Examining multiple etiologies underlying white matter disease in aging adults

检查老年人白质疾病的多种病因

• 批准号: 10214485
• 负责人: Elizabeth E Moore
• 金额: $ 4.04万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-05-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214485
• 关键词: Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Amyloidosis; Anatomy; Area; Autopsy; Biological Markers; Blood flow; Brain; Cardiac; Cardiovascular system; Cerebral small vessel disease; Cerebrospinal Fluid; Cerebrum; Clinical; Clinical Management; Cognitive aging; Data; Dementia; Deposition; Diffusion Magnetic Resonance Imaging; Disease; Education; Elderly; Episodic memory; Etiology; Functional disorder; Goals; Gold; Hippocampus (Brain); Hypoxia; Image; Impaired cognition; Individual; Institutes; Knowledge; Lead; Learning; Life; Lipids; Location; Magnetic Resonance Imaging; Measures; Memory; Memory Loss; Mentorship; Microcirculation; Microtubules; Modeling; Neurobiology; Neuropsychology; Oligodendroglia; Outcome; Parietal; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Physicians; Physiologic pulse; Prevalence; Research; Resources; Science; Scientist; Statistical Data Interpretation; Stroke; Techniques; Temporal Lobe; Testing; Time; Tissues; Training; Universities; Vascular Diseases; Vascular blood supply; White Matter Disease; abeta accumulation; age related; arterial stiffness; career; clinical phenotype; executive function; familial Alzheimer disease; follow-up; frontal lobe; hyperphosphorylated tau; in vivo; information processing; insight; memory consolidation; memory retrieval; molecular marker; novel; processing speed; skills; vascular injury; vascular risk factor; white matter; white matter change; white matter damage

PROJECT SUMMARY Cerebral white matter changes are common in aging adults and contribute to adverse clinical consequences. Vascular disease, specifically arterial stiffness, is thought to be the most prevalent etiology underlying white matter disease. Arterial stiffness may lead to hypoxia in downstream tissue, leaving the deep white matter tracts that lack collateral blood supply especially vulnerable. However, mounting evidence has implicated AD pathology, including amyloid-β (Aβ) and hyperphosphorylated tau (ptau), as important contributors to white matter disease. These pathologies may contribute to white matter damage in tracts overlapping with regions of Aβ and ptau deposition, such as the frontal lobe, temporal lobe, and hippocampus. Given the strong evidence suggesting vascular disease and AD pathology interact to hasten clinical progression, it is possible that these pathologies exert overlapping effects on particularly vulnerable white matter tracts, accelerating cognitive decline. The proposed research will examine age-related arterial stiffness and in vivo molecular biomarkers of AD pathology in relation to longitudinal decline in white matter microstructure (assessed on diffusion tensor imaging) over a 5-year follow-up period. Analyses will examine associations between the integrity in white matter tracts identified as especially vulnerable to each pathology and cognitive decline. The proposed research will leverage the rich resources of the Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Institute of Imaging Science, Vanderbilt Translational Clinical Cardiovascular Research Group, Vanderbilt Advanced Computing Center for Research and Education, and Vanderbilt Brain Institute. The research will be guided by an interdisciplinary mentorship team, including experts in geriatric neuropsychology, AD, cerebral small vessel disease, magnetic resonance imaging, statistical analysis, clinical management of abnormal cognitive aging, and AD molecular biomarkers. The parallel training plan will facilitate the candidate’s acquisition of the necessary knowledge and skills to study the etiologies of white matter disease in abnormal cognitive aging and propel her into a successful career as an independent physician scientist. Understanding the etiology of age-related white matter changes, especially the vulnerability of specific tracts and corresponding clinical consequences, would provide critical information regarding the neurobiology underlying cognitive decline. Findings will offer more comprehensive information regarding how white matter disease integrates into AD pathogenesis.

项目摘要 脑白质变化在老龄化的成年人中很常见，并导致不良临床后果。 血管疾病，特别是动脉僵硬，被认为是白色最普遍的病因 物质疾病。动脉刚度可能导致下游组织中缺氧，留下深白质 缺乏附带血液供应的区域特别脆弱。但是，越来越多的证据已经实施了广告 病理学，包括淀粉样蛋白β（Aβ）和高磷酸化的TAU（PTAU），作为白色的重要贡献者 物质疾病。这些病理可能会导致与区域重叠的区域中的白质损害 Aβ和PTAU沉积，例如额叶，临时叶和海马。有强有力的证据 提示血管疾病和AD病理与急速临床进展相互作用，这些可能有可能 病理对特别脆弱的白质区域执行重叠影响，加速认知 衰退。拟议的研究将检查与年龄相关的动脉刚度和体内分子生物标志物 与白质微观结构纵向下降有关的AD病理学（对扩散张量进行评估 成像）在5年的随访期内。分析将检查白色完整性之间的关联 物质区被认为特别容易受到每种病理和认知能力下降的影响。提议 研究将利用范德比尔特大学范德比尔特记忆与阿尔茨海默氏症中心的丰富资源 范德比尔特转化临床心血管研究小组的成像科学研究所，范德比尔特 高级研究和教育计算中心以及范德比尔特脑研究所。研究将是 在跨学科心态团队的指导下，包括老年神经心理学专家，广告，大脑 小血管疾病，磁共振成像，统计分析，异常的临床管理 认知衰老和AD分子生物标志物。并行培训计划将促进候选人的 获得必要的知识和技能来研究异常白质疾病的病因 认知衰老，并将她推向了独立的物理科学家的成功职业。理解 与年龄相关的白质的病因发生变化，尤其是特定道的脆弱性和 相应的临床后果将提供有关神经生物学基础的关键信息 认知能力下降。调查结果将提供有关白质疾病如何的更全面的信息 整合到AD发病机理中。