Effects of traumatic brain injury (TBI) &

post traumatic stress disorder (PTSD)

on Alzheimer’s disease (AD) in Veterans using ADNI

(DOD ADNI)

Michael W. Weiner

Effects of traumatic brain injury (TBI) &

post traumatic stress disorder (PTSD)

on Alzheimer’s disease (AD) in Veterans using ADNI

(DOD ADNI)

Michael W. Weiner

ALZHEIMER’S DISEASE• An amyloid-β facilitated tauopathy

• Synapse loss, neurodegeneration associated with progressive memory problems leading to dementia

• Dementia due to AD, MCI due to AD, preclinical AD. No disease modifying treatment/prevention

• AD runs in families and APOE4 is a major risk factor. Other genes involved

• AD commonly occurs with other pathologies

• Many treatment trials, mostly aimed at Aβ– All failures, but recently…..

BIOGEN STUDYPre-specified Interim Analysis:

A Randomized, Double-blind, Phase 1b Study (PRIME) of Aducanumab

(BIIB037), an Anti-Beta-Amyloid Monoclonal Antibody, in Subjects with Prodromal or Mild Alzheimer’s Disease

Jeff Sevigny,1 Ping Chiao,1 Leslie Williams,1 Tianle Chen,1 Yan Ling,1 John O’Gorman,1 Jim Ferrero,1 Alvydas Mikulskis,1 Christoph Hock,2 Roger Nitsch,2 Alfred Sandrock11Biogen Idec, Cambridge, MA, USA; 2Neurimmune Holding AG, ZurichSevigny J, Chiao P, Williams L, et al. A Randomized, Double-blind, Phase 1b Study (PRIME) of Aducanumab (BIIB037), an Anti-Beta-Amyloid Monoclonal Antibody, in Subjects with Prodromal or Mild Alzheimer’s Disease. Presented at: 12th International Conference on Alzheimer's and Parkinson's Disease. Mar 18– 22, 2015 Nice, France.Educational resource provided in response to unsolicited request (Content current 22-Mar-2015)BA-US-0072

STUDY DESIGN

Sevigny J, Chiao P, Williams L, et al. A Randomized, Double-blind, Phase 1b Study (PRIME) of Aducanumab (BIIB037), an Anti-Beta-Amyloid Monoclonal Antibody, in Subjects with Prodromal or Mild Alzheimer’s Disease. Presented at: 12th International Conference on Alzheimer's and Parkinson's Disease. Mar 18– 22, 2015 Nice, France.

BA-US-0072 Educational resource provided in response to unsolicited request (Content current 22-Mar-2015)

EFFECTS ON BRAIN AMYLOID

Sevigny J, Chiao P, Williams L, et al. A Randomized, Double-blind, Phase 1b Study (PRIME) of Aducanumab (BIIB037), an Anti-Beta-Amyloid Monoclonal Antibody, in Subjects with Prodromal or Mild Alzheimer’s Disease. Presented at: 12th International Conference on Alzheimer's and Parkinson's Disease. Mar 18– 22, 2015 Nice, France. BA-US-0072 Educational resource provided in response to unsolicited request (Content current 22-Mar-2015)

CHANGE OF MINI-MENTAL STATE EXAM

Sevigny J, Chiao P, Williams L, et al. A Randomized, Double-blind, Phase 1b Study (PRIME) of Aducanumab (BIIB037), an Anti-Beta-Amyloid Monoclonal Antibody, in Subjects with Prodromal or Mild Alzheimer’s Disease. Presented at: 12th International Conference on Alzheimer's and Parkinson's Disease. Mar 18– 22, 2015 Nice, France. BA-US-0072

Educational resource provided in response to unsolicited request (Content current 22-Mar-2015)

M. Weiner, P. Aisen, R Petersen, C. Jack, W. Jagust, J Trojanowski, L. Shaw, A. Toga, L. Beckett, D. Harvey, R.

Green, A Saykin, J Morris, N Cairns, L Thal (D)John Hsiao, Neil Buckholz, Private Partners Scientific Board

(PPSB) Site PIs, Study Coordinators and over 1500 subjects

enrolled in 58 Sites in US and Canada

FUNDED BY NATIONAL INSTITUTE ON AGINGNIBIB,NIMH,NINR,NINDS,NCRR,NIDA and CIHR

ADNI2Multimodality Neuroimaging

Structural imaging

T1weighted

T2 weighted FLAIR DTI

ASL MRI fMRI FDG PET Amyloid PET 8

RISK FACTORS FOR AD

• Age and family history (Apoe-4) !!!

• Traumatic brain injury, concussion

• Many others– Obesity, diabetes, hypertension,

cerebrovascular disease, stroke, low SES, low education, lack of exercise, smoking, etc.

– Including PTSD

BACKGROUND• Many studies show an epidemiological

association of TBI with dementia of the Alzheimer’s type

• Autopsy studies show an association of TBI with amyloid accumulation

• There has been no prospective study of TBI and PTSD on AD using biomarkers.

