology does not
mean that cognitive deficits are detected, as about one-third of cognitively nonimpaired

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people at around age 75, and half of those around age 85, have in vivo markers [amyloid
positron emission tomography (PET) scan] of underlying AD pathology.6 Additionally, AD
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pathology often co-exists with other pathologies, such as synucleinopathies and vascular
disease, that contribute to cognitive deficits, raising uncertainty about direct causality
between specific underlying pathology and predominant clinical syndrome.7

MRI
Although the earliest site of AD pathology is often phosphotau accumulation in brainstem
nuclei,8,9 the earliest atrophy on magnetic resonance imaging (MRI) is detected in the
cerebrum.10 In the classic amnestic AD syndrome, early atrophy can be appreciated in the
hippocampi and precuneus (Fig. 1).10 Interestingly, however, hippocampal atrophy is best
linked to APOE ε4 polymorphism and the amnestic pattern of late-onset Alzheimer’s
disease (LOAD), but may not be a primary feature of early-onset (EOAD) presentations,
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which have more early posterior cortical involvement.11–13 Many LOAD atrophy patients
also often have prominent posterior involvement,14 irrespective of the syndromic
presentation; this pattern often can assist the clinician in discriminating AD from other
pathologies that can manifest with similar clinical syndromes. For example, corticobasal
syndrome (CBS) is an FTD-spectrum disease that may be associated with AD or
frontotemporal lobar degeneration (FTLD) pathology. Patients with CBS due to underlying
AD pathology have parietal-predominant atrophy, in contrast to the frontal-predominant
atrophy of CBS due to FTLD pathology.15 Thus, identifying posterior-predominant atrophy
(i.e., precuneus and posterior cingulate) on imaging is suggestive of underlying AD
pathology, as it generally is a feature across AD syndromes (Fig. 1). Atrophy in AD is not
always symmetric, such as in logopenic variant primary progressive aphasia (lvPPA)
patients, in whom AD is the underlying pathology, and atrophy is first observed in the left
temporoparietal junction.16
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Identifying the above anatomical features often is aided by viewing structural (T1) brain
images in different planes (Fig. 1). FDA- and CE-approved automated algorithms are now
available in clinical practice for establishing areas of atrophy in a single subject compared
with normal populations, as well as for evaluating progression of atrophy.17 It remains to be
seen how these programs will add to diagnostic accuracy in terms of their sensitivity and
specificity, relationship to clinical outcomes and to underlying pathology, as well as how
different automated techniques relate to each other or to nonautomated volumetric
quantification methods.

When evaluating a patient with cognitive dysfunction for suspected AD or other

neurodegenerative disease, it is important to evaluate for cerebral amyloid angiopathy
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(CAA) using hemosiderin sensitive sequences (see vascular section). It is worth keeping in
mind that, although a majority of patients with AD have some degree of CAA at pathology,
18 not everyone with CAA has AD.19

Other Imaging Modalities in AD

Functional imaging generally complements structural imaging in AD diagnosis. Clinical
practice has focused on 18F-fluorodeoxyglucose [FDG]-PET and single-photon emission

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computed tomography (SPECT), though functional MRI (fMRI) and even

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magnetoencephalography have elucidated unique associations to pathology and cognitive

syndromes.20,21 Several studies suggest that the spatial patterns of hypometabolism in FDG-
PET and hypoperfusion in SPECT overlap with MRI patterns of atrophy, especially in the
inferior parietal cortex, lateral temporal cortex, posterior cingulate, and/or the pre-cuneus.
22–24 For older patients, it is unclear if FDG-PET adds diagnostic value beyond structural

MRI, though it may be more sensitive in younger AD patients at early disease stages.25 In
our experience, if the clinical syndrome fits AD, but atrophy is not present in expected
locations, then FDG-PET or other biomarkers can be helpful for AD diagnosis.

Recent advances in molecular PET (amyloid and tau) are likely to change imaging practices
in AD. Molecular PET can verify the distribution of proteinopathies, such as β-amyloid and
tau due to AD. Amyloid PET allows for the detection of cortical β-amyloid (Fig. 2A),
although the distribution is diffuse across AD variants26 and does not correlate well with
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clinical syndromes.27 Recent work suggests that amyloid positivity in cognitively normal
older adults may predict future decline.28 The recent introduction of tau PET imaging has
shown promise in contributing to diagnostic accuracy on the basis of detecting NFT
pathology and, furthermore, the distribution of tau tracer uptake correlates with pathologic
progression (Fig. 2B).8,29 One tau PET tracer recently received FDA approval (https://
www.reuters.com/article/brief-cerveau-technologies-announces-fda-idUSASA09U4Q).
Despite the clear benefits of molecular PET, current limitations include the need for a
specialized PET center and the high cost.

Vascular Dementia
Background
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Cerebrovascular disease can cause cognitive impairments that range in severity from mild
cognitive impairment to VaD. Vascular cognitive impairment (VCI) is an umbrella term that
captures this spectrum of disease, which can result from clinical strokes or subclinical
vascular brain injury. VCI can be identified by both neuroimaging and neuropathologic30
methods, and includes several subtypes, each with its own neuroimaging findings. The most
prevalent etiology of VCI is related to alterations in small vessels, which affect the blood–
brain barrier and white matter (WM).31 The subtypes covered here include sporadic small
vessel disease (SVD), as well as prototypical examples of sporadic and hereditary protein
accumulation vasculopathies, such as Binswanger’s disease, amyloid angiopathy, and
cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL).
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One of the difficulties associated with studying VCI is the frequent overlap of VCI with
other pathological entities. Population-based clinicopathological prevalence rates of pure
VaD range from ~2% to 24%, and that of mixed AD/VaD from ~4% to 22%.32,33 Concurrent
CVD with neurodegenerative pathology appears to lower the threshold for developing
dementia, with the most frequent co-pathologies being AD and/or LBD.34,35

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Small Vessel Disease and Binswanger’s Disease

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SVD is the most common cause of VCI. From a clinical perspective, VCI due to SVD is
characterized by gradually progressive cognitive impairment, typically in the domains of
processing speed and executive functions,36 as well as motor slowing and changes in
balance.37,38 In addition to small vessel ischemia and hemorrhages, SVD is associated with
blood–brain-barrier compromise,39 a state of chronic cerebral hypoperfusion, and WM
degeneration.40,41

The “classic” neuroimaging biomarkers of SVD include various types of white matter
hyperintensities (WMH)42 and lacunar infarcts (strokes). The WMHs of vascular etiology
can present as multiple punctuate or confluent periventricular lesions, leukoaraiosis, and
subcortical lesions (Fig. 3A). Lacunar infarcts, characterized by cavitating lesions or
lacunes, are typically confined to the WM and subcortical gray matter (GM), and are thought
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to be on a continuum with WMH as biomarkers of SVD. Understanding factors that

determine the location and pattern of WMHs is an area of ongoing research. Importantly, not
all periventricular WMHs are due to SVD. For instance, posterior periventricular WMH may
be associated with AD neuropathology, rather than typical SVD.43,44 Additionally, more
sensitive imaging modalities such as diffusion MRI have shown that in patients with WMH
on FLAIR/T2 images quantifiable diffusion abnormalities can be detected even in regions of
normally appearing white matter (NAWM), suggesting a greater area is affected than
detected by visual assessment alone.45

Novel quantitative biomarkers of SVD include enlarged Virchow–Robin spaces (eVRS) seen
on T2 sequences, associated in normal elderly with increased risk of incident dementia.26
These enlarged fluid-filled spaces line the brain vasculature and have been associated with
WMHs, lacunar strokes, as well as MCI-AD (Fig. 3B).46,47 The centrum semiovale eVRS
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have been associated with cortical superficial siderosis,48 whereas diffusely spread eVRS
throughout WM has been associated with lobar microhemorrhages.49 Basal ganglia eVRS,
much like deep cortical microbleeds (CMBs), are associated with hypertension. It is
hypothesized that eVRS may in part reflect a state of impaired interstitial fluid drainage,
associated with small vessel angiopathies due to protein failure elimination, such as CAA,
discussed below.48

Cortical microinfarcts (CMI) are also emerging as a potential biomarker for SVD (Fig. 3C).
Smaller than lacunar infarcts, several autopsy series have shown that CMIs are not only
prevalent in individuals with diagnoses of VaD, but also in individuals with AD (~40%) as
well as up to ⅓ of elderly persons without dementia.50–52 Initially described on 7T MRI,23
they may also be detectable on high-quality 3T MRI.52 In addition to the combinatorial
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effect of general vascular injury burden on cognitive impairment, CMIs may have a unique
contribution to cognitive deficits.52

Binswanger’s disease is considered a prototypical clinical syndrome of VCI. Brain imaging

shows progressive confluent subcortical and periventricular WM degeneration on
FLAIR/T2, hypoperfusion on SPECT, and hypometabolism on FDG-PET.36,53 Physiologic
neuroimaging techniques, such as dynamic contrast-enhanced MRI (DCE-MRI),54 for
assessing blood–brain barrier integrity in combination with biofluid markers, have shown a

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characteristic unrelenting progressive course of hypoxic injury with inflammatory disruption

of the blood–brain barrier.36,55
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Other Imaging Modalities in SVD

Additional quantitative biomarkers of SVD are being investigated to further characterize
WM disease, blood–brain barrier disruption, and hypoperfusion. These include diffusion
imaging,56 proton magnetic resonance spectroscopy (1H-MRS), arterial spin labeling (ASL)
perfusion,57 and CO2 inhalation vascular reactivity.58 Biomarkers for detection of early
subclinical stages of cerebrovascular disease might provide a window for intervention,
promising to impact not only VaD but also adverse brain aging as well as neurodegenerative
diseases such as AD, for which CVD is a major risk factor.

