Il processo diagnostico

dell’Alzheimer dalla clinica al neuroimaging

Giovanni B. Frisoni M.D.

Professor of Clinical Neurosciences, University of Geneva

Médecin Responsable, Memory Clinic, Hôpitaux Universitaires de Genève

Scientific Director, IRCCS Fatebenefratelli, Brescia, Italy

Disclosures

♦ Sources of Research Support: Wyeth Int.l, Lilly Int.l, Lundbeck Italia,

Roche, Alzheimer’s Association

♦ Consulting Relationships: Piramal, Lilly, BMS, Bayer, Lundbeck, Elan,

Astra Zeneca, Pfizer, Taurx, Wyeth, GE,

Baxter, Envivo

♦ Editorial Boards:

• The Lancet Neurology

• NeuroBiology of Aging

• Alzheimer’s Diseases & Associated

Disorders

• Neurodegenerative Diseases

• Aging Clinical & Experimental Research

♦ Industry-Sponsored Trials: • Florbetapir in Clinical Practice, Lilly

• Flutemetamol in Delirium, GE

• Addedd value of florbetaben, Piramal

♦ Fees > $10,000: None

♦ Stock Equity: • CEREBRO SaRL, Genève

♦ Speaker’s Bureaus: None

Summary

♦ Why early and accurate differential diagnosis?

♦ Biomarkers for early and accurate differential

diagnosis of AD: the concept

♦ Biomarkers for early diagnosis of AD: results from an

Italian multicentre study w/ amyloid PET

Why differential diagnosis?

Frontotemporal Lobar

Degeneration

Dementia with Lewy

Bodies

Vascular Dementia

Diagnosis of FTLD advises

against the use of

cholinesterase inhibitors

and memantine

Diagnosis of DLB strongly

advises against the use of

neuroleptics for their

potentially devastating

effects

The efficacy of

cholinesterase inhibitors

and memantine in pure VD

is not proven.

• Mendes 2007;

Archiniegas 2013

• Boxer 2013

• Piggott 1998 • Erkinjuntti 2002

Rate of progression from mild cognitive impairment to Alzheimer's Disease (AD) in the donepezil-vit E trial

Petersen RC et al. N Engl J Med 2005;352:2379-2388.

Rate of progression from mild cognitive impairment to Alzheimer's Disease (AD) in the donepezil-vit E trial

Petersen RC et al. N Engl J Med 2005;352:2379-2388.

Non AD

degenerative

dementias

AD dementias

No degenerative

pathology

Summary

♦ Why early and accurate differential diagnosis?

♦ Biomarkers for early and accurate differential

diagnosis of AD: the concept

♦ Biomarkers for early diagnosis of AD: results from an

Italian multicentre study w/ amyloid PET

Frisoni GB et al. Nat Rev Neurol 2010

-20 -15 -10 -5 0 5 10 15 20

Years after diagnosis of dementia

Asymptoma

tic phase

Mild Cognitive

Impairment

(MCI)

phase

Dementia

phase

% Abnormality

of biomarkers

Symptoms, biology and

biomarkers for Alzheimer’s disease

Cerebral Amyloid deposition

PET amyloid CSF Ab42

Early neurodegeneration

(synaptic dysfunction)

Connectivity in

fMRI

Cortical hypometabolism

on PET

Late neurodegeneration

(neuronal loss, atrophy) CSF Tau Hippocampal

athropy in MRI

Asymptomatic

phase

Sympto

matic

phase

Chronic or healing phase

Biomarkers in the clinical practice: Hepatitis B example

Summary

♦ Why early and accurate differential diagnosis?

♦ Biomarkers for early and accurate differential

diagnosis of AD: the concept

♦ Biomarkers for early diagnosis of AD: results from an

Italian multicentre study w/ amyloid PET

Clinical features in progressive and

stable MCI patients from BS, AMS,and STK

pMCI sMCI p

N 29 44

Age (years) 67.6±8.9 65.3±9.4 0.31

Gender (females) 18 (62%) 23 (52%) 0.41

Follow-up time (months) 23.3±16.3 31.8±16.5 0.033

Baseline MMSE 26.7±1.6 27.5±1.8 0.053

MMSE yearly change -4.6±5.4 0.1±0.8 <0.0001

ApoE ε4 genotype 15 (58%) 21 (51%) 0.61

Prestia, Scheltens, Nordberg, et al., Neurology 2013

Progression to dementia is more

frequent with increasing marker positivity

4%

100%

Prestia, Scheltens, Nordberg, et al., Neurology 2013

Independent confirmation with 97 ADNI MCIs

Shaffer et al., Radiology 2013;266:583-91

Independent confirmation in a multricentre

study with 1.697 MCI patients

Vo

s e

t a

l., B

rain

20

15

Bocchetta et al. for the Disease Markers Special Interest Group

of the European Alzheimer’s Disease Consortium. Alzheimers Dement 2014

Clinical vignette: answers

At least ONE abnormal amyloid +

ONE abnormal neuronal injury marker

At least ONE

abnormal

amyloid +

ONE

abnormal

neuronal

injury marker,

n = 36

INDIA-FBP

Incremental diagnostic value of

18F‐Florbetapir imaging in patients with

cognitive impairment

EARLY RESULTS

11C PIB

18F florbetapir Wong et al JNM 2010

18F flutemetamol Mathis et al., JNM 2007

18F florbetaben Barthel et al Lancet Neurol 2011

• Cyclotron required

• Half life 20’

