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8/13/2019 Wolk Workshop
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Clinical Implications of
Discordant BiomarkersDavid A. Wolk, M.D.
Assistant Professor of Neurology
Assistant Director, Penn Memory CenterPerelman School of Medicine at the
University of Pennsylvania
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Chief Complaint/HPI
IP presented at age 65
Husband initiated visit due to her forgetfulness and confusion
Forgets aspects of prior situations; conflate separate events
Forgets conversations
Corroborated by children and best friend May have begun after D/C of Prempro year before
She admitted to relying on lists more and forgetting appts
(including initial evaluation)
Occasional word-finding problems Always had difficulty with names, but more so
No disorientation to time or place
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HPI (cont)
Minimal functional change
Clerical work for husbands law practice
Occasionally forgets item when shopping
No issues driving, cooking, handling finances
No issues with BADLs
Some struggles with low mood over last 1-2
years Sister with AD
Paxil has helped
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PMHx
Osteopenia
Diet-controlled hyperlipidemia
GERD
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Fam/Soc Hx
Mother with AD developed in 80s
Sister with mild AD at age 70
Remote tobacco use 1-2 glasses/wine every 3 or 4 days
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Physical Examination
General medical exam was unremarkable
Neurological exam
CNs II-XII intact
Motor: Strength and tone were WNL; no
adventitial movements
Sensation intact to all modalities
Normal RAM/FNF
Gait was steady with normal stride, armswing
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Mental Status Examination
0/15 on Geriatric Depression Scale
MMSE: 29/30
CDR: 0.5
WMS LM Immediate: 10/25; Delay: 9/25 (eMCI criteria forADNI 2)
BNT and category fluency ~ 1.5 SDs below mean
Speech was fluent with good comprehension
Visual constructions, processing speed, sequencing and otherexecutive functioning tasks were normal
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Studies
B12 and TSH WNL MRI Brain: occasional hyperintensities in
deep and subcortical white matter. No other
findings
MCImemory plus other (language)
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Quantitative MRI Measures
SPARE AD: -0.85 (Normal)
-Spatial pattern classifier
developed by C. Davatzikos
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FDG PETNo regional
hypometabolism
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Level of Certainty
Diagnostic Category Biomarker DrivenProbability of AD
Etiology
Presence of CerebralAmyloidosis (PET,
CSF)
Evidence of NeuronalInjury (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.,Alzheimers & Dementia, 2011
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Level of Certainty
Diagnostic Category Biomarker DrivenProbability of AD
Etiology
Presence of CerebralAmyloidosis (PET,
CSF)
Evidence of NeuronalInjury (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.,Alzheimers & Dementia, 2011
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Level of Certainty
Diagnostic Category Biomarker DrivenProbability of AD
Etiology
Presence of CerebralAmyloidosis (PET,
CSF)
Evidence of NeuronalInjury (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.,Alzheimers & Dementia, 2011
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Level of Certainty
Diagnostic Category Biomarker DrivenProbability of AD
Etiology
Presence of CerebralAmyloidosis (PET,
CSF)
Evidence of NeuronalInjury (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.,Alzheimers & Dementia, 2011
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Follow-up
Over next year, patient and family describedsignificant improvement. Stated would not have ever
come to PMC if had been doing as well
Based on testing and hx, reversion to normal
Followed ~7 years to presentstill c/o word-finding
lapses and forgetfulness, but latter only when
stressed
Occasional struggles with depression related to multiplelife stressors
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Psychometric Measures
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Repeat MRI and PET in Year 6 and 7 unchanged
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Chief Complaint/HPI
WB presented at age 66 with memory andlanguage complaints
Cognitive sxs began 1 year prior to presentation Forgetting appointments
Poorer orientation to time
Difficulty with remembering driving directions
Word-finding issues and losing train of thought
Denied mood sxs
Volunteered at soup kitchen, chores aroundhouse without difficulty, no issues with basicADLs
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PMHx
Prostate CA s/p prostatectomy
S/p hernia repair
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Medicines
Donepezil 10 mg daily
Pepcid
Tylenol PM
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Fam/Soc Hx
Mother died of PD in 70s
Father lived to 93 y.o. without cognitive issues
1 brother and 2 sisters who are healthy Rare alcohol
1 ppd x 25 years, no longer smoking
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Mental Status Examination
MMSE: 28/30
CDR: 0.5
CERAD 10-item word-list learning and recall ~1.5 SDs below
mean
BNT impaired (20/30); normal verbal fluency
Visual constructions inconsistent
Good processing speed, borderline sequencing
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Studies
Blood work WNL
MRI: mild to moderate generalized cortical
atrophy with commensurate mild
ventriculomegaly; occasional punctate areasof white matter signal changes
MCImemory plus other (language,visuospatial)
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Quantitative Structural MRI
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FDG PETdecreased parietal lobe uptake L >
R and left temporal lobe consistent with AD
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Level of Certainty
Diagnostic Category Biomarker DrivenProbability of AD
Etiology
Presence of CerebralAmyloidosis (PET,
CSF)
Evidence of NeuronalInjury (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.,Alzheimers & Dementia, 2011
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Level of Certainty
Diagnostic Category Biomarker DrivenProbability of AD
Etiology
Presence of CerebralAmyloidosis (PET,
CSF)
Evidence of NeuronalInjury (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.,Alzheimers & Dementia, 2011
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CSF Biomarkers
A: 213pg/ml (92; Sens: 69.6%, Sp: 92.3%)
P-tau: 69pg/ml (> 23; Sens: 67.9%, Sp: 73.1%)
Tau/A: 0.60 (>0.39; Sens: 85.7%, Sp: 84.6%)
Repeated 2 years later
A 203pg/ml; tau: 113pg/ml; p-tau: 76pg/ml
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Level of Certainty
Diagnostic Category Biomarker DrivenProbability of AD
Etiology
Presence of CerebralAmyloidosis (PET,
CSF)
Evidence of NeuronalInjury (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.,Alzheimers & Dementia, 2011
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Level of Certainty
Diagnostic Category Biomarker DrivenProbability of AD
Etiology
Presence of CerebralAmyloidosis (PET,
CSF)
Evidence of NeuronalInjury (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.,Alzheimers & Dementia, 2011
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Follow-up
Over next year, further cognitive and functional
decline
More forgetfulforgot son was with him at sporting event
when went to bathroom
Trouble recognizing more distant family at funeral Unable to do checkbook
MMSE 26/30 with mild multiple domain impairment
Dxd with AD
Follo p
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Follow-up
18 months after initial visit
Unable to learn way around cruise ship Less engaged in conversations
Still meticulous about his self-care and clothing/belongings
MMSE 22/30
Memory testing poorer0/10 recall on CERAD and 6/25LM Delayed Recall
24 months after initial visit
Mild further decline (MMSE 19/30)
Follow up
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Follow-up
Over next year (24-36 months after initial visit), more
significant decline Sleeping much of the day, delusions vs hallucination
Poorer self-care
Mild parkinsonism
Lewy Body Variant of AD
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Conclusions Conflicting biomarkers add complexity to diagnosis
and prognostication Choice of cutoffs may significantly influence meaning
Amyloid positivity in absence of neurodegeneration
by MCI stage may predict slower evolution and
possibility that AD is not cause of memory sxs
Evidence of neurodegeneration, even in absence of
evidence of cerebral amyloid, may predict more
imminent decline Etiology less clear
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