wolk- case- slides mci2014

8/13/2019 Wolk- Case- Slides Mci2014

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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 forgetfulness and confusion

Forgets aspects of prior situations , may conflate separate events Forgets conversations Needs instruction for tasks she used to do on own Children and best friend corroborated memory issues Husband noted some changes after D/C of Prempro year before

Admits to relying on lists more and has forgotten time of appts(including initial evaluation)

Occasional word-finding problems, but generally fluent and goodcomprehension

Always had difficulty with proper nouns, but more difficult No disorientation to time or place No change in problem solving or judgment


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HPI (cont) She has minimal functional change

Clerical work for husband s law practice Occasionally forgets item when shopping No issues driving, cooking, handling finances No issues with BADL s

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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Medicines

Paroxetine CR 12.5 daily Aspirin

Allegra Supplements


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Fam/Soc Hx

Mother with AD developed in 80 s Sister with mild AD at age 70

Prior 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 SD s below mean Speech was fluent with good comprehension Visual constructions, processing speed, sequencing and other

executive 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

MCI memory plus other (language)


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FDG PET No regionalhypometabolism


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Quantitative MRI Measures

SPARE AD: -0.85 (Normal)


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Level of CertaintyDiagnostic Category Biomarker Driven

Probability of ADEtiology

Presence of CerebralAmyloidosis (PET,CSF)

Evidence of NeuronalInjury (tau, FDG,sMRI)

MCI-core clinicalcriteria

Uninformative Conflicting/indeterminite/untested

Conflicting/indeterminite/untested

MCI due to AD Intermediatelikelihood

IntermediatePositive Untested

Untested Positive

MCI due to AD Highlikelihood

Highest Positive Positive

MCI unlikely due toAD

Lowest Negative Negative

Albert et al., Alzheimer s & Dementia , 2011


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Untested Positive







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CSF Biomarkers Luminex platform

Cutoff s based on premortem CSF for autopsy-confirmed AD cases and CN adults (Shaw et al., Annals ofNeurology, 2009)

A: 124 pg/ml (92; Sens: 69.6%, Sp: 92.3%) P-tau: 26 pg/ml (> 23; Sens: 67.9%, Sp: 73.1%) Tau/A: 0.42 (>0.39; Sens: 85.7%, Sp: 84.6%)

Repeated 5 years later A 187 pg/ml; tau: 94 pg/ml; p-tau: 24 pg/ml Amyloid imaging also positive at that time


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Untested Positive







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Untested Positive







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Follow-up

Over next year, patient and family describedsignificant improvement. Stated would not have evercome to PMC if had been doing as well

Based on testing and hx, reverted to normal Subsequently, had more significant depression

related to multiple life stressors Followed ~7 years to present still c/o word-finding

lapses and forgetfulness, but latter only whenstressed


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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 and language

complaints Cognitive sx s began 1 year prior to presentation

Forgetting appointments

Poorer orientation to time Difficulty with remember driving directions Word-finding issues and losing train of thought

Seen by outside neurologist and had extensive work-up Started on donepezil with significant improvement

Denied mood sx s Volunteered at soup kitchen, chores around house without

difficulty, no issues with basic ADL s


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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 70 s 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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Physical Examination

General medical exam was unremarkable Neurological exam

CNs II-XII intact Motor: Strength and tone were WNL DTRs: 1+ and symmetric Sensation intact to all modalities Normal RAM/FNF Gait was steady with normal stride, armswing


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Studies

Blood work WNL The MRI scan showed mild to moderate

generalized cortical atrophy with

commensurate mild ventriculomegaly. Therewere occasional punctate areas of whitematter signal changes

MCI memory plus other (language,visuospatial)


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Quantitative Structural MRI


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FDG PET decreased parietal lobe uptake R >L and left temporal lobe consistent with AD


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Level of CertaintyDiagnostic Category Biomarker DrivenProbability of AD

Etiology








Untested Positive







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Etiology








Untested Positive







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CSF Biomarkers A: 213 pg/ml (92; Sens: 69.6%, Sp: 92.3%) P-tau: 69 pg/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 203 pg/ml; tau: 113 pg/ml; p-tau: 76 pg/ml


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Etiology








Untested Positive







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Etiology








Untested Positive







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Follow-up Over next year, further cognitive and functional

decline More forgetful forgot 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

F ll


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Follow-up 6 months later

Unable to learn way around cruise ship Less engaged in conversations Still meticulous about his self-care and clothing/belongings Worries about lack of money MMSE 22/30 Memory testing poorer 0/10 recall on CERAD and 6/25

LM II

F ll


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Follow-up 1 year later

Mild further decline (MMSE 19/30) Over next year (2 years from presentation), 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 neurodegenerationby MCI stage may predict slower evolution andpossibility that AD is not cause of memory sx s

Evidence of neurodegeneration, even in absence ofAD, may predict more imminent decline

Etiology unclear


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Thank you!

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