Cerebral Amyloid Angiopathy

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CAA is caused by amyloid deposits in blood vessel walls and is associated with both aging
and AD pathology. Neuroimaging in CAA is characterized by CMBs and progressive diffuse
WMHs.41 CMBs can be seen as small MRI signal voids (hypointensities) on susceptibility-
weighted imaging (SWI) or T2*-weighted gradient-recalled echo (GRE) (Fig. 3D) caused by
microscopic pathological changes such as perivascular deposits of hemosiderin from
microhemorrhages (Fig. 3E).59 In contrast to other disorders associated with the
development of microhemorrhage, such as hypertension, CMBs in CAA tend to be
peripheral in location, located at the cortical gray–WM interface. Overall, the relationship
between CMBs and cognition appears to be nonlinear, with higher counts of CMBs more
consistently associated with cognitive impairment.60

Hereditary Vasculopathies
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A common hereditary cause of vasculopathy is CADASIL.61,62 It predominantly involves

SVD secondary to mutations in the NOTCH3 gene.48,63 Mean age of onset of cognitive and
motor decline is in the 40s, spanning 30s to 70s, with a high co-prevalence of migraine
headaches. Neuroimaging in CADASIL is notable for extensive WM damage including
demyelination and lacunar infarctions as well as hemorrhages, often with relatively unique
involvement of anterior temporal lobes and insulae (Fig. 3F).64 A 2015 study on mice
carrying NOTCH3 mutations suggests that pericytes are the first cells affected. An increase
in Notch3 aggregation leads to a loss of pericytes, resulting in reduced pericyte coverage of
blood vessels, as well as reduced astrocyte polarization, a loss of astrocytic end-foot
coverage, a loss of endothelial junction proteins, and leakage of proteins through the blood–
brain barrier.65 Thus, this mutation might act through disruption of the blood–brain barrier
and other microvascular dysfunction.65 Another recently identified set of mutations
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identified as a relatively common cause of monogenic central nervous system (CNS)

vascular disease is the type IV collagen (COL41A and COL41B) mutations, which often
cause multi-system disease.66–70 These disorders can present with fetal to adult onset. In
adults, the pattern of vascular disease often resembles SVD, but features that help with
diagnosis include deep intracerebral hemorrhage, periventricular cysts involving subcortical
structures, porencephaly, and intracranial aneurysms (Fig. 3G,H).71–73 In addition to
cerebrovascular disease, mutations in these genes are often associated with retinal and renal
vascular disease.69

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Frontotemporal Dementia Spectrum Disorders

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When discussing FTD-spectrum disorders, it is important to distinguish between clinical

syndromes and pathological entities, as some clinical syndromes can have more than one
pathological substrate, and conversely, some pathological entities might present with more
than one clinical syndrome. The term FTD often refers to three clinical syndromes,
behavioral variant frontotemporal dementia (bvFTD) and two types of PPA, the semantic
and nonfluent variants of PPA. Given the distinct neuroimaging findings in the nonfluent and
semantic variants of PPA, these are discussed in the section on PPA below, together with the
logopenic variant of lvPPA (usually due to underlying AD). There are also two motor FTD
syndromes: progressive supranuclear palsy syndrome (PSPS) and CBS. When referring to
the pathological entities, FTLD refers to a collection of three main pathological entities:
FTLD-tau, FTLD-TDP (TAR DNA-binding protein) and FTLD-FUS (fused in sarcoma);
FTLD-tau subtypes include corticobasal degeneration (CBD), progressive supranuclear
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palsy (PSP), and Pick’s disease (PiD).74 Below we present the general neuroimaging
findings associated with bvFTD (clinical syndrome) as well as different imaging
presentations of bvFTD as a function of its underlying FTLD subtype. We also discuss
neuroimaging in PSPS and CBS.

Behavioral Variant of FTD

bvFTD is a neurodegenerative disease that affects personality, behavior, and cognition.75 It
is the most common FTD syndrome,76 with the majority of patients presenting between ages
45 and 64 years of age.77 Studies suggest that it is the most common or second most
common pre-senile dementia.76,78,79 International consensus criteria for possible bvFTD
require three of the following six symptoms to be prominent in the early stages of the
disease: disinhibition, apathy, loss of empathy, hyperorality or changes in dietary habits or
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preferences, simple or complex repetitive movements or behaviors, and a dysexecutive

cognitive profile.75 Probable bvFTD criteria also requires frontal and/or anterior temporal
atrophy on MRI or CT, or hypoperfusion/hypometabolism on PET or SPECT.75 Brain MRI
often can help distinguish bvFTD from other neurodegenerative and psychiatric syndromes.
80,81 However, MRI should be interpreted in the context of clinical symptoms, as

disproportionate atrophy can be subtle or overlooked (one study reviewing radiology reports
for MRI scans in 40 patients subsequently diagnosed clinically with bvFTD found that the
correct diagnosis was considered radiologically in only 10% of cases, despite the presence
of atrophy considered to be consistent with bvFTD82). Atrophy in bvFTD is generally
observed in frontotemporal structures including the insula, anterior cingulate, anterior
temporal lobes, striatum, amygdala, and thalamus.83–85 Neuroimaging profiles can vary
substantially, however, between patients with bvFTD (Fig. 4).86
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Pathological Substrates of bvFTD and Neuroimaging

The underlying pathological substrate of bvFTD affects the spatial distribution of atrophy
observed on brain MRI. The three common pathological substrates of bvFTD (FTLD-tau,
FTLD-TDP, and FTLD-FUS) are each comprised of several subtypes. Tau exists in two
forms that result from alternate splicing: a 3 amino-acid sequence repeat form (3R) and a 4-
repeat form (4R). The most common tau forms associated with bvFTD are PiD (3R), CBD

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(4R), and PSP (4R). Each form of tau pathology usually is associated with a distinct atrophy
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pattern. For example, PiD has asymmetric frontoinsular atrophy that extends into the
anterior temporal lobes and, when severe, has been described as “knife-edge” due to the
severe thinning of the gyri.87 Patients with bvFTD due to CBD, however, show relative
preservation of the frontoinsular area, greater dorsal atrophy, and relative sparing of
temporal and parietal structures.88 Despite historical clinical lore, our recent data suggest
that bvFTD due to CBD pathology is not consistently associated with asymmetric atrophy.
15,88

Of the four subtypes of TDP-43 pathology, types A and B are most commonly associated
with a bvFTD syndrome.89 Type A is usually found in patients with progranulin (PGRN)
mutations (described below).89 Type B pathology is often associated with FTD motor
neuron disease (FTD-MND), and atrophy tends to affect the frontal lobes symmetrically
with insular and anteromedial temporal lobe involvement.86 Finally, FTLD-FUS (usually
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sporadic) is a very rare pathological cause of bvFTD, often presenting with early onset (20s–
40s) with marked psychiatric features and severe caudate atrophy in addition to
frontotemporal involvement.90–92

Genetic Variants and Imaging

Each genetic variant of bvFTD generally is associated with a neuroimaging phenotype.
bvFTD patients with C9orf72 mutation have a variable age of onset (20s–80s) and often
present with psychiatric features including delusions.93,94 C9orf72 carriers are less likely to
present with language findings than PGRN and MAPT carriers. MRI in C9orf72 usually
shows symmetric frontotemporal, thalamic, parietal, and cerebellar atrophy, with less medial
frontal lobe atrophy than in sporadic bvFTD.93,95 Patients with PGRN mutations usually
manifest symptoms around age 60,96 and have a wide range of clinical phenotypes,
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including bvFTD, nfvPPA, or CBS.97 In contrast to C9orf72 patients, imaging in PGRN

patients typically shows asymmetric frontotemporal atrophy extending into the parietal lobes
with sparing of the cerebellum.95,98 Patients with MAPT mutations usually have earlier
symptom onset, often before age 50, with severe temporal lobe atrophy.99,100 Mutations in
FUS often cause ALS, but may rarely cause bvFTD.101

Other Imaging Modalities in bvFTD

In addition to GM atrophy, bvFTD is also associated with WM abnormalities that have been
quantified using volumetric measurements of WM atrophy102 and changes on diffusion
tensor imaging (DTI) metrics.103,104 One study with 30 bvFTD subjects, 39 AD patients,
and 41 cognitively normal controls used DTI to assess WM integrity (WMI), and found
alterations in all DTI metrics [i.e., fractional anisotropy (FA), mean diffusivity (MD), radial
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diffusivity (RD), and axial diffusivity (AD)] in bvFTD compared with controls and AD
patients, especially in frontal regions of interest (ROIs). The authors suggested that DTI
might add complementary information to volumetric analyses and improve the accuracy of
discriminating bvFTD from AD.105 Furthermore, our own recent data (in revision) suggests
that DTI (FA) and ASL perfusion in bvFTD explains additional variance in function and
cognition above and beyond atrophy; DTI and ASL studies in pathologically proven cases

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are needed. These newer imaging modalities might add to our understanding of the
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substrates for impairment in bvFTD and possibly help diagnostically as well.