• Production & injection must be

very close

AMYLOID LIGANDS

• Produced by Avid/Lilly®

• Approved by FDA and EMA

• Half life 110’

• Production & injection can be

as far as 400 km

• Produced by GE®

• Under evaluation by FDA and

EMA

• Same as above

• Produced by Piramal®

• Same as above

Imaging-pathological association

Cla

rk e

t al.,

JA

MA

2011;3

05:2

75

-83

Imaging-pathological association

Aim

Evaluate the incremental diagnostic value of 18F Florbetapir PET (FBP-PET) on top of

routine assessment for diagnosis of

cognitive impairment in a naturalistic

population of patients with cognitive

impairment

Methods

Patients: investigated for cognitive impairment in 21 memory

clinics (UVA) and with a diagnostic probability of AD between

15% and 85%.

Total group size: 246 patients, 27 healthy volunteers

Preliminary results on: 191 patients, 26 healthy volunteers

Physicians in charge formulated diagnosis and diagnostic

confidence before (15-85%) and after (0-100%) FBP-PET.

FBP-PET images were visually examined by 2 nuclear

physicians and reported as Amy pos or Amy neg. In case of

disagreement the images were evaluated by a third expert.

Results

Scan readouts agreement

• Rate of concordance of 215/246 (87.4%)

• Cohen’s Kappa = 0.74 (good agreement)

Results

Inconsistent amy results

AD: 39/132 amy neg (30%)

FTD: 14/35 amy+ (40%)

LBD: 3/4 amy+ (75%)

VD: 2/7 amy+ (29%)

HC: 4/15 amy+ (15%)

Increase of diagnostic confidence in

patients with no change of diagnosis

+10.7%, p<.05 +12.5%, p<.05

Change of diagnosis in

132 AD and 35 FTD before PET

Diagnosis

after PET

FBP-PET

Aβ+ Aβ–

Same (AD) 89 11+2*

FTD 1 8

VD 1 12

LBD 1 -

SMI 1 1

Depression - 5

Total 93 39

132 AD

*SNAP

Diagnosis

after PET

FBP-PET

Aβ– Aβ+

AD - 12

Same (FTD) 17 2

VD 3 -

PDD 1 -

Total 21 14

35 FTD

Conclusions

Based on preliminary results, 18F Florbetapir PET impacts

significantly on diagnosis and

improves diagnostic confidence

of dementia experts.

Alzheimer’s biomarkers in the clinic:

issues to be addressed

- Standard operational procedures

- Guidelines for biomarker use in the clinic

- Incremental diagnostic value

- Naturalistic studies on health outcomes

- Development of national plans to enhance

access to the biomarker-based diagnosis

Alessandro Padovani – SINDEM, Italian Neurological Society

Stefano Bastianello, Andrea Falini – Italian Association of Neuroradiology

Gaetano Bernardi, Giuseppe Castaldo – Italian Society of Laboratory Medicine

(Biochimica Clinica)

Daniela Perani, Giovanni Lucignani – Italian Association of Nuclear Medicine

Corinna Porteri – Study Group of Bioethics of the Italian Neurological Society

Marco Trabucchi – Italian Psychogeriatrics Association

HOW TO TRANSFER BIOMARKERS IN CLINICAL PRACTICE?

An Italian pathway for the transfer of biomarkers to clinical practice

Acknowledgements

Alessandro Padovani co-PI

Ugo P Guerra Nuclear Medic

Barbara Paghera Nuclear Medic

Boccardi Marina Study coordinator

Paghera Barbara Nuclear medicine physicians

Pizzocaro Claudio Nuclear medicine physicians

Festari Cristina Project management

Tarallo Anna Project management

Muscio Cristina Project management

Altomare Daniele Data processing

Pievani Michela Data processing

and the INDIA-FBP WORKING GROUP*.

*Full list of INDIA-FBP participants:

http://www.centroalzheimer.org/sito/contenuti/ip_lilly_publications/INDIA-FBP_WORKING_GROUP.pdf

Project link: http://www.centroalzheimer.org/sito/ip_lilly.php

Thank you for your attention