Disclosures current and future strategies Presenter(s) has the - PDF document

10/15/2018 Dementia Diagnosis and Treatment Disclosures current and future strategies Presenter(s) has the following interest to disclose: • Grant /research from: University of California, NIH/NIA K23AG055688 • Consulting for: ExpertConnect, Barclays, Grifols S.A. • Principal investigator for: AbbVie Richard Tsai MD MBA Assistant Professor of Neurology Associate Director, AD and FTD Clinical Trials Program University of California, San Francisco Memory and Aging Center Why is dementia important? Outline • 1 in 8 Americans > 65 yo affected • ~$277 billion direct cost in 2018 1. Introduction 2. Alzheimer’s dementia differential diagnosis a) Use of biomarkers 3. Dementia treatment strategies a) Asian American considerations 4. What’s new on the horizon? a) Tau PET b) Clinical trials against Aβ, tau • Percentage change in cause of death 2000 to 2013 Alz Association fact sheet, Alzheimer's & Dementia: 2015 11:332-384 1

10/15/2018 Asian Americans and Dementia Dementia Phenotypes and Pathology Rates of dementia in Asian Americans AD lvPPA • Recent studies suggest rates of dementia in Chinese (8‐10%) comparable to PCA those in U.S. • Asian Americans 7% of U.S. population over age 65 • Caucasian 19.3/1000 person‐years, Chinese 13.7/1000, Japanese 14.8/1000, AD tau Filipinos 17.3/1000 Incorrect/stigmatized perception of dementia continues β‐amyloid • 60% of Chinese Americans, 70% of Vietnamese Americans think dementia is part of normal aging • ~66% Chinese Americans thought late stage symptoms were early Fei et al., Alz Dis Assoc Disord, 2009; Lam et al., Int Psychogeriatr, 2008; Woo Asian J Psychiatr 2016; Nguyen et al. Asian J Pscyhiatr 2016 Alzheimer’s dementia presentations Alzheimer’s dementia diagnosis Detailed history & physical 1. Typical amnestic Earliest symptoms 1. Poor memory 2. Poor judgement, decision making a) Memory Behavioral – disinhibition, compulsions,  disgust, 2. Language variant b) diet change (logopenic variant aphasia) c) Motor – early falls, parkinsonism 1. Word finding difficulties Language ‐  fluency, word meaning loss d) 2. Trails off, “talks around” e) Mood* 3. Visual spatial variant Neuropsychology (memory test) (posterior cortical atrophy) • MMSE good but does not capture behavioral changes • 1. Readings lines of text Chinese seem to respond same as caucasian 2. Judging space and distance Reversible dementia lab work (B12, TFT) 3. Can only see one thing at a time MRI brain 4. Maneuvering, identifying objects Kramer et al. 2004 , Tsai et al. 2015 2

10/15/2018 MRI brain Moments of confusion 1. Rule out other causes of memory loss, you never know! 1. Young age, <65 2. Assess for degree of vascular burden 2. Behavioral changes a) previous silent infarcts? need secondary stroke prevention? 3. Motor changes 3. Assess for atrophy 4. Language changes a) Anterior vs posterior 5. MMSE/neuropsychology test not so bad! b) Asymmetry? 6. No progression over time 7. Suspicion of other causes (mood, drugs, poor sleep etc) FTD AD CBS Biomarkers can now help β‐amyloid biomarker pitfalls 1. β‐amyloid PET scan (florbetapir, flutemetamol, florbetaben) 2. Lumbar puncture CSF β‐amyloid/tau testing AD “like” <600 pg/ml >375 pg/ml Positive >60 pg/ml Negative 1. Beware of false positives with increasing age 2. Does not indicate severity florbetapir F‐18 flutemetamol F‐18 florbetaben F‐18 3

10/15/2018 β‐amyloid biomarker appropriate use criteria Alzheimer’s dementia Treatment Cholinesterase inhibitors 1. Patients with persistent or progressive unexplained mild cognitive impairment 2. Patients satisfying core clinical criteria for possible Alzheimer’s disease because of unclear ‐caution against patients with bradycardia, conduction system clinical presentation, either atypical clinical course or etiologically mixed presentation disease 3. Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age) ‐common gastrointestinal side effects can be avoided with a Amyloid imaging is inappropriate in the situations listed below. patch 1. Patients with core clinical criteria for probable Alzheimer’s disease with typical age of onset 2. To determine dementia severity NMDA antagonist 3. Solely based on a positive family history of dementia or presence of APOE4 4. Patients with a cognitive complaint that is unconfirmed on clinical examination ‐had mild effects against behavioral agitation 5. In lieu of genotyping for suspected autosomal mutation carriers 6. In asymptomatic individuals 7. Non‐medical usage (e.g. legal, insurance coverage, or employment screening) Johnson et al. Alzheimers Dement 2013 Depression is under‐recognized in Chinese Americans Alzheimer’s dementia Treatment Interventions for mood and/or behavioral agitations Chinese Caucasians American • Citalopram improved on agitation, global impression, (n=140) (N=140) caregiver distress (CitAD trial) Depression 35% 15% • Generally use SSRIs first, then consider low dose, short acting BZD or atypical antipsychotics • Behavioral interventions may be equally effective! Antidepressants 12% 37% Caregiver health Average Education (yr) 13.1+5.3 16+2.7 • Caregivers are at increased risk for depression, poor health • Importance of “saving face” associated with worse caregiver outcomes (Levenson, personal communication) Porsteinsson AP, et al. JAMA 2014, Richardson TJ, et al. Curr Psychiatry Rep 2013 Chao et al. Am J Ger Psych, 2014 4

