UCSF Memory and Aging Center 2016 Best Practices in Mild Cognitive - PDF document

UCSF Memory and Aging Center 2016 Best Practices in Mild Cognitive Impairment & Dementia Bruce L. Miller, MD A.W. and Mary Margaret Clausen Distinguished Professor in Neurology Director, Memory and Aging Center Co-Director, Global Brain Health Institute Joint Appointment in Psychiatry UCSF School of Medicine 12/8/2017 UCSF Mission Bay Campus, Sculpture Mark di Suvero Disclosures Criteria for Dementia Advisor / Director: Grants: Cognitive or behavioral symptoms that: • The Tau Consortium – Scientific Advisor • National Institute of Health/National Institute of Aging grants: P50AG023501, P01AG019724, • interfere with usual function • The John Douglas French Foundation – Medical Advisor P50 AG1657303 & T32 AG023481 • The Larry L. Hillblom Foundation – Medical Advisory • • represent a decline from previous levels of Centers for Medicare & Medicaid Services Board (CMS) Dementia Care Ecosystem • Global Brain Health Institute (GBHI) – Co-Director 1C1CMS331346-01-00 performance • Cambridge Biomedical Research Centre and its subunit, • UCSF/Quest Diagnostics Dementia Pathway the Biomedical Research Unit in Dementia (UK) • are not explained by delirium or major psychiatric Collaboration Research Grant • American Brain Foundation (ABF) – Board Member • J. David Gladstone Institutes Subcontract • University of Washington ADRC – External Advisor (Grinberg):1U54NS100717-01 disorder • Stanford University ADRC – External Advisor Cognitive impairment is measured through • Arizona Alzheimer’s Disease Center (ADC) – External Royalties: Advisor • Cambridge University Press 1. history taking from the patient and • Massachusetts Alzheimer Disease Research Center – • Guilford Publications, Inc. External Advisor • Oxford University Press knowledgeable informant • International Society of FTD – USA-President, Executive • Neurocase Committee • Elsevier, Inc. 2. objective cognitive testing 1 12/8/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Women & Alzheimer’s Disease • 5 million Americans live with AD - ⅔ are women • ⅔ of Alzheimer’s caregivers are women, many will have to take time off or resign from their jobs. • After 60, a woman has 1 in 6 chance develop AD. • By 2050, 16 million in US ,135 million worldwide will have dementia, and millions more family members and friends will suffer alongside those Today 5.3 million By 2050, dementia diagnosed. Americans aged 65+ population will nearly years living with triple to 13.8 million; cost dementia; cost of $220B/y of $1,160 trillion/y The Women’s Alzheimer’s Movement thewomensalzheimersmovement.org Dementia is Expensive Neurodegenerative Causes Alzheimer’s disease Average Annual Per Person Average Annual Per Person frontotemporal dementia Medicare Spending Medicaid Spending Lewy body disease $23,497 $25,000 $9,000 $8,182 and more $8,000 $20,000 $7,000 $6,000 $15,000 $5,000 $4,000 $10,000 $7,223 $3,000 $2,000 $5,000 $1,000 $349 $- $- Dementia Seniors without Seniors with Alzheimer's Seniors without Seniors with Alzheimer's Alzheimer's Disease and Disease and Other Alzheimer's Disease and Disease and Other Other Dementias Dementias cognitive decline that interferes Other Dementias Dementias with everyday functioning memory, executive, behavioral, Source: Kelly MD, Amy S., et al, Annals of Internal Medicine 2015; 163:729-736. Primary funding source: National Institute on Aging. and/or motor symptoms 2 12/8/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Dementia Risk Factors Models of Degenerative Dementia All degenerative dementias have: • Head trauma • Cholesterol – Genetic and sporadic form • Stroke • Homocysteine – Cell culture and animal model • Hypertension • Low exercise • Diabetes • Specific genes • Poor sleep • Social isolation – Preclinical, early symptomatic and • Low cognitive reserve • Hearing loss symptomatic phase • Pollution (?) – Abnormal protein aggregation – Proteins spread from cell to cell Neuropathologic Inclusions Neuropathology Inclusions Aβ -42 & AD • Alzheimer disease: plaque (Aβ -42, 1984), tau tangle (tau, 