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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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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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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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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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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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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
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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Level of CertaintyDiagnostic Category Biomarker DrivenProbability of AD
Etiology
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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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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Level of CertaintyDiagnostic Category Biomarker DrivenProbability of AD
Etiology
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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Level of CertaintyDiagnostic Category Biomarker DrivenProbability of AD
Etiology
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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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!