Cerebrovascular Contributions to Brain Aging and Dementia

描述（由申请人提供）：拟议的工作旨在确定血管健康影响神经完整性的直接机制，进而影响老年人的认知健康，以及确定阿尔茨海默病（AD）的风险如何影响神经环境，在神经环境中，由于对血液供应限制的脆弱性增强，退行性过程不成比例地促进。我们认为，年龄相关的血管健康特定方面的衰退促进了白质组织结构的进行性退行性变化，这种退化是认知能力下降的主要机制。更严重的血管健康状况下降与AD的风险相结合，会导致血脑屏障的破坏，大脑皮层和皮层下灰质的恶化，并导致老年痴呆症

DESCRIPTION (provided by applicant): 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.