Abstract

The overall goal of this project is to deepen our understanding of aging processes and the aging brain in a community-based population. Our projects are thematically linked to an overarching hypothesis based on previous results from our own studies and the literature: that microinfarcts are key pathophysiological processes in late life brain dysfunction.
Aims 1 &2 will test hypotheses regarding 4 late-life brain outcomes: 1) Development of dementia and AD;2) Trajectories of global cognitive decline incorporating sophisticated modern psychometric analyses;3) Standard microscopic neuropathological measures;and 4) Novel biochemical neuropathological markers, including soluble A(S oligomers, markers of regional oxidative damage, and inflammatory markers.
Aim 1. Exploit unique clinical records to test hypotheses about the association between mid- and late-life micro- and macro-vascular conditions and late-life brain outcomes.
Aim 1 will take advantage of the >117,000 person-years of medical record data available from the cohort.
Aim la. Test hypotheses related to type 2 diabetes (DM). We will identify the independent and joint contributions of mid-life and late-life insulin resistance and hyperglycemia on late-life brain outcomes to determine whether these outcomes are best explained by insulin resistance, hyperglycemia, or both.
Aim lb. Test hypotheses related to renal disease. We will determine whether mid-life and late-life renal function is associated with greater risk for late-life brain outcomes.
Aim 1 c. Test hypotheses related to atrial fibrillation (AF). We will determine whether AF is associated with higher risk for late-life brain outcomes, whether increased persistence and duration of AF convey additional increased risk, and the extent to which anticoagulation ameliorates risks associated with AF.
Aim 2. Exploit unique ACT study research data to test hypotheses about the association between late-life measures of physical performance, frailty, and late-life brain outcomes. We will follow-up our preliminary finding that timed walk during life is associated with the presence of microinfarcts among autopsied participants to more fully test the hypotheses that decrements in timed walk and the development of frailty precede late-life brain outcomes.
Aim 3. Continue to serve as a valuable scientific resource and improve infrastructure to facilitate external use of ACT data.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AG006781-25
Application #
8310967
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (M2))
Program Officer
Anderson, Dallas
Project Start
1986-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
25
Fiscal Year
2012
Total Cost
$2,393,397
Indirect Cost
$540,231

  Institution

Name
Group Health Cooperative
Department
Type
DUNS #
078198520
City
Seattle
State
WA
Country
United States
Zip Code
98101

  Publications

Keene, C Dirk; Wilson, Angela M; Kilgore, Mitchell D et al. (2018) Luminex-based quantification of Alzheimer's disease neuropathologic change in formalin-fixed post-mortem human brain tissue. Lab Invest :
Flanagan, Margaret E; Larson, Eric B; Walker, Rod L et al. (2018) Associations between Use of Specific Analgesics and Concentrations of Amyloid-? 42 or Phospho-Tau in Regions of Human Cerebral Cortex. J Alzheimers Dis 61:653-662
Gray, Shelly L; Anderson, Melissa L; Hanlon, Joseph T et al. (2018) Exposure to Strong Anticholinergic Medications and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. J Alzheimers Dis 65:607-616
Marcum, Zachary A; Walker, Rod; Bobb, Jennifer F et al. (2018) Serum Cholesterol and Incident Alzheimer's Disease: Findings from the Adult Changes in Thought Study. J Am Geriatr Soc 66:2344-2352
Moreno, Monica A; Or-Geva, Noga; Aftab, Blake T et al. (2018) Molecular signature of Epstein-Barr virus infection in MS brain lesions. Neurol Neuroimmunol Neuroinflamm 5:e466
Condello, Carlo; Lemmin, Thomas; Stöhr, Jan et al. (2018) Structural heterogeneity and intersubject variability of A? in familial and sporadic Alzheimer's disease. Proc Natl Acad Sci U S A 115:E782-E791
Gray, Shelly L; Hart, Laura A; Perera, Subashan et al. (2018) Meta-analysis of Interventions to Reduce Adverse Drug Reactions in Older Adults. J Am Geriatr Soc 66:282-288
Bagi, Zsolt; Brandner, Dieter D; Le, Phuong et al. (2018) Vasodilator dysfunction and oligodendrocyte dysmaturation in aging white matter. Ann Neurol 83:142-152
Locke, Timothy M; Soden, Marta E; Miller, Samara M et al. (2018) Dopamine D1 Receptor-Positive Neurons in the Lateral Nucleus of the Cerebellum Contribute to Cognitive Behavior. Biol Psychiatry 84:401-412
Edlow, Brian L; Keene, C Dirk; Perl, Daniel P et al. (2018) Multimodal Characterization of the Late Effects of Traumatic Brain Injury: A Methodological Overview of the Late Effects of Traumatic Brain Injury Project. J Neurotrauma 35:1604-1619

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