1. 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

2. 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…..

3. BIOGEN STUDY Pre-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 Sandrock1
1Biogen Idec, Cambridge, MA, USA; 2Neurimmune Holding AG, Zurich
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.
Educational resource provided in response to unsolicited request (Content current 22-Mar-2015)
BA-US-0072

4. 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)

5. 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)

6. 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)

7. John Hsiao, Neil Buckholz, Private Partners Scientific Board (PPSB)
FUNDED BY NATIONAL INSTITUTE ON AGING
NIBIB,NIMH,NINR,NINDS,NCRR,NIDA and CIHR
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

8. ADNI2 Multimodality Neuroimaging
Structural imaging
T1weighted
T2 weighted
FLAIR
DTI
ASL MRI
fMRI
FDG PET
Amyloid PET

9. 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

10. 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.

11. 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

12. 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

14. Recruitment: Overall Summary
157 Subjects eligible for Baseline (150 Completed Baseline)
35% PTSD (n = 55)
12% TBI (n =19)
14% Both (n = 22)
39% Controls (n = 61)
252 Clinic Referrals
12% In Process
62% Baseline
26% Exclude/Withdraw
376 SCID Referrals
6% Pending
67% Referred to Clinic
27% Exclude/Withdraw
798 Consents Sent; (478 Signed and Returned)
41% Waiting
47% Received; OK for SCID
12% Exclude/Withdraw
3,508 Completed Screens
23% Mailed Consents
77% Excluded
10,400 Subjects Called
37% Pending
34% Complete Screen
29% Decline
12,867 Brochures Mailed
83% No Response
13% Respond “Yes”
4% Opt Out

15. Recruitment: Race & Ethnicity
Totals
Caucasian
African American
“Other”
Race
Missing from
VA C&P
Latino / Hispanic
Not 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%
Sample of Vietnam Veterans
(VA Comp. & Pension)
67, 925
61.7%
17.8%
3.0%
17.5%
3.8%
78.4%
Mailed
Brochures
12,867
44.3%
17.3%
2.9%
35.5%
4.5%
59.6%
35.9%
Subjects Called
10,400
46.4%
19.8%
2.8%
30.9%
64.4%
31.2%
Baseline
157
83.4%
7.0%
9.6%
10.2%
89.8%

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

17. 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)

18. Reasons for Exclusion at Pre-Screen

19. 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?

20. Successes; Data Analysis Begun: Florbetapir summary N=99
80/266 AV45+
(30%)
10/42 AV45+
(24%) A B
Cortical florbetapir retention (whole cereb ref)
3/31 AV45+
(10%)
4/15 AV45+
(27%)
3/11 AV45+
(27%) 42
70.4
26%
266
75.6
26% 31
67.8
23%
Total N 99 N
Age
% ApoE4+ 15
67.0
31% 11
66.7
29%
S Landau

21. A: 66 year old male TBI patient

22. B: 68 yrs. male TBI patient

23. 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

24. 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
To accelerate the development of treatments by facilitating clin trials, we developed
pool+: BHR uses an economy of scale. Traditionally, each clinical trial recruits separately. They may use online,, web-based prescreen tools. But BHR creates a pre-existing, pre-screened pool of potential subjects

25. How it works
Showcasing a recent PR effort involving B. Smith, a celebrity spokesperson recently diagnosed with late-onset AD
Anyone can go to the website and sign up, not disease specific, although we do a lot of targeted PR/advertising for older adults at risk for AD.

26. 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
take out small text under each number. Streamline. Mention Cogstate and Lumos. Put the cogstate slide right after this.
Come back
Come back…again

27. The Brain Health Registry: How it Works
UCSF IRB approved;
Obtain online consent from all participants
Sign up
Self-reported memory problems, family history of AD, health and lifestyle
Tell us about yourself
Take some tests
take out small text under each number. Streamline. Mention Cogstate and Lumos. Put the cogstate slide right after this.
Come back
Come back…again

28. The Brain Health Registry: How it Works
UCSF IRB approved;
Obtain online consent from all participants
Sign up
Self-reported memory problems, family history of AD, health and lifestyle
Tell us about yourself
Take some tests
Online cognitive tests from Cogstate, Ltd. and Lumosity, Inc.
take out small text under each number. Streamline. Mention Cogstate and Lumos. Put the cogstate slide right after this.
Come back
Come back…again

29. The Brain Health Registry: How it Works
UCSF IRB approved;
Obtain online consent from all participants
Sign up
Self-reported memory problems, family history of AD, health and lifestyle
Tell us about yourself
Take some tests
Online cognitive tests from Cogstate, Ltd. and Lumosity, Inc.
take out small text under each number. Streamline. Mention Cogstate and Lumos. Put the cogstate slide right after this.
Come back
Participants return and repeat tasks every 6 months
Come back…again

30. 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 positivity
Online cog. Tests are provided by 2 partners: Cogstate, and Lumosity.
Cogstate: Australian, pioneer in computerized cog. Testing
195 subjects: study eligibility required individuals to be age 50 years or older, healthy, community dwelling and willing to be informed of possible cognitive decline. Exclusion criteria included self-reported pre-existing cognitive impairment, and neurological or psychiatric disease. For the current study, subjects were required to have completed at least the baseline, 12-, and 24-month assessments.
Chen et al 2010; Lim et al 2012, 2013; Darby et al 2011, 2012, 2014

31. Lumos Labs: Sharing Contacts & Data
11/23/11
Lumos Labs: Sharing Contacts & Data

32. 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
***If possible, turn this into a visual timeline
Encouraging for feasibility of collecting long. Data from a large cohort with very few incentives.
Major goal is to recruit for Ad studies….do we have eligible subjects?
Wanted to ask
Can we make it…yes
Can we get people to join…yes
Is the data we get valid/useful….we had concerns but surprisingly data is very good.
Can we get eligible subs. For AD trials, the right subs in the right places….yes.
how many subs will actually come to clinics for studies…possibly 1 out of 5.

41. SUMMARY BRAIN 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