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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
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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