Wolk Workshop

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


Etiology


CSF)


sMRI)

MCI-core clinical

criteria


nite/untested


nite/untested

MCI due to AD

Intermediate

likelihood

Intermediate

Positive Untested

Untested Positive

MCI due to ADHigh

likelihood


MCIunlikely due to

AD




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Level of Certainty


Etiology


CSF)


sMRI)

MCI-core clinical

criteria


nite/untested


nite/untested

MCI due to AD

Intermediate

likelihood

Intermediate

Positive Untested

Untested Positive

MCI due to ADHigh

likelihood


MCIunlikely due to

AD




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Level of Certainty


Etiology


CSF)


sMRI)

MCI-core clinical

criteria


nite/untested


nite/untested

MCI due to AD

Intermediate

likelihood

Intermediate

Positive Untested

Untested Positive

MCI due to ADHigh

likelihood


MCIunlikely due to

AD




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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


Etiology


CSF)


sMRI)

MCI-core clinical

criteria


nite/untested


nite/untested

MCI due to AD

Intermediate

likelihood

Intermediate

Positive Untested

Untested Positive

MCI due to ADHigh

likelihood


MCIunlikely due to

AD




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Level of Certainty


Etiology


CSF)


sMRI)

MCI-core clinical

criteria


nite/untested


nite/untested

MCI due to AD

Intermediate

likelihood

Intermediate

Positive Untested

Untested Positive

MCI due to ADHigh

likelihood


MCIunlikely due to

AD




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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


Etiology


CSF)


sMRI)

MCI-core clinical

criteria


nite/untested


nite/untested

MCI due to AD

Intermediate

likelihood

Intermediate

Positive Untested

Untested Positive

MCI due to ADHigh

likelihood


MCIunlikely due to

AD




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Level of Certainty


Etiology


CSF)


sMRI)

MCI-core clinical

criteria


nite/untested


nite/untested

MCI due to AD

Intermediate

likelihood

Intermediate

Positive Untested

Untested Positive

MCI due to ADHigh

likelihood


MCIunlikely due to

AD




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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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Wolk Workshop

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