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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
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
AD
Threshold of dementia
Cognitive tests:
no specification for the memory profile
CT or MRI:
proposed for excluding vascular lesions, tumor
CSF:
proposed for excluding meningitis etc
FDG-PET
not mentioned and PIB not known
To be earlier
What is Alzheimer s disease?
Preclinical states First symptoms
35 yrs
Biomarkers
Dementia
AD?
AD?
to be earlier with a higher specificity?
AD?
Very poor free recall Decreased total recall (free+cued) because an insufficient effect of retrieval facilitation with cueing
Temporal horn
Height of the hippocampus
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)
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)
67 67
66 65
62 49
56 31
47 27
40 15
28 3
CSF
MRI
exclusion MTL atrophy
PET-FDG
not specified PT hypo metabolism
PETligand
not known PiB retention
>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
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
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
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
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
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
35 yrs
Specific memory disorders
Dementia
AD Progression
Abnormal
CSF A42 Amyloid imaging FDG-PET MRI hippocampal volume CSF Tau Cognitive performance Function (ADL)
CSF A42 Amyloid imaging
CSF Tau
Normal
Presymptomatic
Prodromal
Dementia
Time
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