Cerebrovascular Contributions to Brain Aging and Dementia

脑血管对大脑衰老和痴呆的影响

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

Accounting Age Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos 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

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项目摘要

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，老年人的认知适应性以及确定阿尔茨海默氏病（AD）的风险如何促进神经环境，从而使变性供应增强而造成易于促进的神经环境，从而使血液供应增强。我们建议，血管健康特定方面与年龄相关的下降会促进白质组织结构的进行性退化性变化，并且这种恶化是认知能力下降的主要机制。血管健康的更先进的下降和AD风险更复杂，导致血液脑屏障，大脑皮层和皮质下灰质的恶化，以及更普遍的认知缺陷。这种延续的具体目的是：（1）确定减少血流和流量调节区域是否与白质病变共定位并预测未来病变的形成。我们预计，与长渗透动脉和流域区域的末端区域接壤的白色物质最容易受到微观结构损害的影响，并且这种损害将直接与白质灌注和血管自动调节的功能神经影像学指标直接相关。（2）表征白质损伤的区域概况并量化白质病变内组织损伤的程度。我们假设在表征白质病变时考虑了定量信息，将为检测认知能力下降和其他临床相关现象提供更大的敏感性。（3）确定具有AD风险的血脑屏障的崩溃是否会促进白质病变的形成。我们假设患有AD风险的个体发生了更大的全身性炎症发生率，这与血液脑屏障的恶化有关，从而增加了由于血管风险而增加的退化过程。综上所述，这些研究将表明，脑白质区域与血管树的特定部分的空间接近是最容易受到临床前大脑血流的影响失调和病变形成。这种初始途径导致非痴呆相关认知能力下降的标准模式。血管功能的逐步下降以及与广告相关的炎症反应结合起来的，有助于细分血液脑屏障和随后认知能力下降的其他退行性变化。这里生成的数据可以为个性化的临床管理提供重要且非常实用的见解，并将确定未来临床干预的机械目标。