Preliminary evidence suggests that ASL perfusion imaging may help to distinguish bvFTD
from other groups with sensitivity and specificity similar to FDG-PET.106 For example,
sensitivity and specificity for ASL to distinguish bvFTD from AD were 83% and 93%,
respectively, compared with 89% and 78% for FDG-PET. Although FDG-PET often can be
useful in helping to differentiate bvFTD from AD, frontotemporal hypometabolism can
occur in frontal variants of AD as well as in primary psychiatric disorders, both of which can
clinically resemble bvFTD.107,108

There have been some recent exciting advances in the development of PET tracers designed
to bind tau paired helical filaments (PHF), allowing one to see in vivo tau distribution. One
such tracer that has been the most studied is 18F-AV1451. Very few studies have been
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conducted in bvFTD at this point. In a few case studies of patients with the MAPT mutation,
in vivo tracer binding occurs in the expected frontotemporal distribution.109–111 A caveat is
that the specificity of some tau tracers has been questioned, as one leading tracer, 18F-
THK5351, has been shown to bind monoamine oxidase B (MAO-B) as well as PHFs.112

Corticobasal Syndrome
Consensus diagnostic criteria define CBS by early asymmetrical cortical symptoms
including limb rigidity, dystonia or myoclonus, oral buccal or limb apraxia, cortical sensory
deficit, and/or alien limb phenomenon.113 CBS can include language and speech
disturbances or begin as a bvFTD syndrome.114 Atrophy in CBS is typically located in
dorsal GM and WM of the posteromedial frontal and perirolandic cortices,88 as well as the
basal ganglia and brainstem.115
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A difficulty in interpreting the historical literature on imaging findings in CBS is that much
was based on cases without pathologically confirmed diagnoses. We now know that CBS
can be caused by different pathological entities, each with its own imaging findings, and
CBD pathology can present with several clinical phenotypes other than CBS, such as
bvFTD, nfvPPA, PSPS, and PCA.116 In our own center’s review of 40 pathologically
confirmed cases of CBS, we found at least four common pathologic substrates for this
syndrome, including CBD (35%), AD (23%), PSP (13%), and FTLD-TDP (13%);15 other
centers have shown as many as 50% of CBS patients to have PSP pathology on autopsy.117

Pathologically confirmed CBD pathology is generally associated with bilateral cortical

atrophy in the dorsolateral pre-frontal cortex, supplementary motor area (SMA), perirolandic
cortex, striatum, and brainstem.15 CBD pathology, however, can manifest as several
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syndromes, each with different neuroimaging signatures that generally adhere to that
syndrome’s atrophy pattern. For example, nfvPPA due to CBD may present with asymmetric
left frontal atrophy. In contrast, CBS due to AD is associated with greater temporoparietal
atrophy compared with CBS due to FTLD-TDP or FTLD-tau (including CBD). Regardless
of the syndrome, CBD pathology usually affects the perirolandic cortex and striatum.15,118

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Progressive Supranuclear Palsy

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Unlike for CBS which has several pathological correlates, the clinical diagnosis of PSPS has
very high correlation with underlying PSP pathology.117 The classic presentation of PSPS,
often referred to as Richardson’s syndrome (RS), presents as an atypical parkinsonism with
a vertical supranuclear gaze palsy or slowing of vertical saccades, as well as prominent
postural instability and falls. PSPS also is often a behavioral disorder; a retrospective review
found that 32% of 62 PSPS patients also met criteria for possible bvFTD at their initial
assessment.119

MRI in PSPS is usually marked by a dilated third ventricle and dorsal midbrain atrophy
along the anteroposterior diameter, as well as atrophy of the thalamus, basal ganglia, and
insular and frontal cortices.120,121 Thinning of the superior cerebellar peduncles also is
characteristic of this condition.122 Longitudinal atrophy in the brainstem is at least modestly
correlated with clinical progression.115,123 Midbrain atrophy in PSPS often causes the
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brainstem to take on a hummingbird-like appearance on sagittal view, referred to as the

“hummingbird” or “penguin” sign (Fig. 5).124 DTI studies have shown that PSPS is
associated with widespread alterations in FA and other diffusivity measures in the major
WM tracts of the brain, especially the superior cerebellar peduncles.125–127

Several methods have been created to capitalize on the anteroposterior midbrain atrophy in
PSPS to enhance differential diagnosis, although all are imperfect. One of the possibly more
promising indices, although still controversial, multiplies the midsagittal pons/midbrain area
ratio by the middle/superior cerebellar peduncle width ratio (“P/M x MCP/SCP ratio”),
measured manually. In one study of 33 PSPS, 108 PD, and 19 multiple system atrophy
(MSA) clinically diagnosed patients, this index showed 100% sensitivity and specificity in
discriminating PSPS from PD and MSA.128 Another study recently extended the use of this
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ratio to discriminate PSPS from vascular parkinsonism.129 This approach is being automated
and has shown the ability to distinguish PSPS from PD with comparable accuracy to
manually measured ratios.130 In contrast, measurement of the cerebral peduncle angle (CPA)
on axial view does not appear to be reliable in separating pathologically confirmed PSPS
cases from CBD, MSA, and LBD.131

Some skepticism remains regarding the utility of tau-PET in clinically diagnosed PSPS.
Thus far, only a few small studies have been conducted, but it appears that 18F-AV-1451
binding occurs primarily in subcortical structures, including the putamen, globus pallidus,
subthalamic nucleus and dentate nucleus, as well as the midbrain, but not the neocortex or
WM.132–134 Although these subcortical regions are affected in PSPS, off-target binding is
seen in overlapping regions in neurologically normal controls.134,135 Postmortem study of
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18F-AV-1451 binding in brain tissues suggests that there may be more accurate tracer

binding in AD pathology than FTLD-tau.136 Larger samples with pathological confirmation

are required to better estimate the utility of this tracer in PSPS due to FTLD-tau.

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Primary Progressive Aphasias

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Introduction
The PPAs are a group of three syndromes that share early primary language impairment as
the key diagnostic feature: semantic variant PPA (svPPA), nonfluent/agrammatic variant
PPA (nfvPPA), and lvPPA. According to the current diagnostic criteria,137 impaired single-
word comprehension and object knowledge are at the crux of the diagnosis of svPPA. In
contrast, nfvPPA is characterized by agrammatic language production or effortful, halting
speech with impairments in comprehension of complex syntax but spared single-word
comprehension and object knowledge. A diagnosis of lvPPA requires impaired single-word
retrieval in spontaneous speech and impaired sentence repetition. lvPPA patients often make
phonological errors but have spared motor speech, single-word comprehension and
grammar. SvPPA and nfvPPA are canonical FTD syndromes typically caused by FTLD
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pathology. Eighty-three percent of svPPA patients in our institution’s brain bank have
underlying TDP-43 type C pathology. In contrast, nfvPPA was found to be predominantly
(88%) associated with a variety of tauopathies, although the majority were FTLD-4R-tau
(CBD or PSP), with a smaller number with PiD, as well as AD and other pathologies such as
TDP type A.138,139 The third PPA, lvPPA, is typically associated with AD pathology.140,141
These syndromes begin in discrete locations in the brain, and thus patterns of atrophy and
hypometabolism on FDG-PET can assist with differential diagnosis, especially early in
disease course.137,142 New research suggests that machine learning algorithms can capitalize
on these distinct atrophy patterns to help distinguish between PPA syndromes143 and
possibly even classify the underlying pathological entity.140 These algorithms are not yet
used in clinical practice.

Neuroimaging Patterns in PPA

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Atrophy in svPPA begins with asymmetric involvement of the anterior and inferior temporal
lobes, typically affecting the left hemisphere first (Fig. 6B).16,144 As the disease progresses,
GM loss extends into the insula, orbitofrontal lobe, anterior cingulate, inferior parietal lobe,
medial temporal lobe, basal ganglia, and corresponding areas in the contralateral
hemisphere.144–146 The majority of patients with svPPA have underlying FTLD-TDP type C
pathology. svPPA, however, can be associated with FTLD-tau (PiD and globular glial
tauopathy), and these cases may have more severe striatal and frontal GM and WM atrophy
than FTLD-TDP type C.140

In nfvPPA, atrophy usually begins and is most significant in the left inferior frontal lobe,
insula, and premotor cortex,16,144 spreading with disease progression to other perisylvian
frontal regions, the temporal lobe, anterior parietal lobe, and subcortical areas such as the
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caudate, amygdala, thalamus, and cerebellum (Fig. 6A).146–148 Pathologically confirmed

studies of PPAs generally have been limited by small sample sizes, but early studies suggest
different atrophy patterns as a function of underlying pathology. A recent study suggested
that nfvPPA patients with underlying CBD (n = 9) and PSP (n = 5) pathology both showed
asymmetric frontal atrophy at baseline, but greater overall atrophy was observed in the
nfvPPA-CBD group, particularly in the insula and putamen.139 Additionally, both patient
groups showed longitudinal atrophy in the left precentral gyrus and SMA, but the group with

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PSP pathology showed a greater amount of volume loss over time, including midbrain
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atrophy, whereas those with CBD showed significant volume loss in the left anterior
prefrontal cortex. nfvPPA-PSP had a higher ratio of WM to GM atrophy at baseline than
nfvPPA-CBD.

