Wolk Forum Latest

8/13/2019 Wolk Forum Latest

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David A. Wolk, M.D.Assistant Professor of Neurology

Assistant Director, Penn Memory Center

Perelman School of Medicine at theUniversity of Pennsylvania

Incorporating Biomarkers of Amyloid

and Neurogeneration in Clinical

Evaluation of Mild Cognitive

Impairment

Disclosures: Nothing to disclose


2/25

5 Million


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Clinical and Pathological Course of AD

Pre-Clinical AD

NoSymptoms?

Early ChangesEarly Changes

MCI

Mild

Symptoms

Mild--Mod

Changes

MCI

Mild

Symptoms

MildMod

Changes

ADAD

MildMild--SevereSevere

SymptomsSymptoms

ModMod--SevereSevere

ChangesChanges

NormalNormalClinicalClinical

StateState

PlaquesPlaques

TanglesTangles

CognitiveCognitiveStateState No SymptomsNo Symptoms

PathologicPathologicStateState No DiseaseNo Disease

Clinical

State

Cognitive

State

Pathologic

State


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Petersen Criteria for MCI

Cognitive complaint (preferably corroborated byinformant)

Objective impairment for age and education

Largely intact general cognitive function Essentially preserved activities of daily living

Not demented


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MCI Enriched in Patients with

Prodromal AD

Tomaszewski Farias S et al.Arch Neurol. 2011;66:1151-1157.


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Amyloid Imaging in MCI50-70% Positive

Wolk DA, Klunk WE. Curr Neurol Neurosci Rep. 2009;9:345-352.


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Age-Associated Cognitive Impairment

Park DC, Reuter-Lorenz P.Annu Rev Psychol. 2009;60:173-196.


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Mild Cognitive Impairment Heterogeneous Population

AD

Other neurodegenerative disorders

Age-Associated memory loss

At border of diagnosis of MCI

CVD

Hippocampal sclerosis

Depression

Medications

Peterson RC. N Engl J Med. 2011;364:2227-2234.


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Additional Tests May Enhance

Accuracy of DiagnosisBiomarkers

of AD

Markers of Brain Degeneration

Look for evidence of brain changes in patternconsistent with AD

Structural MRI (atrophy), Glucose PET scans, CSFtau/p-tau

Markers of Brain Pathology Look for molecular evidence of AD

Cerebrospinal Fluid (CSF), Amyloid Imaging

Dubois B et al. Lancet. 2007;6:734-746.


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Abnormal

Normal

Biom

arker

Mag

nitude

Normal MCI Dementia

Clinical disease stage

Preclinical

Modified from Jack CR Jr et al. Lancet Neurol. 2010;9:119.

Psychometrics

Function

Amyloid (PiB)

Brain Structure (MRI)

Brain Physiology (PET)


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Biomarkers Enhance Prediction of Conversion

Jack CR Jr et al. Neurology. 1999;52:1397-1403.

Heister D et al. Neurology. 2011;77:1619-1628.


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Amyloid Imaging and Conversion to AD

in MCI

23/26 patients have had follow-

up ADRC evaluations and

consensus discussion

Overall mean f/u: 21.2

months (6-57 months) 13 PiB positive (Mean: 21.9

months)

10 PiB negative (Mean: 22.3

months)-40%

-20%

0%

20%

40%

60%

80%

PiB Positive PiB Negative

revertersstable

converters

Wolk DA et al.Ann Neurol. 2009;65:557-568.


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NIA-AA MCI Criteria

Diagnostic Category Biomarker Driven

Probability of AD

Etiology

Presence of Cerebral

Amyloidosis (PET,

CSF)

Evidence of Neuronal

Injury (tau, FDG,

sMRI)

MCI-core clinical

criteria

Uninformative Conflicting/indetermi

nite/untested

Conflicting/indetermi

nite/untested

MCI due to AD

Intermediate

likelihood

Intermediate

Positive Untested

Untested Positive

MCI due to ADHigh

likelihood

Highest Positive Positive

MCIunlikely due to

AD

Lowest Negative Negative

Albert et al.,Alzheimer

s & Dementia, 2011


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NIA-AA MCI Criteria

Do these biomarkers provide differential

information about the timing of progression?

