Advisory Council April 2014 Meeting Presentation: Military AD Program Update

04/29/2014

ADVISORY COUNCIL ON ALZHEIMER'S RESEARCH, CARE, AND SERVICES

Tuesday, April 29, 2014

 

Militarily-Relevant Peer Reviewed Alzheimer's Disease Research Program September Update

Anthony Pacifico, PhD
The views expressed in this briefing are those of the author and do not reflect official policy or position of the Department of the Army, Department of Defense or the U.S. Government.

Program Mission

The mission of the MRPRA is two-fold. The MRPRA seeks to 1) build an integrated program devoted to understanding the association between Traumatic Brain Injury (TBI) and Alzheimer's disease (AD), and 2) to reduce the burden on those affected by TBI-AD symptoms, especially in the military community.

MRPRA Overarching Challenges

  • Consistent with the program's overall goals, this MRPRA funding opportunity requires applications to address only one of the following MRPRA overarching challenges:
    • The paucity of research resources to examine the interrelationship between TBI and subsequent AD for military veterans that is suitable to inform or create large-scale clinical studies.
    • The need for technologies, tests, interventions or devices with the potential to diagnose AD at its earliest stages.
    • The need for technologies, tests, interventions or devices with the potential to directly benefit individuals suffering from the symptoms of TBI or AD with respect to quality of life for those affected.
    • The identification and validation of clinical best practices to directly benefit individuals suffering from the symptoms of TBI or AD, while reducing caregiver burden.

Focus Areas: The Way Ahead

  • Imaging: Development of anatomic and molecular imaging strategies that will address the MRPRA Overarching Challenges.
  • Genomics/Proteomics: Genetic, Proteomic and epigenetic studies (or technologies) intended to develop research resources in accordance with the MRPRA Overarching Challenges.
  • Quality of Life: Technologies, tests, interventions, studies or devices that will positively impact the quality of life of those affected by the symptoms of TBI or AD.
  • Pathology of Tau: Novel research and technologies dedicated to unraveling the basic pathobiological mechanisms of Tau.

Portfolio Analysis via IADRP

International Alzheimer's Disease Research Portfolio screen shot Pie Chart: Care, Support and Health Economics of Alzheimer's Disease (3); Molecular Pathogenesis and Physiology of Alzheimer's Disease (9); Diagnosis, Assessment, and Disease Monitoring (6); Translational Research and Clinical Interventions (1); Epidemiology (2).

Dr. Michael Sierks

Arizona State University
“Oligomeric neuronal protein aggregates as biomarkers for TBI and AD”

  • Novel, and potentially cost-effective strategy for detecting the early events after traumatic brain injury (TBI) and for long-term monitoring.
  • Technology can also be used for probing the formation of plaques.
  • Library of nanobodies for:
    • oligomeric beta-amyloid aggregate species
    • a-synuclein aggregate species
    • oligomeric tau
    • fibrillar beta-amyloid and a-syn
Biomarkers Cumulative Oligomeric Abeta in Human Brain Tissue
The binding intensities of A4 and C6T to the human brain tissue samples were averaged.
* = Results significant to AD group.

Early work showing the detection of a toxin specific to Alzheimer's disease (AD). The toxin, Abeta was not detected in brain tissue from Parkinson's patients (PD) when compared to controls (ND).

Dr. Bruce Lamb

Cleveland Clinic
“Novel Genetic Models to Study the Role of Inflammation in Brain Injury-Induced Alzheimer's Pathology”

  • Project tracks two different sources of inflammation; namely the peripheral monocytes of the bloodstream, and the microglia innate to the brain.
  • Using an injury model with mice that overproduce beta-amyloid, Dr. Lamb showed that beta-amyloid exacerbated the growth of the injury compared to controls.
  • In the Thalmus of these mice the immune response was altered.
Inflammatory Cascade Model Altered Immune Reaction
Model of How the Inflammatory Cascade Following TBI Impacts AD Pathologies Altered Immune Reaction in a Mouse Model of AD (R1.40) Compared to Non-Transgenic Controls in Various Brain Regions Following TBI
Mouse Worsened Age-Related Cognition Model  
Worsened Age-Related Cognition in a Mouse Model of AD (R1.40) Compared to Non-Transgenic Controls in Following TBI

Dr. Kristine Yaffe

Northern California Institute for Research and Education (NCIRE)
“Endophenotypes of Dementia Associated with Traumatic Brain Injury (TBI) in Retired Military Personnel”