Structural imaging in lvPPA is marked by volume loss in the left temporoparietal junction,
including the middle temporal gyrus and angular gyrus, as well default mode network
(DMN) hubs such as the hippocampal formation, posterior cingulate cortex, and precuneus.
140,149 Longitudinally, atrophy in lvPPA encroaches into the anterior and medial temporal

lobe, as well as into homologous regions in the opposite hemisphere.146 Although the
majority of lvPPA cases are due to underlying AD pathology, some cohorts have found a
subset of patients (0–31%) that are amyloid negative (Aβ-) on PET; these patients might
have FTLD-TDP pathology.140,150,151 Atrophy, WM integrity, and FDG-PET
hypometabolism may advance more anteriorly into the anteromedial frontal temporal lobes
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and medial temporal lobes in the Aβ-cohort, consistent with FTLD pathology.150,151

Diffusion Tensor Imaging

Alterations in WM integrity, measured by DTI and tractography, generally appear to
recapitulate the patterns of GM atrophy that help distinguish between PPA syndromes, but
the extent of WM compromise has consistently been found to extend outside the zone of
atrophy,152–154 although the findings may vary as a function of the specific metric analyzed
(i.e., RD versus AD).155 The utility of DTI as a surrogate of disease progression is being
further validated by studies correlating changes in WM integrity with changes in
cognitive156,157 and clinical158 symptoms in PPA.

svPPA patients have DTI changes in many brain regions (generally more left lateralized),
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including the uncinate fasciculus, inferior longitudinal fasciculus, corpus callosum, and
inferior frontal and orbitofrontal WM.153,155,159 nfvPPA patients show aberrant WM
changes in the left frontal lobes, with involvement of subcortical tracts and the uncinate
fasciculus.156,160 In one study, when DTI metrics were combined with cortical thickness,
nfvPPA (n = 13) and svPPA (n = 13) could be distinguished from each other with a
sensitivity of 0.92 and specificity of 0.85.161 lvPPA patients, however, show broad, bilateral
front-temporoparietal WM tract changes153,159 that are similar to those seen in classic AD.
160 Given the small number of subjects in these studies, the results require validation in

larger cohorts.

Dementia with Lewy Bodies and Parkinson’s Disease Dementia

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Parkinsonian syndromes are often associated with cognitive impairment that can progress to
dementia. PDD and dementia with Lewy bodies (DLB) are among the most common
neurodegenerative diseases in older adults.162–164 PDD and DLB share many symptoms, and
many consider these disorders to be along a spectrum, although some have argued that these
disorders affect different anatomical pathways.165–167 Pathologically, DLB and PDD are
characterized by intraneuronal α-synuclein “Lewy body” inclusions in neurons of the cortex,
brainstem, and substantia nigra.162,168 The primary differentiating feature between PDD and
DLB is the timeline of symptom emergence: onset of cognitive symptoms before or within

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the same year as onset of motor symptoms warrants a diagnosis of DLB, and motor
symptoms that precede cognitive decline by at least a year warrant a PDD diagnosis.162,165
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The central feature of DLB is progressive cognitive decline in executive and visuospatial
functions and, usually later in the disease, memory. Other core and associated features
include cognitive fluctuations, visual hallucinations, neuroleptic sensitivity, and rapid eye
movement (REM) sleep behavior disorder.

Typically considered senile dementias, their incidence increases with above age 65. In light
of the increased prevalence of mixed pathologies in elderly, distinguishing DLB from other
conditions is complicated by the prevalence of copathologies, with several pathology studies
suggesting that ~66% to 77% of clinically diagnosed DLB cases have comorbid DLB and
AD pathology (DLB + AD).169–173

Brain MRI of patients with DLB may not be diagnostically informative, as patients often
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have diffuse mild cortical atrophy with no distinct regional pattern. A pathologically
confirmed study of 42 DLB cases found that in cases of DLB pathology with low-to-
intermediate likelihood of comorbid AD and Braak NFT stage ≤IV (n = 20), global atrophy
on MRI was not significantly different than controls, with no identified regional patterns,
and atrophy was minimal compared with both DLB + AD and AD. In 22 patients with
mixed DLB + AD pathology, the spatial distribution of atrophy on MRI generally mapped
onto the same areas atrophied in AD and correlated with Braak NFT stage, suggesting that
AD pathology drives atrophy in these patients.174 These findings are in contrast to those of
clinically-, rather than pathologically-, diagnosed patients. For example, one voxel-based
morphometry (VBM) meta-analysis of 218 DLB clinically diagnosed patients showed
reduced right lateral temporal/insular and left lenticular nucleus/insular GM compared with
219 healthy controls.175 When clinically diagnosed DLB and AD have been compared using
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VBM analysis, no consistent regions of atrophy differentiated the two, with the possible
exception of relatively preserved medial temporal lobe volume in DLB compared with AD.
176–179

Structural MRI findings in PDD have been variable, though a lack of autopsy-confirmed
studies on this topic raises concerns about pathological confounds. A meta-analysis of GM
VBM studies comparing clinically diagnosed patients with PDD to healthy controls showed
greater volume loss in the medial temporal lobe and basal ganglia in PDD patients.180 Given
pathological comorbidities were not ruled out in this study, it is possible that this finding is
reflective of underlying AD rather than α-synuclein pathology. One study based on clinical
diagnosis alone suggests that atrophy in PDD is generally similar to DLB,181 whereas some
found slightly less atrophy in PDD compared with DLB,182,183 which had greater medial
temporal volume loss.183,184 Multiple studies found more atrophy in clinically diagnosed
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PDD than in PD without dementia;185,186 again, none have entirely ruled out pathological
comorbidities with autopsy of all patients.

DTI in parkinsonian syndromes usually shows decreased WM integrity.187 DTI has shown
promise as a way to distinguish AD from DLB, as clinically diagnosed DLB involves
reduced FA in the parieto-occipital WM tracts compared with AD.188–190 Several studies
have observed WM abnormalities in PDD compared with PD and healthy controls as

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measured by FA and MD.191,192 For example, one study of 20 clinical PD patients and 21
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clinical PDD patients showed reduced FA in the corpus callosum and the superior
longitudinal fasciculus in PDD, and this reduction correlated with Mini-Mental State
Examination (MMSE) scores.193

Fluorodopa PET and dopamine transporter (DAT) imaging uses the ligand I-fluoropropyl-
carbomethoxy-3β-4-iodo-phenyltropane (123I-FP-CIT SPECT or “DaTSCAN”) to assess
DAT uptake in the nigrostriatal pathway (Fig. 7).194 The primary utility of DaTSCANs is in
differentiating DLB from other nonparkinsonian neurodegenerative disorders, particularly
when parkinsonian motor symptoms are absent or subtle in a suspected DLB case and
differential diagnosis between DLB and AD is, as a result, especially difficult.195 One small
autopsy-confirmed study of four pure DLB, four DLB with comorbid AD and/or CVD, nine
AD (6 had comorbid CVD), and three other neurodegenerative patients (1 CBD, 1 FTLD,
and 1 unspecified)196 found that reduced nigrostriatal DAT uptake was more accurate than
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clinical diagnosis alone in predicting DLB pathology compared with non-DLB disorders,
with a sensitivity of 88% and specificity of 100%.196 A 2012 meta-analysis that included
three studies using clinically diagnosed DLB, as well as the aforementioned autopsy-
confirmed study, came to similar conclusions, that DaTSCAN was specific and sensitive in
distinguishing DLB from other causes of cognitive impairment: pooled sensitivity was
calculated as 86.5%, and pooled specificity was 93.6%.197 A longitudinal study with 20
clinically diagnosed DLB patients found that DaTSCAN could detect emerging DLB before
patients met full clinical criteria.198 There is some concern about false negatives with
DaTSCAN. In one study of 67 clinically diagnosed DLB patients, seven participants had a
normal DaTSCAN when first evaluated;199 five of these seven with normal baseline
DaTSCANs were retested and had abnormal scans 9–38 months later. This suggests that a
repeat scan may be warranted in cases where DLB is strongly suspected and an initial
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DaTSCAN is normal.199 Importantly, DaTSCANs cannot distinguish DLB from PDD or

PD, as nigrostriatal DAT uptake is reduced in both disorders.195,200

One study of 21 DLB (only 3 pathology-proven) and 21 AD (only 2 pathology-proven)

subjects showed that combining FDG-PET with global Pittsburgh compound B (PiB)
retention and hippocampal volume greatly increases the ability to discriminate these
disorders (area under ROC = 0.98).201 Another FDG-PET study of 25 patients with clinical
AD and 20 with clinical DLB showed that the patients with DLB had greater occipital and
posterior temporoparietal hypometabolism, and that this finding could help separate the two
conditions, albeit with lower sensitivity (64.3%) and specificity (65.2%) than other clinical
information such as informant report of motor coordination or cognitive testing.202 Despite
the promise of techniques such as DaTSCAN, FDG-PET, and PiB PET, they are not yet part
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of routine clinical care in many places.203 Other novel ligands that might help identify loss
of dopaminergic signaling in vivo are being developed.203 Attempts to develop PET ligands
for α-synuclein have not been successful,204 but could be helpful in improving the ability to
diagnose DLB and PDD earlier and to differentiate them from AD or other
neurodegenerative diseases.