10/15/2018 Tau PET correlates with Alzheimer’s disease anatomy Alzheimer’s dementia What’s new on the horizon? Ossenkoppele et al. Brain, 2016 Alzheimer’s disease clinical trial update Tau PET correlates with Alzheimer’s disease severity β‐amyloid as a target Aβ Ab • Lowered Aβ in brain • Patient balance issues Aβ Ab BACEi • • TBD Endpoints in right direction, but not • Moved Aβ in brain enough! • No clinical benefit so far • Not sure if enough crossed BBB • Did not budge Aβ in brain Xia et al. JAMA Neurology 2017, Barret et al. JNM 2017 5

10/15/2018 Alzheimer’s disease clinical trial update Alzheimer’s disease clinical trial update β‐amyloid as a target Tau as a target • Reducing expression • Boosting cellular breakdown • Inhibiting assembly • Stabilizing microtubules • Disrupting aggregates • Inhibiting spread of misfolded tau • Tau vaccines jury is still out may not be effective may need to be given early before any symptoms Holtzman et al 2016 Chinese Outreach team 外展團隊 Some ongoing tau therapy clinical trials.. • Bilingual and bicultural staff • TPI‐287 in AD, PSP, CBS (phase I) completed • Dr. Howard Rosen (neurologist) 羅森醫師，神經內科 • BMS‐986186 Ab in PSP (phase II) – English – 英文 • RO 7105705 Ab in AD (phase I) • Dr. Richard Tsai (neurologist) 蔡孟鈞醫師，神經內科 – Mandarin, English • AbbVie C2N8E12 Ab in PSP (phase II) – 國語，英文 • Marian Tse (research assistant) 謝譚敏兒， 研究助理 • AbbVie C2N8E12 Ab in AD (phase II) – Cantonese, Toishanese, Mandarin, English – 廣東話，台山話，國語，英文 • Salsalate in PSP (phase 1) completed • Kevin Lieu (research assistant) 廖嘉麒，研究助理 – Cantonese, English • Salsalate in AD (phase 1) – 廣東話，英文 6

10/15/2018 Outreach clinics Thank You Numbers so far (2018) 華人外展計劃診所 618 patients UCSF Memory and Aging Center > 60% pts years of education: 0 to 6 • Chinatown Public Health Center Adam Boxer MD PhD Cindy Barton, RNP Jennifer Richards • Gil Rabinovici MD 華城公共衛生局  Diagnosis 診斷 Bruce Miller MD Paige Mumford Amy Wolf Julio Rojas‐Martinez MD PhD  Alzheimer’s 阿茲海默 149 Sophie Lin, PhD Mary Koestler, RN, PhD  MCI 輕微認知障礙 79 Zachary Miller, MD Noelle Ohanesian Lauren Fisher Renaud LaJoie PhD  Normal 正常 16 Alexandre Bejanin PhD and many many more…..  DLB 路易體失智症 13 Adrienne Visani  FTD 額顳痴呆 4 Viktoriya Bourakova Amelia Strom  Parkinson’s 帕金森 2 Peter Ljubenkov, MD  PSP 進行性上眼神經核麻痺症 4 Howie Rosen, MD  Chinese Hospital  CBD 大腦皮質基底核退化症 13 Yann Cobigo, PhD  東華醫院 Jesse Brown PhD  TBI 腦外傷 5 William Seeley MD  Vascular dementia 腦中風 11 June Jung, PhD  Other 其它 Scott Fields, PharmD 54 Emma Hare Emmeline Chuu Dan Luong Ryan Powers Chiara Corbetta‐Rastelli Alzheimer’s disease clinical trial update Alzheimer’s disease clinical trial update Solanezumab Solanezumab A) Memory test • 11% difference but not significant p = 0.10 B)Functional test • 1 point difference baseline 80 wk 80wk change Honig et al. 2018 7