  • Dr. Yaffe's team surveyed nearly 300 veterans at two veteran retirement homes which were located in Washington D.C. and Northern California.
  • 56% of those surveyed had a history of TBI.
  • TBI was associated with psychiatric symptoms such as depression, anxiety, and post-traumatic stress disorder (PTSD).
  • Veterans with TBI had problems answering orientation questions (a sign of cognitive impairment): 23.3% for the hospitalization group, 18.3% for the TBI group, and 15.4% for non-TBI group. (n=54)
  • Veterans with TBI were also more likely to have subjective memory complaints (26.7% for TBI hospitalization group, 20.6% for the TBI group, 10.8% for the non-TBI group). (n=156)
  • A total 114 patients reported multiple diagnoses.
  • Data will be correlated with structural MRI.
Psychiatric Diagnoses by TBI Status
Photos of the Veterans Home of California and Armed Forces Retirement Home

Dr. Michael Weiner

Northern California Institute for Research and Education (NCIRE)
“Effects of Traumatic Brain Injury (TBI) and Post-Traumatic Stress Disorder (PTSD) on Alzheimer's disease (AD) in Veterans using Imaging and Biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI)”

  • Use the ADNI machinery to understand TBI and neurodegenerative disease in Vietnam-era veterans.
  • Study Vietnam-era population to understand the future of veterans returning from OIF/OEF.
  • More than 10,000 veterans were contacted to form the cohort.
  • Study#1 (2012): Look at Vietnam Veterans (n=195) with signs of TBI and/or PTSD and perform a comprehensive battery of neuroimaging, CSF analyses, and neuropsychological testing.
  • Study#2 (2013): Look at Vietnam Veterans (n=195) with signs of MCI.
  • Both studies are accruing patients across all 19 sites.
  • Data will become available via the ADNI database.
DOD ADNI Clinic Sites
Clinic Name Principal Investigator City, State
Banner Sun Health Research Institute Marwan Sabbagh, MD Sun City, Arizona
University of California, Irvine Ruth Mulnard, D.N.Sc. Irvine, CA
University of California, San Diego James Brewer, MD, PhD La Jolla, CA
University of Southern California Lon Schneider, MD Los Angeles, CA
Stanford University Jerome Yesavage, MD Palo Alto, CA
University of California, San Francisco Howard rosen, MD San Francisco, CA
Georgetown University Brigid Reynolds, RN, MSN, NP   Washington, DC
Howard University Thomas Obisesan, MD Washington, DC
Wien Center for Clinical Research Ranjan Duara, MD Miami Beach, FL
Premiere Research Institutes Carl Sadowsky, MD West Palm Beach, FL
Rush University Debra Fleischman, PhD Chicago, IL
Brigham and Women's Hospital Gad Marshall, MD Boston, MA
Duke University P. Murali Doraiswamy, MD Durham, NC
Columbia university Yaakov Stern, PhD New York, NY
Weill Cornell University Norman Relkin, MD, PhD New York, NY
University of Rochester Medical Center Anton Porsteinsson, MD Rochester, NY
Medical University of South Carolina Jacobo Mintzer, MD North Charleston, SC  
University of Washington Medical Center   Elaine Peskind, MD Seattle, WA
University of Wisconsin Sterling Johnson, PhD Madison, WI

http://www.adni-info.org/DOD.aspx

http://adni.loni.usc.edu/data-samples/access-data/

Portfolio Analysis via IADRP

International Alzheimer's Disease Research Portfolio screen shot Pie Chart: Care, Support and Health Economics of Alzheimer's Disease (3); Molecular Pathogenesis and Physiology of Alzheimer's Disease (9); Diagnosis, Assessment, and Disease Monitoring (6); Translational Research and Clinical Interventions (1); Epidemiology (2).

Program Steering Comittee

  • FY13 PSC Members:
    • Dr. Anthony Pacifico (Department of the Army (DOA))
    • Dr. Robert Kane (DOA)
    • CAPT Jack Tsao (Department of the Navy (DON))
    • Col (R) Mike Jaffee (University of Virginia)
    • Ms. Ashley Fisher (DOA)
    • Dr. Laurie Ryan (National Institute on Aging (NIA))
    • Dr. Neil Buckholtz (NIA)
    • Dr. Bryan Traynor (NIA)
    • Dr. Nina Silverberg (NIA)
    • Dr. Stuart Hoffman (US Dept. of Veterans Affairs)
    • Dr. Roderick Corriveau (National Institute of Neurological Disorders and Stroke (NINDS))
    • Dr. Deborah Babcock (NINDS)
    • Dr. Valerie Trabosh (DOA)
    • LTC Sarah Goldman (DOA)
    • Dr. Brenda Bart-Knauer (DOA)
  • FY13 External Advisory Board Members:
    • Dr. Maria Carillo (Alzheimer's Association)
    • Dr. Heather Snyder (Alzheimer's Association)
    • COL Dallas Hack (DOA)
    • COL John Scherer (DOA)
    • Dr. Kenneth Curley (DOA)
    • CAPT Doug Forcino (DON)

Contact Info

Dr. Anthony Pacifico
Program Manager, Militarily Relevant Peer-Reviewed Alzheimer's Disease Research Program
United States Army Medical Research and Materiel Command
Anthony.M.Pacifico.CIV@mail.mil


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