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Prion Disease and Other Rapidly Progressive Dementias

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A RPD is defined as a condition that progresses from first symptom onset to dementia
(decline in more than one cognitive domain with functional impairment) in less than 2 years,
but the progression often occurs quicker than this.56 The prototypical causes of RPD are
prion diseases (PrD),205,206 including sporadic (sporadic Jakob–Creutzfeldt disease, sJCD),
accounting for 85% of PrD cases, genetic (gPrDs) (10–15% of PrD cases), and acquired
(variant and iatrogenic JCD, respectively, vJCD and iJCD, as well as kuru) (1% of cases).
207–209 The genetic forms have been historically classified by their clinicopathological

features into three categories: genetic Jakob–Creutzfeldt disease (gJCD), Gerstmann–

Sträussler–Scheinker (GSS), and Fatal Familial Insomnia (FFI). It is worth noting, however,
that PrDs do not always present rapidly. For instance, within the gPrDs, although FFI and
almost all types of fJCD present with a RPD course (fast-progressing gPrD), most GSS
patients exhibit a course longer than 3 years and some patients can live for more than a
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decade (slow-progressing gPrD).210 A definitive diagnosis of PrD currently requires

pathological examination of brain tissue.211 CSF tests can sometimes be helpful, but most
except the new reverse templating quake-induced conversion assay (RT-QuIC) are
nonspecific.212 MRI, however, is fundamental to antemortem diagnosis205 and sometimes
even is useful in differentiating specific etiological and molecular subtypes of sJCD.213
Unfortunately, the majority of MRIs in patients ultimately shown to have sJCD are misread
and the diagnosis is missed in radiology reports.214

The quintessential neuroimaging findings associated with sJCD (as well as some other prion
diseases) are T2/FLAIR and DWI hyperintensities in the cortex (known as cortical
ribboning) and deep GM nuclei, which can be symmetric or asymmetric, with
accompanying restricted diffusion on the apparent diffusion coefficient (ADC) map (Fig. 8).
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215,216 In sJCD, MRI shows greater sensitivity (91–96%) and specificity (92–94%) than

almost any other diagnostic test for differentiating JCD from other RPDs (the RT-QuIC test
applied to CSF and olfactory mucosa brushings might be coming close or even exceeding
specificity of MRI).205,216–219 Generally in sJCD, GM hyperintensities on DWI are more
evident (brighter) than FLAIR hyperintensities, and they are hypointense on ADC,
suggesting restricted diffusion.215 Sometimes, hypointense cortical ribboning is difficult to
see on ADC, but this can be improved with eddy current distortion correction.
Unfortunately, this technique often is only available in research settings.220 The proposed
2017 UCSF Modified JCD MRI criteria for sJCD diagnosis are shown in Table 1, and were
modified from previous criteria.215 DWI hyperintensities generally involve both cortical and
subcortical GM (68% of cases), and less frequently the cortex (24%) or basal ganglia (2–
5%) alone.215,217 When considering subcortical involvement in sJCD, the striatum,
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especially the caudate, seems to be preferentially involved, often with a decreasing

anteroposterior gradient of involvement.221 sJCD can be subclassified into about six
“molecular” subtypes based on the molecular weight of protease-resistant prions (type 1 or
2) and on the genotype at the methionine (M)/valine (V) polymorphic codon 129 (MM, MV
or VV) in the prion protein gene (PRNP). Some of these subtypes appear to have particular
patterns of involvement on MRI, although there is overlap. Knowing the subtype ante

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mortem by MRI (as typing requires brain tissue) can help with prognostication of survival
and expected symptomatology.222,223
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Although visual assessment of DWI is critical diagnostically, quantitative approaches to DTI

appear to identify more completely the pattern of reduced MD in GM. Our cross-sectional
quantitative analyses demonstrated preferential involvement of parietal and temporal lobes,
posterior cingulate, thalamus and deep nuclei, generally with less involvement of frontal and
occipital lobes.224 Interestingly, despite the WM involvement in sJCD not generally being
appreciated by visual assessment of standard sequences, with DTI analysis we found
significant globally reduced WM MD, suggesting possible primary involvement of WM,
rather than changes secondary to neuronal degeneration/loss.225 Given heterogeneous
cortical and subcortical involvement across subjects, however, group-wise analyses may
underestimate areas of actual brain involvement, even when quantitative assessment is
performed, due to the effect of averaging. Currently, single-subject MD quantification
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experiments are under investigation, with promising results.226

Imaging findings in acquired PrDs vary. Dura mater contamination cases appear similar to
sJCD, although cases with codon 129 MM have more thalamic involvement. Cadaveric-
derived pituitary hormone (often growth hormone) cases might show preferential cerebellar
and thalamic involvement compared with most sJCD cases.227,228 Variant JCD (vJCD) often
shows not only cortical involvement but also the “pulvinar sign,” in which the pulvinar is
brighter than the anterior putamen on DWI and T2-weighted images. Sometimes both the
pulvinar and dorsomedial thalamic nuclei are involved, giving the so-called hockey stick
sign.229,230 These thalamic findings, however, can also rarely be found in sJCD,231,232 as
well as in certain infections and metabolic disorders, such as Wernicke’s encephalopathy.
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Not only do neuroimaging findings in gPrDs vary across the major forms (e.g., gJCD, GSS,
and FFI), but also between mutations and even sometimes within families.210 In gJCD, MRI
often resembles sJCD.208,233,234 In FFI, such prototypical MRI findings of sJCD are usually
absent, but can show atrophy.234–236 In GSS, cerebellar or global atrophy can be found,
whereas FLAIR, DWI, and ADC abnormalities are uncommon.215,235

Many other conditions other than JCD can present as RPD (Fig. 9). Some nonprion RPD
conditions present with MRI findings similar to those seen in JCD. For example, Bartonella
encephalopathy, Wilson’s disease, Wernicke’s encephalopathy, mitochondrial diseases,
voltage gated potassium channel (VGKC)-complex antibody-associated dementia,237–241
and extrapontine myelinolysis,242,243 may show reduced diffusion in the cortical and
subcortical GM. Seizures can also result in DWI cortical ribboning and deep GM nuclei
hyperintensities with reduced diffusion;242 unlike in sJCD, these MRI abnormalities resolve
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within a few days of seizure control.

With some exceptions, such as those noted above, most non-JCD RPDs do not show reduced
diffusion in GM. Many present with prominent FLAIR hyperintensities, such as in antibody-
mediated encephalopathies or viral encephali-tides.244,245 Moreover, such signal alterations
often show preferential distribution, such as the patchy medial temporal hyperintensities
observed in limbic encephalopathies or the involvement of posterior regions in posterior

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reversible encephalopathy syndrome (PRES).244,246 Finally, the imaging evaluation of an

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RPD should always incorporate the use of contrast, another helpful tool that can show
enhancement in other rapidly progressing conditions such as vasculitis, CNS lymphoma,
intravascular lymphoma, and antibody-mediated encephalitides.205,247 If JCD is being
considered and the DWI and ADC scans are unclear diagnostically, consider acquiring
b2000 axial and coronal DWI and ADC sequences to better distinguish artifact from true
restricted diffusion.226

Idiopathic Normal Pressure Hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of
dementia characterized by a combination of clinical and radiographic findings. The clinical
presentation of this communicating hydrocephalus includes the triad of cognitive
impairment, gait disturbance, and urinary incontinence248 along with ventriculomegaly on
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neuroimaging, in the context of normal CSF pressure.249 Ventriculomegaly, however, is not

specific to iNPH and therefore requires the clinician to rule out numerous other causes, such
as obstructive hydrocephalus and ventricular enlargement secondary to atrophy
(hydrocephalus ex vacuo). iNPH is important to diagnose, because if it is caught early, it is
one of the few treatable, if not reversible, dementias.250,251 If a patient’s clinical and
neuroimaging features are suggestive of NPH, usually a large-volume (30 or more cc)
lumbar puncture (LP) (known as “tap test”) and/or a 72-hour lumbar CSF drain trial is
performed as a diagnostic test looking for transient symptomatic and objective improvement,
mostly in gait and urinary incontinence, to identify subjects most likely to benefit from shunt
implantation. Response rates often are in the ~60–80% range, but vary considerably between
studies, possibly due to several factors, including the measures used to assess NPH and
outcomes.248,250–253 Because the clinical presentation of iNPH frequently is not specific and
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diagnostic neuroimaging parameters have suboptimal sensitivity and specificity, the

diagnosis of iNPH can be difficult and remains controversial.

