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

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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,

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10/15/2018 1 Dementia Diagnosis and Treatment

current and future strategies

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

Disclosures

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

Outline

  • 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

Why is dementia important?

Alz Association fact sheet, Alzheimer's & Dementia: 2015 11:332-384

  • Percentage change in cause of death 2000 to 2013
  • 1 in 8 Americans > 65 yo affected
  • ~$277 billion direct cost in 2018
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Rates of dementia in Asian Americans

Asian Americans and Dementia

  • Recent studies suggest rates of dementia in Chinese (8‐10%) comparable to

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,

Filipinos 17.3/1000

Incorrect/stigmatized perception of dementia continues

  • 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

Dementia Phenotypes and Pathology

AD tau β‐amyloid AD lvPPA PCA

Alzheimer’s dementia presentations

1. Typical amnestic

1. Poor memory 2. Poor judgement, decision making

2. Language variant (logopenic variant aphasia)

1. Word finding difficulties 2. Trails off, “talks around”

3. Visual spatial variant (posterior cortical atrophy)

1. Readings lines of text 2. Judging space and distance 3. Can only see one thing at a time 4. Maneuvering, identifying objects

Alzheimer’s dementia diagnosis

Detailed history & physical

Earliest symptoms a) Memory b) Behavioral – disinhibition, compulsions, disgust, diet change c) Motor – early falls, parkinsonism d) Language ‐ fluency, word meaning loss e) Mood*

Neuropsychology (memory test)

  • MMSE good but does not capture behavioral changes
  • Chinese seem to respond same as caucasian

Reversible dementia lab work (B12, TFT) MRI brain

Kramer et al. 2004 , Tsai et al. 2015

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MRI brain

  • 1. Rule out other causes of memory loss, you never know!
  • 2. Assess for degree of vascular burden

a) previous silent infarcts? need secondary stroke prevention?

  • 3. Assess for atrophy

a) Anterior vs posterior b) Asymmetry?

AD FTD CBS

Moments of confusion

  • 1. Young age, <65
  • 2. Behavioral changes
  • 3. Motor changes
  • 4. Language changes
  • 5. MMSE/neuropsychology test not so bad!
  • 6. No progression over time
  • 7. Suspicion of other causes (mood, drugs, poor sleep etc)

Biomarkers can now help

1. β‐amyloid PET scan (florbetapir, flutemetamol, florbetaben) 2. Lumbar puncture CSF β‐amyloid/tau testing

flutemetamol F‐18 florbetapir F‐18 florbetaben F‐18

Positive Negative AD “like”

<600 pg/ml >375 pg/ml >60 pg/ml

β‐amyloid biomarker pitfalls

  • 1. Beware of false positives with increasing age
  • 2. Does not indicate severity
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β‐amyloid biomarker appropriate use criteria

  • 1. Patients with persistent or progressive unexplained mild cognitive impairment
  • 2. Patients satisfying core clinical criteria for possible Alzheimer’s disease because of unclear

clinical presentation, either atypical clinical course or etiologically mixed presentation

  • 3. Patients with progressive dementia and atypically early age of onset (usually defined as 65

years or less in age) Amyloid imaging is inappropriate in the situations listed below.

  • 1. Patients with core clinical criteria for probable Alzheimer’s disease with typical age of
  • nset
  • 2. To determine dementia severity
  • 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
  • 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

Alzheimer’s dementia Treatment

Cholinesterase inhibitors ‐caution against patients with bradycardia, conduction system disease ‐common gastrointestinal side effects can be avoided with a patch NMDA antagonist ‐had mild effects against behavioral agitation

Alzheimer’s dementia Treatment

Interventions for mood and/or behavioral agitations

  • Citalopram improved on agitation, global impression,

caregiver distress (CitAD trial)

  • Generally use SSRIs first, then consider low dose,

short acting BZD or atypical antipsychotics

  • Behavioral interventions may be equally effective!

Caregiver health

  • 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

Chinese American (N=140) Caucasians (n=140) Depression 35% 15% Antidepressants 12% 37% Average Education (yr) 13.1+5.3 16+2.7

Depression is under‐recognized in Chinese Americans

Chao et al. Am J Ger Psych, 2014

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10/15/2018 5

Alzheimer’s dementia What’s new on the horizon?

