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 [

CLINICAL POST MORTEM MCI 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

Preclinical states

To be earlier

What is Alzheimer’s disease?

First symptoms 3 –5 yrs Current point of diagnosis Biomarkers

AD?

Specific memory disorders

AD?

Dementia

AD?

MCI Drugs Depression Sleep disorders FTD Normal aging Subcortical dementia AD 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

memory measures

FCSRT Total Recall Logical Memory Delayed Recall CERAD verbal Delayed recall

CSF (+) n = 74

13.4

8.12

4.22

CSF (–) n = 111

15.4

13.59

effect size (d)

0.97

0.74

5.63

0.71

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 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)

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

0.2

Normal CSF Pathological CSF (low A beta, high tau/p-tau)

0 0 10 20 30 40 50 60

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)

Being more specific even at the prodromal stage of AD memory CSF MRI NINCDS ADRDA

not specified exclusion

IWG criteria

amnestic ε H type T- P tau

Specificity for Prodromal AD

>90%

Sarazin 2007

>90%

Hanson 2006

exclusion >85%

Colliot 2008

PET-FDG

not specified

PET ligand

not known P–T hypo metabolism >80%

Mosconi 2004

PiB retention >95%

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

1984 NINCDS-ADRDA

clinical pathological entity

MCI

[

CLINICAL POST-MORTEM alzheimer ’ s disease dementia

probable/possible neuropathology

2007 IWG

clinical biological [

CLINICAL BIOLOGICAL

entity

alzheimer ’ s disease

typical / atypical 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

(immunotherapy) … (BACE inhibitor);

Nutricia

(Medical food-Souvenaid);

Sanofi

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: 6) Mixed 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

9) Alzheimer ’

patients who fulfill the criteria for AD with clinical and biomarkers evidence of other co-morbid disorders

7) Asymptomatic at risk:

8) Presymptomatic AD: cognitively normal individuals with in vivo pathophysiological biomarkers of AD cognitively normal individuals with a proven autosomal dominant mutation s pathology: neurobiological changes responsible for AD 10) MCI: patients for whom there is no disease clearly identified

(Dubois et al, Lancet Neurology 2010)