One of the greatest challenges in diagnosing iNPH is that no imaging modality has been
shown consistently between studies to have high sensitivity and specificity. Two imaging
diagnostic indices, the Evans’ index (EI) and the callosal angle (CA), often are used as first-
line quantitative indicators of ventriculomegaly in iNPH on cross-sectional images.249 The
EI (defined as the ratio between the widest diameter of the frontal horns and the maximum
inner diameter of the skull measured in the same axial plane) is a commonly used parameter
to quantify ventriculomegaly, although this ratio varies depending on the location and angle
of the slice and is thus problematic.254 International guidelines suggest a threshold of ≥
0.3,249 whereas some authors recommend a more stringent threshold of ≥ 0.33.255 The EI is
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also not specific for iNPH, and is increased in patients with atrophy.256,257 The CA can help
to distinguish between iNPH and hydrocephalus ex vacuo. It is measured on a coronal plane
at the posterior commissure on a slice that is perpendicular to the anterior/posterior
commissure (AC-PC) plane. Patients with iNPH usually have smaller angles, ~50–80°,
compared with those with hydrocephalus ex vacuo (~100–120°),249 such as due to AD and
normal aged subjects.258

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Other structural findings are reported as supportive of iNPH. Focal dilation of cerebral sulci,
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particularly the Sylvian fissures, together with narrowing/effacing of the high convexity and
medial subarachnoid spaces,259 also referred to as “disproportionately enlarged
subarachnoid-space hydrocephalus” (DESH), had a high positive predictive value for
diagnosis of iNPH in a sample of 100 patients (nonpathologically proven) from the Japanese
SINPHONI cohort.259 A more recent study of a similar number of subjects found DESH to
have high positive predictive value but low negative predictive value (~69% of shunt
responders were DESH negative).251

In addition to these structural changes, prominent aqueductal flow voids appreciated on T2-
weighted imaging are often described in iNPH, in which CSF flow is accelerated.260
Increased aqueductal CSF flow was found to be a positive predictor of a good response to
shunting.261
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WM abnormalities are commonly observed onT2-weighted images in iNPH.249

Periventricular hyperintensities (PVH), indicative of transependymal CSF absorption and
altered brain water content, are included in the international diagnostic guidelines, though
deep white matter changes (DWMC) can also be observed.249,262 Although
neuropathological evidence consistently finds WM involvement in iNPH,263 the use of WM
abnormalities for iNPH diagnosis remains controversial, especially given the high
prevalence of ischemic demyelination and infarction in the elderly population. Tullberg et al
found that DWMC and PVH did not help accurately differentiate iNPH (n = 29) from
Binswanger’s disease (n = 17).264 DTI is now being studied to further elucidate the role of
WM disease in NPH,265 and initial results suggest that it may assist with differential
diagnosis.266–269
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Other advanced MRI techniques have been proposed together with DTI to go beyond the
limits of structural imaging to help diagnose iNPH more accurately. New CSF quantification
techniques such as Time-SLIP sequences are being investigated to gain better insight into
CSF flow behavior in NPH.270 The role of functional imaging in NPH is being explored as
well: a recent study found DMN connectivity to correlate with the severity of cognitive
decline in NPH patients.271 At present, however, the ideal imaging methodologies for the
diagnosis of NPH remain to be determined.

Cerebellar Conditions: Multiple System Atrophy, Spinocerebellar Ataxias,

and Huntington’s Disease
Cerebellar neurodegenerative diseases are a heterogeneous group of disorders, the most
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common of which are MSA, the spinocerebellar ataxias (SCAs), and idiopathic cerebellar
ataxias (IDCAs).

Multiple System Atrophy

MSA is a progressive neurodegenerative disease characterized pathologically by widespread
α-synucleinpositive glial cytoplasmic inclusions in the striatonigral and/or
olivopontocerebellar regions. Clinically, MSA presents with a combination of progressive
autonomic failure and motor symptoms. When motor symptoms include parkinsonism that is

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poorly responsive to levodopa, it is called MSA-parkinsonism or (MSA-P). When the

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prominent motor features are cerebellar, the syndrome is called MSA-cerebellar (MSA-C).
272 MSA-C and MSA-P likely represent a phenotypic spectrum rather than two distinct

syndromes. The diagnostic accuracy of MSA is somewhat low and varies greatly (64–88%),
depending on whether the evaluation was performed by a specialist or general neurologist
and whether established criteria are used. When applied correctly, particularly by those with
knowledge of parkinsonian and cerebellar disorders, the specificity of the MSA clinical
criteria to describe the neuropathological findings is quite good (86% to 99%).273,274

Imaging biomarkers have been developed in an attempt to differentiate MSA from other
parkinsonian and/or cerebellar conditions presenting with similar symptoms. MSA-C often
shows the classic “hot cross bun” (HCB) or “cruciform T2” sign, which is characterized by
pontomedullary hyperintensity on axial T2/FLAIR and/or proton-density weighted MRI,
often with accompanying middle cerebellar peduncle and cerebellar hemisphere
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hyperintensity (Fig. 10).275–277 This sign can help differentiate MSA from other
parkinsonian syndromes,276,278,279 but it is neither pathognomonic for MSA-C nor is it
always present. As the HCB sign is likely due to gliosis resulting from degeneration of
pontine and cerebellar neurons and the traversing pontocerebellar fibers,275,280 it is also
found in other diseases causing olivopontocerebellar atrophy,275 including SCA1 (21%),281
SCA2 (64%),281 SCA3, SCA7, SCA13, SCA17,282 dentatorubral pallidoluysian atrophy
(DRPLA),283 and very rarely in vJCD284 and CNS vasculitis.285 Furthermore, recent studies
show that a combination of midbrain, corpus callosum, and cerebellar atrophy occurs more
frequently than the “hot cross bun” (HCB) or putaminal rim sign (see below for MSA-P).286
Several studies have shown that compared with PD and PSP, MSA has significantly greater
striatum, brainstem, and cerebellar atrophy.287–293 One study by Ngai et al suggested that
mild MCP FLAIR hyperintensity can also occur in normal individuals independent of age.
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294 Proton-density weighted imaging may be more sensitive and allow earlier detection of

this sign than standard T2/FLAIR MRI.277

The syndrome of MSA-P does not typically demonstrate the HCB sign. Instead, structural
imaging may show dorsal putaminal atrophy, putaminal GRE/T2 hypointensity compared
with the globus pallidus and red nucleus, and a nonspecific, hypertintense T2 “slit-like”
putaminal rim on 1.5T MRI, also known as the “putaminal rim sign.”295,296 Although this
latter sign can help distinguish MSA-P from MSA-C and PD, on a 3.0T MRI the putaminal
rim sign can be seen in normal 30–60 years olds subjects.286

One study using DTI with tract-based spatial statistics (TBSS), found MSA had increased
MD in the corticospinal tract, middle and inferior cerebellar peduncles, and medial
lemniscus compared with controls.297 Compared with PD, MSA showed widespread
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reduced FA and increased MD, and compared with PSP, MSA showed increased MD in the
anterior thalamic radiations and superior cerebellar peduncles.297 Diffusion, PET, and
SPECT imaging also have identified abnormalities in MSA-P and MSA-C compared with
controls,287,297–305 and in some studies compared with PD287,297,306–308 and PSP.
287,297,301,302

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The Spinocerebellar Ataxias

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The SCAs are an autosomal-dominantly inherited, clinically diverse group of

neurodegenerative disorders featuring progressive cerebellar ataxia, at times with other
accompanying signs and/or symptoms. Though all of the SCAs may present with a
cerebellar phenotype and accompanying cerebellar atrophy, a few have other clinical and
neuroimaging findings. The classic CT or MRI of a SCA patient demonstrates only
cerebellar atrophy. The “pure” cerebellar phenotype is seen in SCA variants 5, 6, 8, 10, 11,
14–16, 22, and 26, whereas types 4, 18, 21, 23, 25, and 27 may demonstrate a more complex
clinical phenotype also without relatively circumscribed cerebellar atrophy.38 For example,
SCA4, SCA18, SCA23, and SCA25 can present with sensory neuropathy, and SCA 10 may
present with epilepsy.309

The remaining SCAs can present with other imaging findings, but are also distinguished by
their clinical presentation. Brainstem atrophy may be seen in SCA1, 2, 3, 7, and 13.309
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Caudate atrophy may be seen in SCA1 and SCA3, with executive cognitive impairment on
neuropsychological testing.310 Variable cognitive deficits can occur in SCA2, SCA12,
SCA17, and SCA19, all of which also demonstrate generalized cerebral atrophy.283,311
Some SCAs may even present with parkinsonism and/or spasticity, which can make it
difficult to distinguish these clinically from MSA, PSP, or hereditary spastic parapareses
(HSPs).312 Though patients with SCA17 usually present with early ataxia or dementia, with
or without epilepsy, many patients later show parkinsonism, dystonia, saccadic slowing,
hyperreflexia, and/or mutism on examination. SCA3 (i.e., Machado–Joseph disease),
probably the most common SCA,283 may be the most variable in its phenotypic
presentation, which can include pure cerebellar ataxia, parkinsonism, spastic paraplegia,
neuropathy, impaired temperature sense, pseudoexophthalmos, faciolingual myokymia,
dystonia, and/or restless legs syndrome,313–315 and can present with atrophy of the frontal
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lobes, temporal lobes, and globus pallidus.316 SCA7 is distinguished by associated

dyschromatopsia and retinal disease (pigmentary macular degeneration).317

Other neurodegenerative, autoimmune, and paraneoplastic conditions that can mimic MSA
or the SCAs clinically should also be considered in patients presenting with progressive
ataxia. IDCAs refer to a group of sporadic disorders of unknown etiology, characterized by
the constellation of cerebellar symptoms occurring in late life. Since its original description,
318 many cases of IDCA eventually have been identified as various forms of MSA, SCAs,

paraneoplastic disorders, Friedreich’s ataxia, fragile-X-associated tremor/ataxia syndrome

(FXTAS), and autosomal recessive cerebellar ataxias.319–321 IDCA associated with
parkinsonism has been clinically distinguished from MSA-C by the latter showing the HCB
sign with high sensitivity (97%) and specificity (100%).322 DRPLA presentations vary
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depending on the age of onset. Early onset cases typically feature ataxia, myoclonus, and
epilepsy, whereas late-life presentations have symptoms identical to Huntington’s disease
(HD).283,323 Characteristic MRI findings in DRPLA, in addition to brainstem and cerebellar
atrophy, are subcortical WM lesions, the latter of which usually are not seen in MSA, HD, or
the SCAs.283 Hypertrophic olivary degeneration is also characteristic of DRPLA.

