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
DISCLOSURE
1)
Reimbursed travels for speaking engagements,
congress participation or educational activities:
Eisai, Janssen-Cilag, Novartis
2)
Consultancy:
Affiris, BMS, Eli Lilly, Pfizer, Roche
3)
Funding for my Institution:
Novartis, Roche
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
CLINICAL
[
POSTMORTEM
dementia
probable/possible
AD
neuropathology
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
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
To be earlier
What is Alzheimer’s disease?
Preclinical
states
Current
point of
diagnosis
First
symptoms
3–5 yrs
Biomarkers
AD?
Specific
memory
disorders
AD?
Dementia
AD?
Subcortical
dementia
MCI
Drugs
Sleep disorders
Depression
AD
FTD
Normal aging
Confusion
Vascular disorders
Low free recall
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
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)
1
Control of
encoding
with cueing
2
Facilitate the
retrieval
with cueing
FCSRT (cued recall measures)
is the best predictor of AD pathology
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
memory measures
AD: can the exam predict the pathology?
Wagner M et al, Neurology 2012
PET
imaging
A specific pattern in Molecular
Neuroimagery (Klunk et al., 2004)
• PET-PiB.
Increased radioligand 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)
specific pattern of CSF changes (low A beta; high tau
and P-tau levels) even at an eary stage
No progression to AD
1.0
0.8
0.6
0.4
Normal CSF
Pathological CSF
0.2
(low A beta,
high tau/p-tau)
0
0
10
20
30
40
50
Time (months)
60
Normal CSF
67
66
62
56
47
40
28
Pathological CSF
67
65
49
31
27
15
3
(Hansson et al. LN, 2006)
Being more specific
even at the prodromal stage of AD
memory
NINCDS ADRDA
CSF
not specified exclusion
MRI
PET-FDG
PETligand
exclusion
not specified
not known
P–T hypo
metabolism
PiB
retention
IWG
criteria
amnestic ε
H type
Abeta
T- P tau
MTL atrophy
Specificity for
Prodromal
AD
>90%
>90%
>85%
>80%
>95%
Sarazin
2007
Hanson
2006
Colliot
2008
Mosconi
2004
Rowe
2007
Sarazin et al. Neurology. 2007;69:1859-2016. Hansson et al. Lancet Neurol. 2006;5:228–234. 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.
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
New Diagnostic approach
Before 2007
1) dementia: loss of autonomy
2) 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
1) an amnestic syndrome of the hippocampal type
2) 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
The conceptual shift
alzheimer’s disease
1984
NINCDS-ADRDA
clinical pathological
entity
CLINICAL
[
MCI
POST-MORTEM
dementia
probable/possible
neuropathology
alzheimer’s disease
2007
IWG
clinical biological
entity
CLINICAL
typical / atypical
BIOLOGICAL
Biomarkers
[
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…
The new lexicon
1) 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)