The new criteria for Alzheimer s disease
ADI - London, March 2012
Pr Bruno Dubois Head of the Dementia Research Center (IMMA) Director of INSERM Research Unit (ICM) Salptrire Hospital Paris 6 University
DISCLOSURE
1)
Reimbursed travels for speaking engagements, congress participation or educational activities: Eisai, Janssen-Cilag, Novartis Consultancy: Affiris, BMS, Pfizer, Roche Funding for my Institution: Novartis, Roche
2)
3)
1984
The NINCDS-ADRDA criteria
The rules
1) The diagnosis of AD is clinico-pathological: it cannot be certified clinically and needs a post-mortem confirmation to be ascertained 2) The diagnosis of AD can only be probable 3) The diagnosis of AD can only be made when the disease is advanced and reaches the threshold of dementia
MCI
dementia probable/possible AD
CLINICAL POSTMORTEM
neuropathology
1984
The NINCDS-ADRDA Criteria : a 2-Step Process
Dementia of the Alzheimer type
AD
Threshold of dementia
McKhann et al, 1984
Cognitive tests:
no specification for the memory profile
CT or MRI:
proposed for excluding vascular lesions, tumor
No reference to biomarkers in the NINCDS ADRDA criteria (1984)
CSF:
proposed for excluding meningitis etc
FDG-PET
not mentioned and PIB not known
Main limitations of the NINCDS-ADRDA diagnostic criteria
A low accuracy (60 to 80%) because they do not take into account the specific features of the disease Late in the course of the disease only when the dementia threshold is reached !
Two requirements: 1) to be earlier 2) to be more specific
1) To be earlier: potential benefits
Obtain appropriate treatment earlier
Stop searching for other causes
Help the family to understand and accept Financial and legal plans while competent
Enable the patient and family to make lifestyle choices
Induce better adherence and management of other medical conditions Take appropriate steps to prevent injury (driving, weapons) Get greater access to help within the healthcare system and within communities Participate in clinical trials with disease modifier treatments
from Cummings, 2011
To be earlier
What is Alzheimer s disease?
Preclinical states First symptoms
35 yrs
Current point of diagnosis
Biomarkers
Specific memory disorders
Dementia
AD?
AD?
to be earlier with a higher specificity?
AD?
1) Specific memory tests
Amnestic syndrome of the hippocampal type
Dubois and Albert, Lancet Neurology, 2004
Very poor free recall Decreased total recall (free+cued) because an insufficient effect of retrieval facilitation with cueing
FCSRT (cued recall measures) is the best predictor of AD pathology
memory measures
FCSRT Total Recall Logical Memory Delayed Recall CERAD verbal Delayed recall
CSF (+) n = 74 CSF () n = 111 effect size (d)
13.4 8.12 4.22
15.4 13.59 5.63
0.97 0.74 0.71
AD: can the exam predict the pathology?
Wagner M et al, Neurology 2012
2) A specific profile of MTL atrophy on MRI
Atrophy in Alzheimers disease Prodromal AD 15% Mild dementia 25% Moderate dementia 40% Choroid fissure
Temporal horn
Height of the hippocampus
Qualitative MTL Rating Scale Scheltens, JNNP 1992
3) PET imaging
PET-FDG. Pooled sensitivities and specificities (9 studies) of 86% for temporo-parietal hypometabolism (Patwardhan, 2004)
PET-PiB. Increased radioligand retention in AD compared to control subjects (Klunk, 2004)
A specific pattern in Molecular Neuroimagery
4) specific pattern of CSF changes (low A beta; high tau and P-tau levels) even at an eary stage
1.0 0.8 0.6 0.4 Normal CSF 0.2 0 0 10 20 30 40 50 60 Pathological CSF
(low A beta, high tau/p-tau)
No progression to AD
Time (months)
Normal CSF Pathological CSF
67 67
66 65
62 49
56 31
47 27
40 15
28 3
(Hansson et al. LN, 2006)
2) being more specific even at the prodromal stage of AD
memory
NINCDS ADRDA New criteria Specificity for Prodromal AD
CSF
MRI
exclusion MTL atrophy
PET-FDG
not specified PT hypo metabolism
PETligand
not known PiB retention
not specified exclusion amnestic H type Abeta T- P tau
>90%
Sarazin 2007
>90%
Hanson 2006
>85%
Colliot 2008
>80%
Mosconi 2004
>95%
Rowe 2007
Sarazin et al. Neurology. 2007;69:1859-2016. Hansson et al. Lancet Neurol. 2006;5:228234. Colliot et al. Psychiatr Sci Hum Neurosci. 2008;6:68-75. Mosconi et al. Neurology. 2004;63:2332-2340. Rowe et al. Alzheimers Dement. 2007;3.