Friedreich’s ataxia can also mimic SCAs clinically. In late stages of disease, MRI can show
narrowing of the AP diameter of the cervical spinal cord.309 The early stages of FXTAS may

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 Staffaroni et al. Page 21

resemble MSA both clinically and with T2 hyperintensity in the middle cerebellar
peduncles.257,324,325 Finally, autoimmune and paraneoplastic cerebellar disorders, including
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anti-Yo or antiglutamic acid decarboxylase antibody syndromes, may present with evidence
of subacute inflammation and corresponding cerebellar T2/FLAIR hyperintensity and
contrast enhancement, or with chronic cerebellar degeneration on T1-weighted sequences.
326,327

Huntington’s Disease
HD is an autosomal dominant neurodegenerative condition caused by a trinucleotide repeat
expansion of CAG in the huntingtin gene on chromosome 4 that results in progressive motor,
cognitive, and behavioral dysfunction.

The most consistently reported structural neuroimaging finding in HD is striatal atrophy.

Longitudinal large cohort studies with hundreds of subjects, such as PREDICT-HD and
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TRACK-HD, have demonstrated that higher CAG repeat lengths and even premotor HD
(pmHD) are associated with faster rates of striatal atrophy.328–330 Importantly, striatal
atrophy can occur before the onset of motor symptoms.329 In a study from our center of 13
patients with pmHD and 13 age and gender-matched controls, smaller caudate volume
combined with quantitative phase measurements on 7T MRI GRE sequences improved the
prediction of time to disease onset (disease burden score).331 Surface-based morphometry
with 3T MRI in pmHD subjects with executive dysfunction has shown evidence of
anteromedial paraventricular caudate atrophy, supporting prior neuropathological studies,
332,333 and indicating that this imaging measurement may be useful as a very early disease

biomarker. In manifest (motor) stages of HD, structural MRI typically demonstrates global
volume loss throughout the cerebrum, basal ganglia, brainstem, and cerebellum,334 though
the caudate, putamen, nucleus accumbens, and amygdala remain the most atrophic.
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There is increasing evidence that WM volume reduces years before motor symptoms of HD
arise,329,335–338 and loss of WM integrity in the striatum and corpus callosum on voxel-
based MRI and DTI is associated with onset, cognitive decline, motor symptoms, and
apathy.339–343 Interestingly, fMRI studies incorporating blood oxygen level-dependent
contrast and FDG-PET studies have shown a tendency for corticostriatal–thalamic
overactivation/hypermetabolism in early pmHD and corticostriatal underactivation/
hypometabolism in later stages of HD, which suggests that overactivation/hypermetabolism
may precede the latter and represent dysfunction and/or compensatory overactivity.344–350
Additionally, MR spectroscopy has demonstrated that higher levels of myoinositol in the
putamen correlate with motor symptoms in 25 patients with pmHD and 30 patients in the
early stages of HD.351
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Emerging Technologies
An exciting era of neuroimaging biomarkers in dementia has begun, in which advances in
technology are being met with similar advancements in statistical techniques and
computational power. Machine learning algorithms are being utilized to grapple with these
data for the purpose of diagnostic decision making. As noted throughout the text, these
studies of diagnostic accuracy are critically dependent on pathologically confirmed cases.

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 Staffaroni et al. Page 22

Furthermore, longitudinal studies promise to improve the utility of these methods as markers
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of disease progression. As the availability of longitudinal datasets increases, it becomes

possible to define empirically derived ROIs, which may bolster our ability to reliably track
disease progression compared with traditional, anatomically defined ROIs.352,353 At the
same time that sophisticated analytic techniques are being developed, investigation of new
techniques to quantify critical molecular and cellular neuropathological processes continues.
For instance, ongoing efforts are examining the utility of PET ligands sensitive to
inflammation, such as the Translocator Protein-18 kDa (TSPO),354 to supplement the
information provided by amyloid and tau-PET tracers discussed above.

Another promising field in neuroimaging is the study of connectomics, which utilizes data
from fMRI and/or DWI to quantify relationships between brain regions, often using
mathematical models from graph theory, where brain regions are represented as “nodes” and
relationships between them as “edges.”355 Higher order cognitive functions are increasingly
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viewed as emergent properties of discrete large-scale neuronal networks. Furthermore,

pathological processes underlying neurodegenerative diseases are thought to have a
predilection for, and propagate within, intrinsically vulnerable networks. One methodology
for defining and studying these networks is task-free or “resting state” functional
neuroimaging (tf-fMRI), which assumes that regions of the brain that show temporal
covariations in BOLD signal are coupled in their function.356 In addition to its role in
defining the brain’s functional networks, tf-fMRI is being evaluated as a potential early
biomarker of degenerative disease.357,358 The majority of studies thus far have been
conducted in AD, which is known to cause altered network connectivity, particularly within
the DMN. Functional connectivity shows promise for early detection of AD
pathophysiology. For instance, altered DMN connectivity has been observed in cognitively
normal individuals at increased risk of AD, based on positive amyloid scans (florbetapir)
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and in asymptomatic APOE ε4 carriers with negative amyloid scans.357

DWI data provides an alternative view of brain connectivity using structural, rather than
functional relationships. Whereas edges in tf-fMRI data represent the strength of covariation
in blood flow between brain regions, in structural connectivity analyses these edges
represent the density or number of myelinated neuronal axons between regions.359 The
incremental validity of these metrics over traditional DTI is being evaluated. The study of
connectivity in dementia will benefit greatly from endeavors such as the Human
Connectome project, which has set out to better define the functional and structural
connectome in healthy participants using high resolution acquisition protocols and advanced
analytic techniques. Ultimately, the most powerful models of neurodegeneration will
combine multimodal neuroimaging techniques with careful phenotyping, as well as
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molecular and cellular biomarkers of disease with the promise of serving as powerful
markers of therapeutic efficacy in future clinical trials.

Conclusion
Neuroimaging modalities improve the diagnosis of dementia, may be important biomarkers
for clinical trials, and may offer the ability to improve the antemortem prediction of
pathologic entities via several mechanisms. As we gain a greater appreciation for the

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 Staffaroni et al. Page 23

specific atrophy patterns associated with specific pathologies, volumetric imaging can lend a
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role in predicting pathology. Molecular PET imaging is particularly exciting for its potential
to bind specific molecular targets that will help elucidate pathology in vivo. Finally, as we
gain a greater appreciation for the role of vascular dysfunction and WM pathology across the
spectrum of dementing conditions, a variety of imaging techniques are being developed to
better appreciate and track these changes.

Acknowledgments
We would like to thank Caroline Prioleau for her help with figure construction.

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Fig. 1. T1 imaging in amyloid-PET confirmed AD variants

(A) LOAD 75-year-old female (MMSE: 17) with hippocampal atrophy on axial and coronal
planes. Precuneus atrophy can be appreciated on sagittal imaging, along with some mild
frontal atrophy. (B) EOAD 59-year-old female with cognitive impairments in multiple
domains including memory and executive functioning (MMSE: 23; MOCA: 15). Prominent
biparietal atrophy can be observed on sagittal and coronal planes, with relatively preserved
medial temporal lobes on axial reconstruction compared with LOAD. (C) lvPPA female with
lvPPA (MMSE: 28). Atrophy is lateralized to the left, primarily in the left temporoparietal
region as seen on axial and coronal images. The precuneal atrophy observed on the sagittal
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images is typical of AD pathology. (D) PCA patient (MMSE: 18) with significant occipital
and parietal atrophy, shown by arrows on all three planes. *Nonneurologic orientation (right
is right). *Abbreviations: MMSE, mini-mental state examination; MoCA, Montreal
Cognitive Assessment; LOAD, late onset Alzheimer’s disease; EOAD, early onset
Alzheimer’s disease; PCA, posterior cortical atrophy.
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Fig. 2. Molecular positron emission tomography (PET) in Alzheimer’s disease (AD)

(A) Amyloid PET using Pittsburgh compound B. Heat map range (colored bar) of amyloid
tracer uptake defined by distribution volume ratio (DVR). Amyloid PET has been approved
for clinical use, and AD diagnosis is based on cortical amyloid ligand uptake. Amyloid
ligands tend to have nonspecific uptake in the white matter, and thus the clinician should
focus on the poor distinction of the cortical–subcortical junction as pathology enters the
cortex. (B) Tau PET using AV1451 tracer. This image is provided by courtesy of Dr. Gil
Rabinovici and Viktoriya Bourakova.
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Fig. 3. Neuroimaging in vascular dementia

(A) Subcortical and periventricular white matter hyperintensities (WMH) in sporadic small
vessel disease (SVD) on T2/FLAIR (fluid-attenuated inversion recovery). (B) Enlarged
Virchow–Robin spaces (eVRS) on T2 sequence. (C) Cortical microinfarct shown as a
hypointense T1 lesion. (D) Cortical microbleeds on T2* SWI sequence. (E) Superficial
siderosis on T2* susceptibility-weighted imaging (SWI). (F) Anterior temporal lobe WMH
in CADASIL on T2/FLAIR. (G,H) Axial MRI in a 46-year-old woman with COL4A1
mutation and medically refractory seizures, long-standing cognitive decline and right
hemiparesis since early childhood. Axial T2 FLAIR (G) image shows extensive white matter
signal abnormality (dotted arrow), with white matter cysts (arrow), and porencephaly
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(arrowheads). Axial susceptibility-sensitive image at the same level (H) reveals multiple
remote hemorrhages of varying size throughout the brain (arrows as examples). Part (c) used
with permission from Hilal S, Sikking E, Shaik MA, et al. Cortical cerebral microinfarcts on
3T MRI: a novel marker of cerebrovascular disease. Neurology 2016;87(15):1583–1590.
https://doi.org/10.1212/WNL.0000000000003110.
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Fig. 4. Neuroimaging in pathologically confirmed frontotemporal dementia (FTD) patients

