role of amyloid imaging in the revised criteria for the diagnosis of alzheimer disease serge...

ROLE OF AMYLOID IMAGING IN THE REVISED CRITERIA FOR THE

DIAGNOSIS OF ALZHEIMER DISEASE

Serge Gauthier, MD, FRCPCMcGill Center for Studies in Aging

Douglas Mental Health University Institute, Montreal, Canada

DISCLOSURES

Member of advisory board, DSM, speaker or investigator with Affiris, Astellas, Astra-Zeneca, Bayer, Baxter, BMS, Elan, Epix, ExonHit,

GE Health Care, Janssen-Cilag, Lundbeck, Lilly, Merz, Myriad, Neurochem, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough, Servier, Sonexa, UBC, Wyeth

OUTLINE

• Natural history of AD

• NIA-AA revised diagnostic criteria for dementia caused by AD

• NIA-AA criteria for MCI due to AD

• NIA-AA criteria for pre-clinical AD

• Use of biomarkers in therapeutic studies

• Issues for application in clinical practice

PROGRESSION OF SYMPTOMS IN ALZHEIMER’S DISEASE

Lovestone & Gauthier 2000

AD Progression

Abnormal

Normal TimePresymptomatic eMCI LMCI Dementia

CSF Aβ42

Amyloid imagingFDG-PETMRI hippocampal volumeCSF TauCognitive performanceFunction (ADL)

FDG-PET

MRI hippocampal volume

CSF Aβ42

Amyloid imaging

Cognitive performance

Function (ADL)

CSF Tau

Aisen PS, Petersen RC, Donohue MC, et al. Alzheimers Dement. 2010;6:239-246.

OUTLINE







DIAGNOSTIC CRITERIA FOR PROBABLE AD IN 1984

Dementia established clinically, eg deficit in memory and one or more areas or cognition, interfering with daily life, progressing gradually

No disturbance of consciousness Onset between 40 and 90 (below 65: early

onset)Absence of other brain or systemic disease

that could account for the dementia

DIAGNOSTIC CRITERIA FOR PROBABLE AD IN 2011

Dementia established clinically, eg deficit in two or more areas or cognition, interfering with daily life, progressing gradually

No disturbance of consciousness Any ageAbsence of other brain or systemic disease

that could account for the dementiaOptional evidence of AD pathophysiology

using biomarkers

BIOMARKERS IN AD

• Biomarkers of Aß deposition * spinal fluid Aß levels (low) * PET amyloid imaging (high)• Biomarkers of neuronal injury * spinal fluid tau levels (high) * MRI looking at hippocampus, temporal lobe or whole brain (smaller) * FDG-PET (areas of reduced metabolism) * SPECT (areas of reduced blood flow)

SPINAL FLUID (CSF) IN AD

Total tau in neuronal axons Phosphorylated tau

in tangles

A1-42 in senile plaques

A42 Tau Ptau

AD ↓↓ ↑↑ ↑↑

MCI ↓ or N ↑ or N ↑ or N

Control

N N N

BIOMARKERS IN AD


PIB -ve

PIB +ve

BIOMARKERS IN AD


SPINAL FLUID (CSF) IN AD

Total tau in neuronal axons Phosphorylated tau

in tangles

A1-42 in senile plaques

A42 Tau Ptau

AD ↓↓ ↑↑ ↑↑

MCI ↓ or N ↑ or N ↑ or N

Control

N N N

BIOMARKERS IN AD


2

3

10

4

Rated area

MRI IN AD

BIOMARKERS IN AD


[18F]FDG normal vs AD

BIOMARKERS IN AD


SPECT scan of normal control vs AD

Normal Control Alzheimer’s DiseaseSandra E. Black-S&W-U of T

AD Progression

Abnormal

Normal TimePresymptomatic eMCI LMCI Dementia

CSF Aβ42

Amyloid imagingFDG-PETMRI hippocampal volumeCSF TauCognitive performanceFunction (ADL)

FDG-PET

MRI hippocampal volume

CSF Aβ42

Amyloid imaging

Cognitive performance

Function (ADL)

CSF Tau

Aisen PS, Petersen RC, Donohue MC, et al. Alzheimers Dement. 2010;6:239-246.

DIAGNOSTIC CRITERIA FOR PROBABLE AD USING BIOMARKERS(Modified from McKhann et al, 2011)

Aß Neuronal injury

• Probable AD with + + high likelihood• Probable AD with + or untested untested or +

intermediate likelihood• Probable AD dementia untested or conflicting results• Possible AD dementia + +

(atypical clinical presentation)

* Unlikely AD dementia - -

PERSON WITH EARLY ONSET DEMENTIA(from Kadir et al, 2011)

• 53 year old woman practicing nursing

• Two year history of cognitive problems at home and at work, confirmed by relatives

• No family history of AD; ApoE 4/4 carrier

• MMSE 27 down to 13 over five years

Longitudinal changes in cerebral glucose metabolism with progression of AD

27/30 21/30 13/30

Kadir, Marutle et al Brain 2010.

