Clinical Implications of Discordant Biomarkers

David A. Wolk, M.D. Assistant Professor of Neurology Assistant Director, Penn Memory Center Perelman School of Medicine at the University of Pennsylvania

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

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

PMHx
Osteopenia Diet-controlled hyperlipidemia GERD

Medicines
Paroxetine CR 12.5 daily Aspirin Allegra Supplements

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

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

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 for ADNI 2) BNT and category fluency ~ 1.5 SDs below mean Speech was fluent with good comprehension Visual constructions, processing speed, sequencing and other executive functioning tasks were normal

Studies
B12 and TSH WNL MRI Brain: occasional hyperintensities in deep and subcortical white matter. No other findings MCI memory plus other (language)

Quantitative MRI Measures

SPARE AD: -0.85 (Normal) -Spatial pattern classifier developed by C. Davatzikos

FDG PET No regional hypometabolism

Level of Certainty
Diagnostic Category Biomarker Driven Probability of AD Etiology Uninformative Presence of Cerebral Amyloidosis (PET, CSF) Evidence of Neuronal Injury (tau, FDG, sMRI) MCI-core clinical criteria Conflicting/indetermi Conflicting/indetermi nite/untested nite/untested

MCI due to AD Intermediate likelihood

Positive
Intermediate Untested Positive Negative

Untested
Positive Positive Negative

MCI due to AD High Highest likelihood MCI unlikely due to AD Lowest

Albert et al., Alzheimer s & Dementia, 2011

Level of Certainty
Diagnostic Category Biomarker Driven Probability of AD Etiology Uninformative Presence of Cerebral Amyloidosis (PET, CSF) Evidence of Neuronal Injury (tau, FDG, sMRI) MCI-core clinical criteria Conflicting/indetermi Conflicting/indetermi nite/untested nite/untested

MCI due to AD Intermediate likelihood

Positive
Intermediate Untested Positive Negative

Untested
Positive Positive Negative

MCI due to AD High Highest likelihood MCI unlikely due to AD Lowest

Albert et al., Alzheimer s & Dementia, 2011

CSF Biomarkers
Luminex platform
Cutoff s based on premortem CSF for autopsyconfirmed AD cases and CN adults (Shaw et al., Annals of
Neurology, 2009)

A: 124 pg/ml (<192; Sens: 96.4%, Sp: 76.9%) Tau: 52 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

Level of Certainty
Diagnostic Category Biomarker Driven Probability of AD Etiology Uninformative Presence of Cerebral Amyloidosis (PET, CSF) Evidence of Neuronal Injury (tau, FDG, sMRI) MCI-core clinical criteria Conflicting/indetermi Conflicting/indetermi nite/untested nite/untested

MCI due to AD Intermediate likelihood

Positive
Intermediate Untested Positive Negative

Untested
Positive Positive Negative

MCI due to AD High Highest likelihood MCI unlikely due to AD Lowest

Albert et al., Alzheimer s & Dementia, 2011

Level of Certainty
Diagnostic Category Biomarker Driven Probability of AD Etiology Uninformative Presence of Cerebral Amyloidosis (PET, CSF) Evidence of Neuronal Injury (tau, FDG, sMRI) MCI-core clinical criteria Conflicting/indetermi Conflicting/indetermi nite/untested nite/untested

MCI due to AD Intermediate likelihood

Positive
Intermediate Untested Positive Negative

Untested
Positive Positive Negative

MCI due to AD High Highest likelihood MCI unlikely due to AD Lowest

Albert et al., Alzheimer s & Dementia, 2011

Follow-up
Over next year, patient and family described significant 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 present still c/o word-finding lapses and forgetfulness, but latter only when stressed
Occasional struggles with depression related to multiple life stressors

Psychometric Measures

Repeat MRI and PET in Year 6 and 7 unchanged

Chief Complaint/HPI
WB presented at age 66 with memory and language 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 around house without difficulty, no issues with basic ADLs

PMHx
Prostate CA s/p prostatectomy S/p hernia repair

Medicines
Donepezil 10 mg daily Pepcid Tylenol PM

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

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

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

Studies
Blood work WNL MRI: mild to moderate generalized cortical atrophy with commensurate mild ventriculomegaly; occasional punctate areas of white matter signal changes MCI memory plus other (language, visuospatial)

Quantitative Structural MRI

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

Level of Certainty
Diagnostic Category Biomarker Driven Probability of AD Etiology Uninformative Presence of Cerebral Amyloidosis (PET, CSF) Evidence of Neuronal Injury (tau, FDG, sMRI) MCI-core clinical criteria Conflicting/indetermi Conflicting/indetermi nite/untested nite/untested

MCI due to AD Intermediate likelihood

Positive
Intermediate Untested Positive Negative

Untested
Positive Positive Negative

MCI due to AD High Highest likelihood MCI unlikely due to AD Lowest

Albert et al., Alzheimer s & Dementia, 2011

Level of Certainty
Diagnostic Category Biomarker Driven Probability of AD Etiology Uninformative Presence of Cerebral Amyloidosis (PET, CSF) Evidence of Neuronal Injury (tau, FDG, sMRI) MCI-core clinical criteria Conflicting/indetermi Conflicting/indetermi nite/untested nite/untested

MCI due to AD Intermediate likelihood

Positive
Intermediate Untested Positive Negative

Untested
Positive Positive Negative

MCI due to AD High Highest likelihood MCI unlikely due to AD Lowest

Albert et al., Alzheimer s & Dementia, 2011

CSF Biomarkers
A: 213 pg/ml (<192; Sens: 96.4%, Sp: 76.9%) Tau: 127 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

Level of Certainty
Diagnostic Category Biomarker Driven Probability of AD Etiology Uninformative Presence of Cerebral Amyloidosis (PET, CSF) Evidence of Neuronal Injury (tau, FDG, sMRI) MCI-core clinical criteria Conflicting/indetermi Conflicting/indetermi nite/untested nite/untested

MCI due to AD Intermediate likelihood

Positive
Intermediate Untested Positive Negative

Untested
Positive Positive Negative

MCI due to AD High Highest likelihood MCI unlikely due to AD Lowest

Albert et al., Alzheimer s & Dementia, 2011

Level of Certainty
Diagnostic Category Biomarker Driven Probability of AD Etiology Uninformative Presence of Cerebral Amyloidosis (PET, CSF) Evidence of Neuronal Injury (tau, FDG, sMRI) MCI-core clinical criteria Conflicting/indetermi Conflicting/indetermi nite/untested nite/untested

MCI due to AD Intermediate likelihood

Positive
Intermediate Untested Positive Negative

Untested
Positive Positive Negative

MCI due to AD High Highest likelihood MCI unlikely due to AD Lowest

Albert et al., Alzheimer s & Dementia, 2011

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

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 poorer 0/10 recall on CERAD and 6/25 LM Delayed Recall

24 months after initial visit

Mild further decline (MMSE 19/30)

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

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 sx s Evidence of neurodegeneration, even in absence of evidence of cerebral amyloid, may predict more imminent decline
Etiology less clear

Thank you!