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T1 MRI images in genetic and pathological forms of FTD, highlighting pathological

propensities toward symmetry and regional predilections. Figure used with permission from:
Gordon E, Rohrer JD, Fox NC. Advances in neuroimaging in frontotemporal dementia. J
Neurochem 2016;138:193–210. https://doi.org/10.1111/jnc.13656.
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Fig. 5. Neuroimaging in progressive supranuclear palsy syndrome (PSPS)

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(A,B) Sagittal and (C) coronal T1-weighted images from a 61-year-old man with PSPS
(MMSE 27) and autopsy-proven FTLD-PSP pathology. (A) Reduced midbrain area (arrow)
compared with the pons. Thinned superior cerebellar peduncles on coronal section (B;
arrows) are observed compared with the middle cerebral peduncles (C; arrows). Adapted
with permission from Vitali P, Migliaccio R, Agosta F, Rosen H, Geschwind M.
Neuroimaging in dementia. Semin Neurol 2008;28(4):467–483.
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Fig. 6. Coronal T1-weighted MRI in patients with primary progressive aphasias (PPA)
(A) nfvPPA in a 66-year-old woman, MMSE: 28. Left predominant atrophy of the
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operculum is evident (arrow). (B) svPPA in a 66-year-old man with MMSE: 26. Atrophy is
most prominent in the left perisylvian region, including the medial temporal lobes (arrow).
Adapted with permission from Vitali P, Migliaccio R, Agosta F, Rosen H, Geschwind M.
Neuroimaging in dementia. Semin Neurol 2008;28(4):467–483.
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Fig. 7.
DaTSCAN (FP-CIT) in a healthy control (A) and patients with Parkinson’s disease (B),
Alzheimer’s disease (C), and dementia with Lewy bodies (D). Used with permission from
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Walker Z, Costa DC, Walker RW H, et al. Differentiation of dementia with Lewy bodies
from Alzheimer’s disease using a dopaminergic presynaptic ligand. J Neurol Neurosurg
Psychiatry 2002;73(2):134–140.
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Fig. 8. Magnetic resonance imaging(MRI) findings in pathologically proven Jakob–Creutzfeldt

disease (JCD)
Note that in sporadic JCD the abnormalities are usually more evident on diffusion-weighted
imaging (DWI) (C,E,G) than on fluid-attenuated inversion recovery (FLAIR) images
(D,F,H). Orientation is radiologic, with right side of image being left side of the brain. (A,B)
A 21-year-old woman with probable variant JCD. MRI shows the “double hockey stick
sign”: bilateral thalamic hyperintensity in the mesial pars (mainly dorsomedian nucleus) and
posterior pars (pulvinar) of the thalamus. Also note the “pulvinar sign,” with the right
posterior thalamus (pulvinar) being more hyperintense than the anterior putamen on the
FLAIR image (B). (C,D) A 52-year-old woman with MRI showing strong hyperintensity in
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bilateral striatum (solid arrows, both caudate and putamen) and slight hyperintensity in
mesial and posterior thalamus (dotted arrow). (E,F) A 68-year-old man with MRI showing
hyperintensity in bilateral striatum (note anteroposterior gradient in the putamen, which is
commonly seen in JCD), thalamus, right insula (dotted arrow), anterior and posterior
cingulate gyrus (arrow, L > R), and left temporal-parietal-occipital junction (arrow). (G,H)
A 76-year-old woman with MRI showing diffuse hyperintense signal mainly in bilateral
parietal and occipital cortex, right posterior insula (dashed arrow), and left inferior frontal
cortex (arrow), but no significant subcortical abnormalities. Reprinted with permission from
Vitali P, Migliaccio R, Agosta F, Rosen H, Geschwind M. Neuroimaging in dementia. Semin
Neurol 2008;28(4):467–483.
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Fig. 9. Nonprion rapidly progressive dementia and ataxia syndromes

Note that in these cases, the abnormalities are seen better on the FLAIR (A,C,E) that the
DWI (B,C,F) images. Orientation is radiologic, with right side of image being the left side
of the brain. (A,B) A 66-year-old man with intravascular lymphoma. (A) FLAIR multifocal
abnormalities involving cerebral and cerebellar gray and white matter in a vascular
distribution. These lesions, also involving the right hippocampus, showed patchy
enhancement after contrast administration (not shown). (B) DWI shows a right
periventricular focal region with diffusion restriction; DWI hyperintensity is common in
lymphomas. (C,D) A 65-year-old woman with anti-Yo paraneoplastic cerebellitis. Magnetic
resonance imaging (MRI) shows mild diffuse hyperintensity of the cerebellar, compared
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with the cerebral, cortex with slight atrophy of the lateral folia. Note (C) the strong
hyperintense FLAIR signal in superior, medial cerebellum (arrows), and (D) no major
hyperintensity in the axial DWI scan. (E,F) A 60-year-old woman with paraneoplastic
limbic encephalitis and FLAIR MRI showing hyperintensity of bilateral insula, medial
(arrows) and inferior temporal cortex, hippocampus, amygdala (E) on FLAIR and only
subtle hyperintensity (F) on DWI. FLAIR, fluid-attenuated inversion recovery; DWI,
diffusion-weighted imaging; MRI, magnetic resonance imaging. Reprinted with permission
from Vitali P, Migliaccio R, Agosta F, Rosen H, Geschwind M. Neuroimaging in dementia.
Semin Neurol 2008;28(4):467–483.
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Fig. 10.
T2-weighted axial MRI of the pontine-middle cerebellar peduncle (MCP) junction in a
patient with MSA-C. Black arrows point to MCP hyperintensity. White arrows point to the
hot cross bun sign in the pons. Bilateral cerebellar hemisphere atrophy is also present.
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Table 1

UCSF 2017 Proposal of MRI Criteria for JCD Diagnosis

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Diagnosis UCSF 2017 Modified JCD MRI criteriaa

MRI definitely JCD DWIb > FLAIR cortical ribboningc hyperintensity in:

1. Classic pathognomonic: cingulate,d striatum, and > 1 neocortical gyrus (often precuneus, angular, superior
parietal, superior frontal, middle frontal, or lateral temporal gyrus)

a. Supportive for subcorticale involvement:

i. Striatum with decreasing anterior–posterior gradient

ii. Corresponding ADC hypointensity

b. Supportive for cortical involvement:

i. Asymmetric involvement of midline neocortex or cingulated

ii. Sparing of precentral gyrusf

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iii. Corresponding ADC cortical ribboning hypointensity

2. Cortex only (> 3 gyri); see supportive for cortex (above)

MRI probably JCD 1. Unilateral striatum or cortex (≤ 3 gyri); see supportive for subcortical and cortex (above)

2. Bilateral striatum (see supportive for subcortical) or posteromedial thalamus; see supportive for subcortical
(above)

3. DWI > FLAIR hyperintensities only in limbic areas, with corresponding ADC hypointensityg

MRI probably not JCD 1. Only FLAIR/DWI abnormalities only in limbic areas, where hyperintensity can be normal (e.g., insula,
anterior cingulate, and hippocampi), and ADC map does not show corresponding restricted diffusion
(hypointensity)

2. DWI hyperintensities due to artifact (signal distortion); see other MRI issues (below)

3. FLAIR > DWI hyperintensitiesh; see other MRI issues (below)

MRI definitely not JCD 1. Normal

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2. Abnormalities not consistent with JCD

Other MRI issues In prolonged courses of sJCD (~ >1 year), brain MRI might show significant atrophy with loss of DWI
hyperintensity, particularly in areas previously with restricted diffusion.

To help distinguish abnormality from artifact, obtain b2000 diffusion sequences in multiple directions (e.g., axial
and coronal).

Abbreviations: ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; JCD, Jakob–
Creutzfeldt disease; MRI, magnetic resonance imaging.
a
Modified from Vitali et al 2011.215
b
Recommended minimum standard diffusion sequence parameters to best identify cortical ribboning: axial and coronal DWI/ADC b = 1000 second
cm2 or b = 2000 second cm2, depending on scanner field strength and capabilities to achieve satisfactory image quality. At 3T, b = 2000 may be
preferred due to higher contrast to background for abnormal gray matter diffusion.
c
Involvement of cortical gray matter with sparing of underlying or adjacent white matter.
d
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Mid and posterior cingulate preferred over anterior due to anterior air-brain artifact especially on axial acquisition (anterior acceptable if coronal
acquisition). Can be symmetric, but if so prefer ADC hypointensity correlate.
e
Subcortical = deep nuclei, in decreasing order of frequency caudate, putamen, thalamus (posteriomedial or diffuse), globus pallidus (rare). ADC
often shows corresponding and earlier involvement than DWI.
f
If precentral gyrus is preferentially involved consider nonprion diagnoses (e.g., seizures and Wernicke’s).

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g
DWI > FLAIR with reduced ADC in limbic or other cortical regions also can occur in HSV encephalitis360,361 and seizures362,363 depending
on clinical picture, these should be ruled out.
h
Consider T2-shine through.364
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