Examining multiple etiologies underlying white matter disease in aging adults

项目摘要 大脑白色物质变化在老年人中很常见，并导致不良临床后果。 血管疾病，特别是动脉僵硬，被认为是最普遍的病因基础白色 物质病。动脉僵硬可能导致下游组织缺氧，留下深部白色物质 缺乏侧支供血的血管尤其脆弱。然而，越来越多的证据表明， 病理学，包括淀粉样蛋白-β（Aβ）和过度磷酸化的tau（ptau），作为白色的重要贡献者 物质病。这些病理可能导致与脑白质区域重叠的脑束中的白色物质损伤。 Aβ和ptau沉积，如额叶、颞叶和海马。鉴于有力的证据 提示血管疾病和AD病理相互作用加速临床进展，这些可能是 病理对特别脆弱的白色物质束产生重叠影响，加速认知 下降这项拟议中的研究将检查年龄相关的动脉硬度和体内分子生物标志物， 与白色物质微观结构纵向下降相关的AD病理学（根据扩散张量评估 影像学检查），随访5年。分析将检查白色的完整性与 被确定为特别容易受到每种病理和认知能力下降的影响的物质束。拟议 这项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病中心的丰富资源 范德比尔特，范德比尔特，影像科学研究所，转化临床心血管研究组 高级计算研究和教育中心和范德比尔特大脑研究所。这项研究将 由跨学科导师团队指导，其中包括老年神经心理学、AD、大脑专家 小血管病变，磁共振成像，统计分析，异常临床处理 认知老化和AD分子生物标志物。平行培训计划将有助于候选人 获得必要的知识和技能，研究异常白色疾病的病因， 认知老化，并推动她成为一个成功的职业生涯作为一个独立的医生科学家。理解 与年龄相关的白色物质变化的病因学，特别是特定神经束的脆弱性， 相应的临床后果，将提供有关神经生物学基础的关键信息， 认知能力下降研究结果将提供关于白色物质疾病如何 整合到AD发病机制中。

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.