Kadir, Marutle et al Brain 2010

New Amyloid-Binding PET Tracers

• 11C-labeled PiB was the 1st PET ligand to bind amyloid in living patients. It has a short half-life (20 min) so is difficult to use

• Ligands under study (florbetaben, florbetapir and flumetamol) are labeled with 18F and provide a wider window for scanning.

Status of new PET tracers

• One product (florbetapir) has been submitted for approval in the US

• An FDA advisory committee meeting (Jan 20, 2011) showed interest in moving forward with the approval of this compound for PET imaging of β-amyloid but raised issues to be resolved before FDA approval

Florbetaben detects all types of β-amyloid deposits in the brain

• Florbetaben binds to all aggregated forms of β-amyloid

Amyloid depositionBielschowsky F-19 Florbetaben

Non-neuritic/ Diffuse

Neuritic/ cored

vascular

OUTLINE







PATTERNS OF SYMPTOMS IN TYPICAL AD

Lovestone & Gauthier 2000

MCI AMNESTIC TYPE

* Memory complaint, preferably confirmed by an informant

* Memory impairment relative to age- and education-matched normal subjects

• Relatively normal general cognitive function

• Largely intact activities of daily living• Not demented

PERSON WITH MCI

• 62 year old man practicing law

• Came alone complaining of difficulties at work (remembering jurisprudence and preparing his speeches for the court)

• Wife reached on the phone says he has no problems at home

• MMSE 30, MoCA 26, Boston Naming 13/15

MoCA

►One-page► 30-point scale► 10 minutes to administerwww.mocatest.org

DIAGNOSTIC CRITERIA FOR MCI DUE TO AD USING BIOMARKERS

(Modified from Albert et al, 2011)

Aß Neuronal injury• MCI due to AD + +

high likelihood• MCI due to AD + untested

intermediate likelihood untested +• MCI possibly due to AD untested or conflicting• MCI unlikely due to AD - -

PERSON WITH MCI

• Told he has MCI likely due to AD -> early retirement from law practice and chose to start a cholinesterase inhibitor

• Interested in studies to delay progression towards dementia

OUTLINE







PERSON CONCERNED ABOUT RISK OF AD

• 55 year old woman consulting because she took care of her mother, dying at 85 with AD

• No cognitive symptoms

• MMSE 30, MoCA 30

DIAGNOSTIC CRITERIA FOR PRECLINICAL AD USING BIOMARKERS

(Modified from Sperling et al, 2011)

Aß Neuronal Symptoms

injury• Asymptomatic + - -

cerebral amyloidosis (ACA) • ACA + evidence of neuronal + + -

injury (NI)• ACA + NI + subtle cognitive + + +

decline

PERSON CONCERNED ABOUT RISK OF AD

• Told he has a higher risk of developing AD in later life, as she suspected from her family history.

• No specific test results given or put in medical file.

• Interested in studies to delay progression towards MCI and Dementia

OUTLINE







USE OF AMYLOID SCAN IN CLINICAL TRIALS FOR AD

• Help to confirm the diagnosis of AD at any stage

• Proof of concept of the amyloid-lowering effects of medications

With the Advent of Disease Modifiers Early Detection of AD Becomes Even More

Important

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

Elan/Wyeth ABLilly GSI

Baxter IVIgTauRx MTC

Lilly ABPrana MPACAllon Peptide

Novartis vacElan/Wyeth vac

Wyeth GSIPfizer RAGE

Elan Aß-aggreg inhib.BMS GSI

Astellas/Comentis ßSIRoche AB

Merck vacGSK AB

Pfizer ABHoffmann-LaRoche AB

GSK/Affiris ABEisai GSI

Pfizer / Medivation Ahist

Antibody

Active Vaccination

Other mechanisms not related to Aβ

Gamma Secretase Inhibitor

Adapted from E. Siemers ICAD 2008

PIB PET SCAN IN AD BEFORE AND AFTER IMMUNOTHERAPY

OUTLINE







WHY AN EARLIER DIAGNOSIS OF AD?

• Pragmatic need of individual patients for a medical diagnosis (early retirement where appropriate)

• Relief from uncertainty about nature of symptoms

• Allow for better planning for financial affairs, for medical care, for participation in research

• Break current deadlock on disease modification

Unresolved issues with very early diagnosis of AD

• Risk of false positive diagnosis (need to follow-up longitudinally)

• Risk of catastrophic reaction

• No proven long-term treatments

• Additional costs for tests

• Can this be done in primary care practice?

CONCLUSIONS

• The revised diagnostic criteria for AD will facilitate research on new treatments

• Biomarkers are an essential component of the diagnosis of AD in very early stages

• Ethical considerations are important for the person undergoing assessment and for society as a whole

role of amyloid imaging in the revised criteria for the diagnosis of alzheimer disease serge...

Documents

adniaaa criteria

spinal fluid tau levels

levels low

revised criteria

dementiadiagnostic criteria

brain smaller

role of amyloid imaging

probable ad