Conflicting results considered uninformative

What is the meaning of discordance between

amyloid and neurodegenerative measures

Likelihood of AD etiology?

Likelihood of progression?

Does it matter which measure (amyloid vs.

neurodegenerative) is positive or negative?


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Abnormal

Normal

Biom

arker

Mag

nitude

Normal MCI Dementia

Clinical disease stage

Preclinical

Modified from Jack CR Jr et al. Lancet Neurol. 2010;9:119.

Psychometrics

Function

Amyloid (PiB)

Brain Structure (MRI)

Brain Physiology (PET)


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Relationship of Amyloid andNeurodegeneration to Time of Progression

-2.5

-2

-1.5

-1

-0.5

0

Stable @ 3 Years

3-Year Conversion

1-Year Conversion

CerebralAmyloid

ControlRe

ferencedz-sc

ores

Dickerson & Wolk, Frontiers in Aging Neuroscience, 2013

NeurodegenerationStructural MRI


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P-Tau Tracks Timing of Conversion

Buchhave et al.,Archives Gen Psychiatry, 2011

Cerebral Amyloid:CSF A

Neurodegeneration:CSF phospho-tau


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Concordant Findings Amyloid negative, neurodegeneration negative

Low likelihood AD

Amyloid positive, neurodegeneration positive High likelihood AD

Discordant Findings Amyloid positive/neurodegeneration negative or

amyloid negative/neurodegeneration positive Uninformative

Most importantly, what do these differentgroupings mean for an individuals likelihood ofprogression?

Categorization Based on Biomarkers


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MCI Biomarker Groups

P

ercentofMCIP

atients

0%

20%

40%

60%

80%

Biomarker

Neg

Amyloid

Only

Amyloid &

Neurodeg

Neurodeg

Only

25%

25%0%

4%


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What is Underlying Cause and

Outcome of Each Group Biomarker negative

Unlikely AD, Low rate of conversion

Amyloid + Neurodegeneration High likelihood of AD and high conversion rate

Amyloid only Earlier in disease course versus symptoms not due to amyloid

pathology

Low near-term conversion to dementia

Neurodegeneration Only Non-AD neurodegeneration versus modification of typical

biomarker cascade (neurodegeneration precedes detectableamyloid)

Significant proportion develop dementia


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Average Cortical Thinning Relative to

Controls

Amyloid + Neurodegeneration

(n=114)

Neurodegeneration Only

(n=16)


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Conclusions Biomarkers enhance certainty of diagnosis

Neurodegenerative markers may provide more specificinformation about the timing of progression Allows for earlier treatment and appropriate planning

Concordant biomarkers provide most certainty with

regard to outcomes Other combinations less clear and represent an

important area for further research In particular, neurodegeneration only group displays high

rate of conversion and relatively specific AD patterndespite absence of biomarker evidence for cerebralamyloidosis


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Thank You!!

Funding sources: NIH: P30 AG010129,

K01 AG030514, P50-AG005134,

P30AG010124, Dana Foundation,Alzheimers Association.

Alzheimer's Disease

Neuroimaging Initiative (ADNI) (National

Institutes of Health Grant U01

AG024904)

All work done in collaboration with Brad

Dickerson at MGH


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Risk of Conversion based on Amyloid

Status and Neurodegeneration (AD

Signature Cortical Thinning)

Dickerson & Wolk, Frontiers in Aging Neuroscience, 2013


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Cortical Signature of AD

Disease-defined regions associated withcortical thinning in early AD

Dickerson et al., Cerebral Cortex, 2011

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