The proposed work aims to identify direct mechanisms by which vascular health influences neural integrity, and in turn, cognitive fitness in older adults as well as to determine how risk for Alzheimer's disease (AD) contributes to a neural environment in which degenerative processes are disproportionately facilitated due to enhanced vulnerability to limits in blood supply. We propose that age-associated decline in specific aspects of vascular health promotes progressive degenerative changes in white matter tissue structure and that this deterioration is a primary mechanism of cognitive decline. More advanced decline in vascular health compounded with risk for AD contributes to breakdown of the blood brain barrier, deterioration of the cerebral cortex and subcortical gray matter, and to a more generalized cognitive deficit.
The Specific Aims of this continuation are: (1) to determine whether regions of reduced blood flow and altered flow regulation co-localize with white matter lesions and predict future lesion formation. We expect that white matter bordering the end zones of the long penetrating arteries and watershed areas will be most vulnerable to microstructural damage, and this damage will be directly associated with functional neuroimaging metrics of white matter perfusion and vascular autoregulation. (2) To characterize the regional profile of white matter damage and quantify the degree of tissue damage within white matter lesions. We hypothesize that taking quantitative information into account when characterizing white matter lesions will provide greater sensitivity to detect cognitive decline and other clinically relevant phenomena. (3) To determine whether breakdown of the blood brain barrier with risk for AD promotes white matter lesion formation. We hypothesize that individuals with risk for AD have a greater incidence of systemic inflammation and that this is associated with deterioration of the blood brain barrier, augmenting degenerative processes due to vascular risk. Taken together, these studies would demonstrate that regions of the cerebral white matter with spatial proximity to particular portions of the vascular tree are most susceptible to preclinical cerebral blood flow dysregulation and lesion formation. This initial pathway leads to the standard pattern of non-demented age-associated cognitive decline. Progressive decline in vascular function coupled with an AD-associated inflammatory response contributes to a breakdown of the blood brain barrier and additional degenerative changes predictive of subsequent cognitive decline. Data generated here could provide important and very practical insights for individualized clinical management and would identify mechanistic targets for future clinical intervention.

Public Health Relevance

White matter lesions occur as a result of a decline in vascular health in older adults and contribute to cognitive impairment in this population. This damage is enhanced in individuals with Alzheimer's disease. The proposed studies aim to determine mechanisms, patterns, and cognitive consequences of white matter deterioration in older adults and individuals at risk for Alzheimer's disease through the detailed characterization of cerebrovascular structure and function and measurement of transvascular water exchange and blood brain barrier integrity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
2R01NR010827-06A1
Application #
8514341
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Tully, Lois
Project Start
2007-09-29
Project End
2018-06-30
Budget Start
2013-09-18
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$559,012
Indirect Cost
$230,574
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Purkayastha, Sushmita; Fadar, Otite; Mehregan, Aujan et al. (2014) Impaired cerebrovascular hemodynamics are associated with cerebral white matter damage. J Cereb Blood Flow Metab 34:228-34
Biffi, Alessandro; Sabuncu, Mert R; Desikan, Rahul S et al. (2014) Genetic variation of oxidative phosphorylation genes in stroke and Alzheimer's disease. Neurobiol Aging 35:1956.e1-8
Ryu, Seon Young; Coutu, Jean-Philippe; Rosas, H Diana et al. (2014) Effects of insulin resistance on white matter microstructure in middle-aged and older adults. Neurology 82:1862-70
Foley, Jessica M; Salat, David H; Stricker, Nikki H et al. (2014) Interactive effects of apolipoprotein E4 and diabetes risk on later myelinating white matter regions in neurologically healthy older aged adults. Am J Alzheimers Dis Other Demen 29:222-35
Coutu, Jean-Philippe; Chen, J Jean; Rosas, H Diana et al. (2014) Non-Gaussian water diffusion in aging white matter. Neurobiol Aging 35:1412-21
Fortier, Catherine B; Leritz, Elizabeth C; Salat, David H et al. (2014) Widespread effects of alcohol on white matter microstructure. Alcohol Clin Exp Res 38:2925-33
Stricker, Nikki H; Salat, David H; Foley, Jessica M et al. (2013) Decreased white matter integrity in neuropsychologically defined mild cognitive impairment is independent of cortical thinning. J Int Neuropsychol Soc 19:925-37
Chen, J Jean; Rosas, H Diana; Salat, David H (2013) The relationship between cortical blood flow and sub-cortical white-matter health across the adult age span. PLoS One 8:e56733
Salat, David H; Williams, Victoria J; Leritz, Elizabeth C et al. (2012) Inter-individual variation in blood pressure is associated with regional white matter integrity in generally healthy older adults. Neuroimage 59:181-92
Dobromyslin, Vitaly I; Salat, David H; Fortier, Catherine B et al. (2012) Distinct functional networks within the cerebellum and their relation to cortical systems assessed with independent component analysis. Neuroimage 60:2073-85

Showing the most recent 10 out of 21 publications