1. Changing the criteria for Alzheimer’s disease Alzheimer Europe - Vienna, October 2012
Pr Bruno Dubois
Head of the Dementia Research Center (IMMA)
Director of INSERM Research Unit (ICM)
Salpêtrière Hospital – Paris 6 University 1

2. Consultancy: Affiris, BMS, Eli Lilly, Pfizer, Roche
DISCLOSURE
Reimbursed travels for speaking engagements, congress participation or educational activities: Eisai, Janssen-Cilag, Novartis
Consultancy: Affiris, BMS, Eli Lilly, Pfizer, Roche
Funding for my Institution: Novartis, Roche 2

3. The NINCDS-ADRDA criteria
1984
The NINCDS-ADRDA criteria
The rules
The diagnosis of AD is clinico-pathological: it cannot be certified clinically and needs a post-mortem confirmation to be ascertained
The diagnosis of AD can only be ‘probable’
The diagnosis of AD can only be made when the disease is advanced and reaches the threshold of dementia
neuropathology
CLINICAL
POST-MORTEM
MCI
dementia
probable/possible AD [

4. The current NINCDS-ADRDA diagnostic criteria have several limitations
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

6. 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
Participate in clinical trials with disease modifier treatments
from Cummings, 2011

7. Current point of diagnosis Specific memory disorders
To be earlier
What is Alzheimer’s disease?
Current point of diagnosis
Preclinical states
First symptoms
3–5 yrs
Biomarkers
Specific memory disorders
Dementia
AD?
AD?
AD?

8. Low free recall Subcortical dementia MCI Drugs Sleep disorders
Depression AD
FTD
Normal aging
Confusion
Vascular disorders
Low free recall

9. AD is a progressive amnestic disease
In more than 85% of the cases, AD starts as a progressive amnesic disease in relation with an early involvement of the hippocampus

10. The Different Stages of LT Memory
Dubois and Albert, Lancet Neurology, 2004
Stimulus
Stimulus
Registration
Storage
Retrieval
Attention (depression)
Temporal lobe (AD)
Frontal lobe (aging)
Control of encoding with cueing 1
Facilitate the retrieval with cueing 2

11. FCSRT (cued recall measures) is the best predictor of AD pathology
memory measures
CSF (+)
n = 74
CSF (–)
n = 111
effect size
(d)
FCSRT Total Recall
13.4
15.4
0.97
Logical Memory Delayed Recall
8.12
13.59
0.74
CERAD verbal Delayed recall
4.22
5.63
0.71
AD: can the exam predict the pathology?
Wagner M et al, Neurology 2012

12. A specific pattern in Molecular Neuroimagery (Klunk et al., 2004)
PET imaging
PET-PiB Increased radio-ligand retention in AD compared to control subjects (Klunk, 2004)
PET-FDG Pooled sensitivities and specificities (9 studies) of 86% for temporo-parietal hypometabolism (Patwardhan, 2004) 12

13. Pathological CSF (low A beta, high tau/p-tau)
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
No progression to AD
0.4
Normal CSF
Pathological CSF (low A beta, high tau/p-tau)
0.2 10 20 30 40 50 60
Time (months)
Normal CSF 67 66 62 56 47 40 28
Pathological CSF 65 49 31 27 15 3
(Hansson et al. LN, 2006) 13

14. Being more specific even at the prodromal stage of AD
memory
CSF
MRI
PET-FDG
PET-ligand
NINCDS - ADRDA
not specified
exclusion
exclusion
not specified
not known
IWG criteria
amnestic ε H type
Abeta T- P tau
MTL atrophy
P–T hypo metabolism
PiB retention
Specificity for Prodromal AD
>90% Sarazin 2007
>90% Hanson 2006
>85% Colliot 2008
>80% Mosconi 2004
>95% Rowe 2007
Sarazin et al. Neurology. 2007;69: Hansson et al. Lancet Neurol ;5:228–234. Colliot et al. Psychiatr Sci Hum Neurosci. 2008;6: Mosconi et al. Neurology. 2004;63: Rowe et al. Alzheimers Dement. 2007;3.

15. + 1 or more biomarker present
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 15

16. New Diagnostic approach
Before 2007
dementia: loss of autonomy
elimination of other causes of dementia:
blood exams : endocrinopathies, infectious or inflammatory disorders…
CT-Scan/MRI : vascular lesions, tumor, hydrocephalus…
Diagnosis based on an exclusionary process
Since 2007
an amnestic syndrome of the hippocampal type
integration of biomarkers in the diagnostic process:
a biological signature on CSF
the visualisation of brain lesions with PET amyloid tracer
Diagnosis based on positive arguments

17. clinical pathological
The conceptual shift
1984
NINCDS-ADRDA
alzheimer’s disease
dementia [
MCI
probable/possible
CLINICAL
clinical pathological
entity
POST-MORTEM
neuropathology
alzheimer’s disease
IWG [
typical / atypical
CLINICAL
clinical biological
entity
BIOLOGICAL
Biomarkers

18. Applicability of the New Criteria: When?
1) In research settings: A high diagnostic accuracy is needed for:
study of specific outcomes: requires well phenotyped cohorts
academic research projects: not on heterogeneous population with a low/intermediate likelihood of diagnostic accuracy
inclusion in clinical trials : most of ongoing trials are based on the New Criteria: BMS (γ secretase inhibitor); Affiris (immunotherapy): Roche (immunotherapy); Lilly (BACE inhibitor); Nutricia (Medical food-Souvenaid); Sanofi (immunotherapy) …
2) In specific clinical conditions: BMs increase diagnostic accuracy that may be required in case of:
young onset AD
complex cases: PCA, PPA…
Resarch criteria= research settings 1) study of disease progression, medicosocial or economic aspects…2) validation of BMs 3) trials on highly specific therapeutic agents
differential diagnosis and atypical presentation:

19. The new lexicon AD: starts with the first specific symptoms
and encompasses both the prodromal and dementia phases
2) AD dementia: phase of AD with an impact on ADL
3) Prodromal AD: the early symptomatic, predementia phase of AD
4) Typical AD: common clinical phenotype of AD,
characterized by an early amnestic syndrome of the hippocampal type
5) Atypical AD: less common but well characterized clinical phenotypes
logopenic aphasia, posterior cortical atrophy, frontal variant of AD
The diagnosis of AD needs in vivo evidence of pathophysiological markers
6) Mixed AD: patients who fulfill the criteria for AD
with clinical and biomarkers evidence of other co-morbid disorders
7) Asymptomatic at risk: cognitively normal individuals
with in vivo pathophysiological biomarkers of AD
8) Presymptomatic AD: cognitively normal individuals
with a proven autosomal dominant mutation
9) Alzheimer’s pathology: neurobiological changes responsible for AD
10) MCI: patients for whom there is no disease clearly identified
(Dubois et al, Lancet Neurology 2010)