International Working Group on the New Criteria for the Diagnosis of Alzheimer Disease
B Dubois, H Feldman, C Jacova, J Cummings, S DeKosky, P Barberger, G Frisoni, N Fox, D Galasko, S Gauthier, H Hampel, G Jicha, K Meguro, J OBrien, F Pasquier, P Robert, M Rossor, S Salloway, M Sarazin, L de Souza, Y Stern, P Visser and P Scheltens
Research criteria for the diagnosis of Alzheimer s disease: revising the NINCDS-ADRDA criteria
Dubois et al., Lancet Neurol., 2007
1 major clinical criterion
Amnestic syndrome of the hippocampal type (that can be
isolated or associated to other cognitive / behavioral changes)
+ 1 or more biomarker present
Structural: atrophy of medial temporal lobe (MRI) Biological: changes in biomarkers (CSF) Metabolic neuroimaging: regional hypometabolism on PET Molecular neuroimaging: amyloid ligand retention on PET
Applicability of the New Criteria
In specific conditions clinical: young onset AD or complex cases research: resarch projects; well phenotyped cohorts; clinical trials recommended diagnostic procedure clinical examination and specific memory test (FCSRT) evidence of pathological biomarker (PET amyloid ligand or CSF Abeta and tau levels)
However, they might be used in the future in most of the cases clinical examination and memory tests (FCSRT) MRI with coronal sections
New research criteria for the diagnosis of Alzheimer s disease applied in a memory clinic population
AD versus no AD vs other or no dementia (n=145) dementia (n=223)
Memory Memory + MTA Memory + MTA and CSF 86% 99% 100% 68% 86% 92%
Bouwman et al., Neurology 2011
Accuracy of the new criteria for AD
Mrs. P., 62 year old woman
amnestic syndrome of the hippocampal type ; CDR 0,5
CSF : low A42, high P-Tau; abnormal ratios
Diagnosis: AD prodromal stage
volumetric MRI: volume loss of hippocampi
FDG-PET: hypometabolism on temporal regions
Research study Clinical trial
PiB PET : significant PIB retention in cortical areas
From a clinico-pathological entity
The rules
1) The diagnosis of AD cannot be certified clinically and needs a postmortem confirmation to be ascertained 2) The diagnosis of AD can only be probable 3) The diagnosis of AD can only be made when the disease is advanced and reaches the threshold of dementia
MCI
dementia probable/possible AD
CLINICAL POSTMORTEM
neuropathology
2010
to a clinico-biological entity
The new rules
As biomarkers can be considered as surogate markers of the histopathological changes, the clinical diagnosis can be established in vivo and no more reference to dementia is needed
Alzheimers disease
CLINICAL
typical / atypical
BIOLOGY
Biomarkers
Revising the definition of Alzheimers disease: a new lexicon
AD as a clinical entity that encompasses both predementia and dementia phases. Its diagnosis can be established in vivo based on a dual clinico-biological entity.
MCI is now a label applied when patients do not fulfill the criteria for the clinico-biological phenotype of prodromal AD (memory symptoms not characteristic or biomarker negative).
Paul Aisen (CTAD- 2011): AD is a gradually progressive disorder; MCI and AD dementia are artificial and fuzzy constructs
Dubois et al, Lancet Neurology, 2010
2011
NIA/AD diagnostic Criteria
3 stages AD dementia stage MCI stage preclinical stage 2 types of MCI criteria : for clinical setting for research purposes that are based on the use of biomarkers:
Cognition MCI MCI Likelihood of AD High likelihood Intermediate likelihood Biomarker Evidence (+) amyloid- biomarker AND (+) neuronal injury biomarker* (+) amyloid- biomarker OR (+) neuronal injury biomarker*
MCI MCI
Uninformative situation Unlikely due to AD
Biomarkers fall in ambiguous ranges, conflict, have not be obtained Demonstrated absence of AD-type molecular marker and possible presence of marker suggestive of non-AD disorder
A future challenge: the preclinical states of AD
Two states, before the first cognitive changes, can be isolated in vivo: Asymptomatic at risk for AD (ASR-AD): - with evidence of amyloidosis (brain or CSF): - they will or will not develop AD Presymptomatic AD (PS-AD): - with autosomal dominant monogenic AD mutation: - they will develop AD
>20 yrs
Presence of biomarkers
35 yrs
Specific memory disorders
Dementia
Dubois et al, Lancet Neurology, 2010
AD Progression
Abnormal
CSF A42 Amyloid imaging FDG-PET MRI hippocampal volume CSF Tau Cognitive performance Function (ADL)
CSF A42 Amyloid imaging
FDG-PET MRI hippocampal volume
Cognitive performance Function (ADL)
CSF Tau
Normal
Presymptomatic
Prodromal
Dementia
Time
modified from Aisen PS Alzheimers Dement. 2010
The breakthroughs of the New Criteria
1. 2. 3. 4. 5. 6. establish the clinical-biological definition of the disease highlight and define the amnestic syndrome of hippocampal type highlight the added value of biomarkers for the diagnosis of AD isolate and define the prodromal stage of the disease consider AD as encompassing predementia and dementia stages no more link the diagnosis of AD to a dementia syndrome and restrict MCI to patients that do not fullfil prodromal AD criteria 7. disambiguate the term of AD by limiting it to the clinical phase 8. define subjects asymptomatic at risk for AD (because their risk to clinical conversion is not known) 9. define monogenic mutation carieers as presymptomatic because they will develop the disease 10. define and characterize atypical subtypes
Regulatory perspectives and drug development
qualification process by EMA of CSF biomarkers in prodromal AD
release for consultation (February 2011)
adoption by CHMP (April 2011)
qualification process by EMA of low hippocampal volume in prodromal AD
release for consultation (September 2011)
Ongoing studies based on the New criteria:
BMS ( secretase inhibitor): FCSRT- CSF Affiris (immunotherapy): FCRST- MRI Roche (immunotherapy): FCSRT- CSF Lilly (BACE inhibitor): FCRST- CSF- PET amyloidligand Nutricia (Souvenaid), Sanofi
Conclusion
Evolving criteria (IWG Criteria and the subsequent NIA/AA Criteria) They propose a common conceptual framework:
the entire course of AD from the asymptomatic onset to the severe/ dementia form is captured biomarkers are increasingly important in AD research natural history and clinical trials and diagnosis in specific cases
Application of criteria and biomarkers in clinical practice is evolving rapidly
