Chetelat- Mci - Slides

8/13/2019 Chetelat- Mci - Slides

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Inserm-EPHE-Universit de Caen/Basse-Normandie, UnitU1077, GIP Cyceron, CHU Cte de Nacre, Caen, France

Gal Chtelat

12th Annual Mild Cognitive

Impairment (MCI) Symposium

Saturday, January 18th 2014


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Nothing to disclose


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Seab et al., 1988 : Hippocampal atrophy

Ferris et al., 1980

Klunk et al., 2004Control AD

Baron et al., 2001 : throughout the whole brain

Minoshima et al., 1994

MRI

FDG-

PET

PiB-PET


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PUTTING THE PIECES OF THE PUZZLE TOGETHER:MULTIMODAL NEUROIMAGING

GM ATROPHY

fMRI ACTIVITY

Activation

Resting state

WM Atrophy

DTI

WM DISRUPTION


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Sequence of events


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Hardy et al., 1992; 2002

THE AMYLOID HYPOTHESIS IS A LINEAR MODEL

Our hypothesis is that deposition

of amyloid protein (A), the main

component of the plaques, is the

causativeagent of Alzheimer's

pathology and that the

neurofibrillary tangles, cell loss,

vascular damage, and dementia

follow as a direct result of this

deposition.(Hardy & Higgins, 1992)


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1) Amyloid TEP imaging

2) Atrophy (MRI) and

hypometabolism (FDG-PET)

3) Cognitive deficits

THE BIOMARKER MODEL FOLLOWS THE SAME ORDERING

Jack et al., Lancet Neurol 2010; 2013

Hardy et al., 1992; 2002


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1) Regional discrepancy


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La Joie et al., J Neurosci, 2012

RELATIONSHIPS BETWEEN BIOMARKERS: VOXELWISE CORRELATIONS

NS

NS

ATROPHY HYPOMETABOLISM AMYLOID LOAD


10/41Chtelat et al., Annals of Neurology, 2010

Controls: healthy

elderly without

memory complaints

SCI: elderly with subjective

cognitive impairment

(memory complaints)

MCI: patients with mild

cognitive impairment

(Petersen et al., 2005)

AD: patients with

Alzheimers disease

(NINCDS-ADRDA)

Correlations between baseline PiB and baseline atrophy


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NS NS NS

D. REGIONAL PiB-SUVR versus REGIONAL GM volume within each clinical group

Controls SCI MCI AD

Correlations between baseline PiB and baseline atrophy

Chtelat et al., Annals of Neurology, 2010

Larger GM volume in High versus Low PiB controls GM atrophy in High versus Low PiB SCI

Chtelat et al., Brain, 2010


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value

-1 1-0.5 0.5

hypo-atro = Zhypo minus Zatro

VOXELWISE COMPARISON BETWEEN

HYPOMETABOLISM AND ATROPHY IN AD

La Joie et al., J

Neurosci, 2012

Chtelat et al.,

Brain, 2008


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DIRECT VOXEL-BASED COMPARISON BETWEEN GREY MATTER

HYPOMETABOLISM, ATROPHY, AND AMYLOID DEPOSITION IN ALZHEIMERS DISEASE

La Joie et al., J Neurosci, 2012


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Dickerson et al., Neurology 2005

Ex

tend

ofHcp

activation

*

**

Scheef et al., Neurology 2012

HIPPOCAMPAL UPREGULATION?


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Hippocampal

atrophy

Cingulum bundle

disruption

Posterior cingulate

hypometabolism

Anterior cingulatecortex(BA32)

Uncinate fasciculus Subgenual cortex (BA25)

Villain et al., J Neurosci, 2008

Fouquet et al., Brain, 2009

Villain et al., Brain, 2010

DISCONNECTION / DIASCHISIS HYPOTHESIS


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La Joie et al.,

J Neurosci, 2012

Delacourte et al.,

Duyckaerts et al;

Braak and Braak

Disconnexion

processes

Weak

relationshipsbetween A

deposition and

atro/hypo

Up-regulation


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Live discussion / Webinar of the Alzheimer research forum: www.alzforum.com

Integrated Brain Imaging Emphasizes Regional Differences in What Changes

When on the Long Descent Into Alzheimers


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2) Variation of the sequence


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Toward defining the preclinical stages of Alzheimers disease:

Stage 0 - - -

Stage 1

Stage 2

Stage 3

A

(PET or CSF)

