This grant will support continuation and expansion of autopsy research on brain aging, dementia, cognitive decline, Parkinson's disease, and stroke in Japanese American men for whom a wealth of prospectively collected information is available by virtue of their long-standing participation in the Honolulu Heart Program and Honolulu-Asia Aging Study. The principal goal is to improve understanding of the pathologic processes that underlie these illnesses and impairments in late life, and to identify risk factors associated with the brain lesions that represent the essential pathogenic processes. As of March 2005 a total of 615 brain autopsies had been done. This number will increase by approximately 50% over the course of the upcoming 5 years. Analyses to date implicate ischemic cerebrovascular disease as the pathogenic process most frequently linked to dementia in this cohort (25% of cases) and identify multiple microinfarcts as the most specific and consistent indicator. Neurofibrillary tangles (NFT) and/or neuritic plaques (NP) are the dominant or sole lesions associated with dementia in 20% of the demented decedents. Cortical Lewy bodies account for 10%, hippocampal sclerosis for 4%, and mixed (codominant) lesions for 18% of the dementia cases. Abnormalities identified in the remaining demented decedents (23%) were limited to generalized atrophy, gliosis, and neuron loss - not implicating a specific pathogenic mechanism. In this population, prevention strategies that reduce the burden of NFT and NP without influencing the other processes would likely have a modest public health impact. Our findings suggest that highly effective prevention programs are likely to require simultaneous targeting of two or more of the underlying processes. Analyses employing neuropathologic lesions as endpoints are conducted in an effort to identify specific risk factors for specific underlying pathogenic processes as an essential preliminary step toward prevention. In addition to accruing additional autopsies, the proposed continuation will support efforts directed toward (1) studies of microvascular ischemic disease, (2) relationships between distributions and densities of microinfarcts and Alzheimer's lesions, (3) relationships between structural characteristics of Circle of Willis arteries and lesions in the brain parenchyma, and (4) identification of the major underlying pathogenic processes responsible for brain atrophy and gliosis, and identification of corresponding risk factors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AG017155-10
Application #
7907607
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Anderson, Dallas
Project Start
2000-06-01
Project End
2012-07-31
Budget Start
2010-08-15
Budget End
2012-07-31
Support Year
10
Fiscal Year
2010
Total Cost
$991,717
Indirect Cost
Name
Kuakini Medical Center
Department
Type
DUNS #
077701613
City
Honolulu
State
HI
Country
United States
Zip Code
96817
Flanagan, Margaret E; Cholerton, Brenna; Latimer, Caitlin S et al. (2018) TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study. J Alzheimers Dis 66:1549-1558
White, Lon R; Edland, Steven D; Hemmy, Laura S et al. (2016) Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies. Neurology 86:1000-8
Abner, Erin L; Nelson, Peter T; Kryscio, Richard J et al. (2016) Diabetes is associated with cerebrovascular but not Alzheimer's disease neuropathology. Alzheimers Dement 12:882-9
W├╝thrich, Christian; Batson, Stephanie; Anderson, Matthew P et al. (2016) JC Virus Infects Neurons and Glial Cells in the Hippocampus. J Neuropathol Exp Neurol :
Kryscio, R J; Abner, E L; Nelson, P T et al. (2016) The Effect of Vascular Neuropathology on Late-life Cognition: Results from the SMART Project. J Prev Alzheimers Dis 3:85-91
Chouraki, Vincent; Beiser, Alexa; Younkin, Linda et al. (2015) Plasma amyloid-? and risk of Alzheimer's disease in the Framingham Heart Study. Alzheimers Dement 11:249-57.e1
Gelber, Rebecca P; Ross, G Webster; Petrovitch, Helen et al. (2013) Antihypertensive medication use and risk of cognitive impairment: the Honolulu-Asia Aging Study. Neurology 81:888-95
Gelber, Rebecca P; Launer, Lenore J; White, Lon R (2012) The Honolulu-Asia Aging Study: epidemiologic and neuropathologic research on cognitive impairment. Curr Alzheimer Res 9:664-72
Rantanen, Taina; Masaki, Kamal; He, Qimei et al. (2012) Midlife muscle strength and human longevity up to age 100 years: a 44-year prospective study among a decedent cohort. Age (Dordr) 34:563-70
de Jong, L W; Wang, Y; White, L R et al. (2012) Ventral striatal volume is associated with cognitive decline in older people: a population based MR-study. Neurobiol Aging 33:424.e1-10

Showing the most recent 10 out of 18 publications