DEPARTMENT OF DEFENSE ADNI

• Study of 200 normal veterans over age 65– History of TBI, PTSD, or controls; 1 yr. F/U

• Study of 200 MCI veterans over age 65– Same groups: 1 yr. F/U

• Study almost identical to ADNI

METHODS• Recruitment uses data-base provided by the

Veterans Administration: Big Challenge

• Telephone screening before referral to sites

• Clinical/Cognitive assessment identical to ADNI. Additional assessment of PTSD

• LP/CSF identical to ADNI

• Imaging identical to ADNI: No FDG PET– DTI, resting state fMRI, no perfusion MRI

Recruitment: Overall Summary

Recruitment: Race & Ethnicity

Totals CaucasianAfrican

American“Other” Race

Missing from

VA C&PLatino /

HispanicNot Latino / Hispanic

Missing from VA

C&P

USA Census Population

(2012 estimate)313,873,685 77.9% 13.1% 9.0% N/A 16.9% 83.1% N/A

Sample of Vietnam

Veterans(VA Comp. &

Pension)67, 925 61.7% 17.8% 3.0% 17.5% 3.8% 78.4% 17.8%

Mailed Brochures

12,867 44.3% 17.3% 2.9% 35.5% 4.5% 59.6% 35.9%

Subjects Called10,400 46.4% 19.8% 2.8% 30.9% 4.5% 64.4% 31.2%

Baseline157 83.4% 7.0% 9.6% N/A 10.2% 89.8% N/A

Subjective Memory Complaints of 157 Baseline Subjects (w/AD8)

Cognitive Status at Clinic Baseline

Cohort % Normal % MCI

Controls (n=55) 96.4% (n=53) 3.6% (n=2)

PTSD (n=51) 86.3% (n=44) 13.7% (n=7)

TBI (n=19) 89.5% (n=17) 10.5% (n=2)

Both (n=21) 81.0% (n=17) 19.0% (n=4)

Total (n=146) 89.7% (n=131) 10.3% (n=15)

Reasons for Exclusion at Pre-Screen

CONCERNS

• Small % of subjects contacted agreed to participate: Very arduous study

• High screen-fail rate

• More drop out as subjects were asked to make clinic visits: Reflects arduous study

• Only a small fraction of Vietnam subjects with TBI and PTSD participate: Generalizability?

Successes; Data Analysis Begun:Florbetapir summary N=99

Co

rtic

al f

lorb

eta

pir

rete

ntio

n

(wh

ole

ce

reb

re

f)

26675.626%

NAge

% ApoE4+

4270.426%

3167.823%

1166.729%

1567.031%

S Landau 12.16.14

80/266 AV45+ (30%)

AB

3/31 AV45+(10%)

10/42 AV45+(24%)

4/15 AV45+(27%)

3/11 AV45+(27%)

Total N99

A: 66 year old male TBI patient

B: 68 yrs. male TBI patient

SUMMARY AND CONCLUSIONS

• This study demonstrates some of the problems with recruiting veterans into AD research trials: high levels of excludes

• More MCI in PTS and TBI groups• Thus far, the results show no effects of TBI or PTSD on AD

measured with biomarkers• We are not even 50% enrolled yet• High excludes and low minorities emphasizes the problems of

biomarker-intensive studies• Emphasizes challenges of clinical trials on veterans

• An online registry for recruitment,

screening, and monitoring progression of neurodegenerative diseases

• Available to investigators for all types of neuroscience studies. Goals”– To accelerate neuroscience research: To establish a

large cohort of participants who are monitored longitudinally

– To provide a pool of eligible participants to other investigators to facilitate their studies by creating a new model of recruitment and screening

– To establish large cohort of TBI/PTS subjects

How it works

The Brain Health Registry: How it Works

UCSF IRB approved;Obtain online consent from all participants

Sign up

Tell us about yourself

Take some tests

Come back

Come back…again

The Brain Health Registry: How it Works

UCSF IRB approved;Obtain online consent from all participants

Sign up

Tell us about yourself

Take some tests

Come back

Come back…again

Self-reported memory problems, family history of AD, health and lifestyle

The Brain Health Registry: How it Works

UCSF IRB approved;Obtain online consent from all participants

Sign up

Tell us about yourself

Take some tests

Come back

Come back…again

Online cognitive tests from Cogstate, Ltd. and Lumosity, Inc.

Self-reported memory problems, family history of AD, health and lifestyle

The Brain Health Registry: How it Works

UCSF IRB approved;Obtain online consent from all participants

Sign up

Tell us about yourself

Take some tests

Come back

Come back…again

Online cognitive tests from Cogstate, Ltd. and Lumosity, Inc.

Self-reported memory problems, family history of AD, health and lifestyle

Participants return and repeat tasks every 6 months

Cogstate Brief Battery:

4 Card tests measuring cognitive function across various domains

Supervised version has clinical validity, reliability, sensitivity to age effects

Has been used in MCI subjects

Longitudinal decline can predict amyloid positivityChen et al 2010; Lim et al 2012, 2013; Darby

et al 2011, 2012, 2014

Lumos Labs: Sharing Contacts & Data

31

Growth of the Brain Health Registry

Over 31,000 participants registered in 18 months 95% say they are willing to be contacted for future

studies 49% of registrants return for 6 month follow-up (since

October 2014) 37% of registrants return for 1 year follow-up (since

April 2015) 57% of returners complete all follow-up tasks The cohort of “returners” is enriched in older

subjects with memory concerns

SUMMARYBRAIN HEALTH REGISTRY

• BHR is available to investigators for recruitment, assessment, longitudinal monitoring of subjects

• Can be used to study TBI, PTS, cognitive problems, emotional problems, genetics

• Not a substitute for in-clinic assessments

• Scalability leads to low costs