Tau PET correlates with Alzheimer’s disease anatomy

Ossenkoppele et al. Brain, 2016

Tau PET correlates with Alzheimer’s disease severity

Xia et al. JAMA Neurology 2017, Barret et al. JNM 2017

Alzheimer’s disease clinical trial update β‐amyloid as a target

Aβ Ab

  • Endpoints in right direction, but not

enough!

  • Not sure if enough crossed BBB
  • Did not budge Aβ in brain

Aβ Ab

  • Lowered Aβ in brain
  • Patient balance issues
  • TBD

BACEi

  • Moved Aβ in brain
  • No clinical benefit so far
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Alzheimer’s disease clinical trial update β‐amyloid as a target may need to be given early before any symptoms

may not be effective jury is still out

  • Boosting cellular breakdown
  • Stabilizing microtubules
  • Inhibiting spread of misfolded tau
  • Tau vaccines
  • Reducing expression
  • Inhibiting assembly
  • Disrupting aggregates

Holtzman et al 2016

Alzheimer’s disease clinical trial update Tau as a target

Some ongoing tau therapy clinical trials..

  • TPI‐287 in AD, PSP, CBS (phase I) completed
  • BMS‐986186 Ab in PSP (phase II)
  • RO 7105705 Ab in AD (phase I)
  • AbbVie C2N8E12 Ab in PSP (phase II)
  • AbbVie C2N8E12 Ab in AD (phase II)
  • Salsalate in PSP (phase 1) completed
  • Salsalate in AD (phase 1)

Chinese Outreach team 外展團隊

  • Bilingual and bicultural staff
  • Dr. Howard Rosen (neurologist) 羅森醫師，神經內科

– English – 英文

  • Dr. Richard Tsai (neurologist) 蔡孟鈞醫師，神經內科

– Mandarin, English – 國語，英文

  • Marian Tse (research assistant) 謝譚敏兒， 研究助理

– Cantonese, Toishanese, Mandarin, English – 廣東話，台山話，國語，英文

  • Kevin Lieu (research assistant) 廖嘉麒，研究助理

– Cantonese, English – 廣東話，英文

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Outreach clinics 華人外展計劃診所

  • Chinatown Public Health Center
  • 華城公共衛生局
  • Chinese Hospital
  • 東華醫院

Numbers so far (2018) 618 patients > 60% pts years of education: 0 to 6

  • Diagnosis 診斷
  • Alzheimer’s 阿茲海默

149

  • MCI 輕微認知障礙

79

  • Normal 正常

16

  • DLB 路易體失智症

13

  • FTD 額顳痴呆

4

  • Parkinson’s 帕金森

2

  • PSP 進行性上眼神經核麻痺症

4

  • CBD 大腦皮質基底核退化症

13

  • TBI 腦外傷

5

  • Vascular dementia 腦中風

11

  • Other 其它

54

Thank You

UCSF Memory and Aging Center

Adam Boxer MD PhD Gil Rabinovici MD Bruce Miller MD Julio Rojas‐Martinez MD PhD Mary Koestler, RN, PhD Zachary Miller, MD Renaud LaJoie PhD Alexandre Bejanin PhD Adrienne Visani Viktoriya Bourakova Amelia Strom Peter Ljubenkov, MD Howie Rosen, MD Yann Cobigo, PhD Jesse Brown PhD William Seeley MD June Jung, PhD Scott Fields, PharmD Emma Hare Emmeline Chuu Dan Luong Ryan Powers Chiara Corbetta‐Rastelli Cindy Barton, RNP Jennifer Richards Paige Mumford Amy Wolf Sophie Lin, PhD Noelle Ohanesian Lauren Fisher and many many more…..

Alzheimer’s disease clinical trial update Solanezumab Alzheimer’s disease clinical trial update 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

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Alzheimer’s disease clinical trial update Solanezumab

β‐amyloid PET scan results

  • no significant differences

CSF β‐amyloid results

  • rise in CSF Aβ40 and Aβ42

– Increased half life? – Carried over from peripheral blood?

Alzheimer’s disease clinical trial update Verubecestat EPOCH trial – in mild to moderate AD (terminated early 2/2017)

  • reduced Aβ in CSF 70‐80%, reduced Aβ in brain (PET) ~2‐4%
  • no clinical benefit

APECS trial – in prodromal AD (terminated early 2/2018)

  • no positive benefit/risk likely to be established

Alzheimer’s disease clinical trial update Aducanumab Alzheimer’s disease clinical trial update Aducanumab

**Open label trials make clinical measurements unreliable!