Markers of neuronal

injury (tau, FDG, sMRI)

Evidence of subtle

cognitive change

- -

-

+++

+

+ +

Sperling al.,Alzheimers & Dementia, 2011


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Duyckaerts, Acta

Neuropathologica,

2011


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This has been integrated in a new version of the model for

the pathological processes; the biomarker sequence

remains unchanged


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Benzinger et al., PNAS, 2013


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Bateman et al., N Engl J Med, 2012


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21%

9%

22%16%

37%

49%

35%

50%

35%

64%

0%

10%

20%30%

40%

50%

60%

70%

Rowe et al.,2010

Morris et al.,2010

Jagust et al.,2012

Rodrigue etal., 2012

Mielke et al.,2012

ApoE4 non-carriers ApoE4 carriers

PIB

n=101/76

PIB

n=158/83

Florbetapir

n=135/40

Florbetapir

n=70/17

PIB

n=361/122

Courtesy of Renaud La Joie, PhD

For review, cf Chtelat et al., Neuroimage: clinical, 2013

APOE4 is associated with a significant increase in Adeposition, a greater

proportion of amyloid-positive individuals in normal elderly


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(Fleisher et al., 2013)

and a decrease in the age of predicted amyloid-positivity

APOE4 non-carriers76 yrs APOE4 carriers56 yrs


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Neuroimaging studies show evidence for AD-like

neurodegenerative changes without Adeposition

Sheline et al., J Neurosci, 2010

Disruption of functional connectivity in PIB-

negativeasymptomatic ApoE4 carriers

Jagust et al., J Neurosci, 2012


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1) APOE4 exerts a graded effect:

Amyloid deposition > metabolism > brain structure

2) There are both A-dependent and A-independent effects of APOE4

Huang, 2010; Huang et Mucke 2012; Liu et al., 2013; Desikan et al., 2013;

Sheline et al., 2010; Jagust et al., 2012

Chtelat & Fouquet,

Rev Neurol, 2013


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Application of the criteria questions the model


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Proportion of

individuals ineach stage :

Jack et al., Ann Neurol, 2012

16%

12%

3%

43%

23%

N = 450

Stage 0

- +

- - -

SNAP* +/-

Stage 1

Stage 2

Stage 3

A

(PET or CSF)

Markers of neuronal


Evidence of subtle

cognitive change

- -

-

+++

+

+ +

* Suspected Non-AD Pathophysiology


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N = 296

Knopman et al., Neurology, 2012

Proportion of

converters to

MCI/dementia

within 15 mths :

Stage 0

- +

- - -

SNAP* +/-

Stage 1

Stage 2

Stage 3

A

(PET or CSF)

Markers of neuronal


Evidence of subtle

cognitive change

- -

-

+++

+

+ +

* Suspected Non-AD Pathophysiology

11%

21%

43%

5%

10%


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The investigators compared the SNAP group to those with

preclinical AD stages 2+3 on various measures. As the most

frequent non-AD pathophysiological processes are cerebrovascular

disease and -synucleinopathy, the SNAP group was expected to

differ from the preclinical AD group on these parameters.


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Jack et al., Neurology, 2013


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11 of our 26 incident amyloid PET-positive

subjects had abnormal hippocampal volume

(n = 4), FDG (n = 2), or both (n = 5) at

baseline. These 11 therefore had abnormal

neurodegenerative biomarkers (FDGPET or

hippocampal volume) with normal amyloid

PET at baseline, but later become amyloid-

positive.

However, our data do show that both

amyloid- first and neurodegeneration-first

biomarker profiles characterize incident

amyloid positivity. Amyloid positivity defines

preclinical AD; therefore, both amyloid-first

and neurodegeneration-first biomarker

profile pathways to preclinical AD exist.


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Neuronal injury could be caused by different factors (with various possible


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Chtelat, Nat Rev Neurol, 2013

Neuronal injury could be caused by different factors (with various possible

sequences): Aand tau patholgies may be partly independent, each under

the influence of common and independent risk factors, and interacting with

each others to promote the AD neuropathological cascadeconsider each

biomarker at the same level with an additive effect on the risk of AD


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Inserm-EPHE-Universit de Caen/Basse-Normandie, Un itU1077,GIP Cyceron, CHU Cte de Nacre, Caen, France

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Chetelat- Mci - Slides