Cerebrovascular Contributions to Brain Aging and Dementia

脑血管对大脑衰老和痴呆的影响

• 批准号: 8514341
• 负责人: DAVID H SALAT
• 金额: $ 55.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-29 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514341
• 关键词: Accounting; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Anatomy; Area; Arteries; Attenuated; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Blood flow; Brain; Cerebral cortex; Cerebrovascular Circulation; Cerebrum; Cholesterol; Clinical; Clinical Management; Cognition; Cognitive; Cognitive deficits; Coupled; Data; Dementia; Dependency; Deterioration; Due Process; Elderly; Environment; Fiber; Functional disorder; Future; Genetic; Health; Homeostasis; Image; Imaging Techniques; Impaired cognition; Incidence; Individual; Inflammation; Inflammatory Response; Intervention; Lesion; Maps; Measurement; Mediating; Metric; Modeling; Nerve Degeneration; Neural Pathways; Pathway interactions; Pattern; Performance; Perfusion; Permeability; Physiological; Physiology; Population; Predisposition; Procedures; Process; Regional Blood Flow; Regulation; Risk; Risk Factors; Secondary to; Serum; Severities; Structure; System; Technology; Testing; Tissues; Trees; Vascular blood supply; Water; Work; aging brain; base; brain tissue; cerebral atrophy; cerebrovascular; clinically relevant; clinically significant; executive function; fitness; gray matter; hemodynamics; indexing; innovation; insight; neuroimaging; neuromechanism; pre-clinical; prevent; public health relevance; relating to nervous system; therapy development; white matter; white matter damage; white matter injury

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.

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适应性，并确定阿尔茨海默病（AD）的风险如何促成神经环境，其中退行性过程由于对血液供应限制的脆弱性增强而不成比例地促进。我们认为，与年龄相关的血管健康的特定方面的下降促进了白色组织结构的进行性退行性变化，这种恶化是认知能力下降的主要机制。血管健康的进一步下降与AD的风险相结合，导致血脑屏障的破坏，大脑皮层和皮层下灰质的恶化， 更普遍的认知缺陷本研究的具体目的是：（1）确定血流减少和血流调节改变的区域是否与白色病变共定位，并预测未来病变的形成。我们预计，长穿通动脉和分水岭区域的末端区域边界的白色物质最容易受到微结构损伤，并且这种损伤将与白色物质灌注和血管自动调节的功能性神经成像指标直接相关。(2)描述白色物质损伤的区域特征，并量化白色物质病变内的组织损伤程度。我们假设，在表征白色病变时考虑定量信息将为检测认知能力下降和其他临床相关现象提供更高的灵敏度。(3)确定具有AD风险的血脑屏障的破坏是否促进了白色病变的形成。我们假设有AD风险的个体有更高的全身性炎症发生率，这与血脑屏障的恶化有关，增加了血管风险导致的退行性过程。总之，这些研究将证明，与血管树的特定部分空间接近的脑白色物质区域最易受临床前脑血流影响 失调和损伤形成。这一初始途径导致非痴呆年龄相关认知能力下降的标准模式。血管功能的进行性下降加上AD相关的炎症反应导致血脑屏障的破坏和其他退行性变化，预测随后的认知能力下降。这里生成的数据可以为个性化临床管理提供重要且非常实用的见解，并将为未来的临床干预确定机制目标。