1986) FTD tau or • Frontotemporal dementia: Pick body (tau, 1990), TDP-43 ubiquitin (TDP43, 2006), ubiquitin (FUS, 2009), PSP, CBD tau C9 (2011) • Parkinson dementia, dementia with Lewy bodies α -synuclein (α -synuclein, 1998) PD, DLB, MSA • Jakob-Creutzfeldt disease: prions (1982) PrP sc CJD 3 12/8/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Functional Connectivity Dorsal Midbrain Tau Spreads Like a Prion Tegmental Network & Tau PET in PSP Functional Connectivity Tau PET 0 2.5 Gardner et al. Ann Neurol 2013, Rabinovici 2015 Courtesy of Marc Diamond Differing Anatomy Defines Dementias MCI Across Diseases Disease Early Deficit Early Strength Disease Imaging Anatomy 1st Symptom Spared AD Memory, Spatial, Social (sometimes Language language) Social behavior Hippocampus posterior Memory, naming, AD temporal-parietal visuospatial Movement bvFTD Behavior, Executive Spatial, Language Frontal (emotional > Navigation, FTD cognitive neocortex) Apathy, behavior memory PPA Language Spatial, Social PD/PDD REM behavior Autonomic, Social, Memory Movement, Amygdala temporal- Behavior, DLB hallucinations DLB Movement, Delirium occipital memory visuospatial 4 12/8/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Psychiatric Changes in Dementia Molecular Changes Underlying AD Shdo, et al., submitted Amyloid Deposition in Autosomal Research Criteria for Alzheimer’s Disease Dominant AD • At least two of the following: • Impairment in ability to remember new information Carriers • Impaired reasoning ability manage complex tasks • Impaired visuospatial abilities • Impaired language functions (speak, read, writie) • Changes in behavior, personality or comportment Non-carriers • Insidious onset of decline and progressive worsening of symptoms and function • Evidence of a causative genetic mutation • Biomarkers for amyloid deposition Years from symptom onset Bateman et al., NEJM 2012 5 12/8/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Amyloid vs. FDG-PET in Differential Amyloid PET vs. CSF Aβ Diagnosis of AD vs. FTD AD (N=62, age 65, MMSE 22) Both negative Normal κ = 0.76 FTD (N=45, age 65, MMSE 22) EMCI κ = 0.65 LMCI κ = 0.71 normal  AD κ = 0.70 Amyloid (PIB) PET visual reads κ = 0.72 90% sensitivity, 83% specificity  abnormal CSF Aβ 1-42 Inter-rater agreement κ =0.96 FDG-PET visual reads 78% sensitivity*, 84% specificity Inter-rater agreement κ =0.72* Both positive 70 autopsy-proven cases PIB: Sensitivity 96%, Specificity 88% FDG: Sensitivity 88%, Specificity 89% Florbetapir cortical retention ratio * - p<0.05 vs. PIB Rabinovici et al. Neurology 2011 Landau et al, Ann Neurol 2013 IDEAS-Study@acr.org T807 Tau PET in AD IDEAS-Study.org • National, open-label study on clinical utility of amyloid PET in ~18,500 Medicare beneficiaries with MCI or dementia of uncertain cause • Eligible patients referred for PET by dementia experts • Scans covered by CMS, performed and interpreted locally • Aim 1: Impact of scan on management plan at 3 months Healthy Very Mild AD Mild AD Severe AD • Aim 2: Impact on major medical outcomes at 12 months The primary hypothesis is that, in diagnostically uncertain cases, amyloid PET will lead to significant changes in patient management, and this will translate into improved medical outcomes 6 12/8/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Tau PET: The New Frontier Treatable Disorders That Present with Cogntive or Behavioral Problems • B12 deficiency Amyloid, tau & brain metabolism • Thyroid deficiency 57 year-old AD • Medication side effects • Depression Brain dysfunction • Alcohol or drug dependency correlates with • Cerebrovascular disease tau but not amyloid • Autoimmune diseases • Sleep disorders Principles • Behavioral, cognitive, motor alterations represent change in the brain • Some changes are progressive & untreatable, What Can We Do? others have treatable component • Insight not invariably present in the patient or in their loved ones • “Do no harm”— not intervening can harm • Decisions around intervention rarely clear and can be heart-wrenching 7 12/8/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]