Changing the criteria forAlzheimer’s disease

Alzheimer Europe - Vienna, October 2012

Pr Bruno DuboisHead 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

The NINCDS-ADRDA criteria

neuropathology

CLINICAL

POST-MORTEM

MCI dementia

probable/possible AD[

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

1984The rules

The current NINCDS-ADRDA diagnostic criteria have several limitations

Two requirements:1) to be earlier2) to be more

specific

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 !

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

Preclinical states

Current point of

diagnosis

3–5 yrs

Specific memory disorders

Dementia

First symptoms

Biomarkers

AD?AD?AD?

What is Alzheimer’s disease?

DrugsMCI Subcortical

dementia

Depression

Normal aging

FTDAD

Vascular disorders

Confusion

Low free recall

Sleep disorders

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 MemoryThe Different Stages of LT Memory

Temporal lobe (AD)

StorageRegistration Retrieval

Stimulus Stimulus

Control of encoding with cueing1

Facilitate the retrieval with cueing2

Frontal lobe (aging)

Attention

(depression)

Dubois and Albert, Lancet Neurology, 2004

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

Wagner M et al, Neurology 2012

AD: can the exam predict the pathology?

• PET-PiB. PET-PiB. Increased radio-ligand Increased radio-ligand retention in AD retention in AD compared to compared to control subjects control subjects ((Klunk, Klunk, 20042004))

• PET-FDG.PET-FDG. Pooled Pooled sensitivities and sensitivities and specificities (9 specificities (9 studies) of 86% for studies) of 86% for temporo-parietal temporo-parietal hypometabolismhypometabolism ((Patwardhan, 2004Patwardhan, 2004))

PET imaging

A specific pattern in Molecular A specific pattern in Molecular Neuroimagery Neuroimagery (Klunk et al., 2004)

(Hansson et al. LN, 2006)

1.0

0.8

0.6

0.4

0.2

0

No p

rogr

essio

n to

AD

0 10 20 30 40 50 60 Time (months)

Normal CSFPathological

CSF (low A beta, high tau/p-

tau)

Normal CSF 67 66 62 56 47 40 28Pathological CSF 67 65 49 31 27 15 3

specific pattern of CSF changes (low A beta; high tau and P-tau levels) even at an eary stage

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;69:1859-2016. 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.

Structural: atrophy of medial temporal lobe (MRI)Biological: changes in biomarkers (CSF)Metabolic neuroimaging: regional hypometabolism on PETMolecular neuroimaging: amyloid ligand retention on PET

Amnestic syndrome of the ‘hippocampal type’ (that can be isolated or associated to other cognitive / behavioral changes)

1 major clinical criterion

+ 1 or more biomarker present

Dubois et al., Lancet Neurol., 2007

Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria

Before 20071) dementia: loss of autonomy2) 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 type2) 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

New Diagnostic approach

neuropathology

CLINICAL

POST-MORTEM

MCI dementiaprobable/possible

Biomarkers

CLINICAL

BIOLOGICAL

typical / atypical

[

[alzheimer’s disease

alzheimer’s disease

The conceptual shift

1984NINCDS-ADRDA

2007 IWG

clinical pathological entity

clinical biological entity

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…

Applicability of the New Criteria: When?

The new lexicon1) AD: starts with the first specific symptoms and encompasses both the prodromal and dementia phases2) AD dementia: phase of AD with an impact on ADL3) Prodromal AD: the early symptomatic, predementia phase of AD4) Typical AD: common clinical phenotype of AD, characterized by an early amnestic syndrome of the hippocampal type5) 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 markers6) Mixed AD: patients who fulfill the criteria for AD with clinical and biomarkers evidence of other co-morbid disorders7) Asymptomatic at risk: cognitively normal individuals with in vivo pathophysiological biomarkers of AD8) Presymptomatic AD: cognitively normal individuals with a proven autosomal dominant mutation9) Alzheimer’s pathology: neurobiological changes responsible for AD10) MCI: patients for whom there is no disease clearly identified

(Dubois et al, Lancet Neurology 2010)