Examining multiple etiologies underlying white matter disease in aging adults

项目总结 脑白质改变在老年人中很常见，并会导致不良的临床后果。 血管疾病，特别是动脉僵硬，被认为是白人最常见的病因。 物质病。动脉僵硬可能导致下游组织缺氧，留下深部白质 缺乏侧支血液供应的区域特别容易受到伤害。然而，越来越多的证据表明AD有牵连 病理，包括淀粉样蛋白-β(Aβ)和过度磷酸化tau(Ptau)，是导致白色的重要因素 物质病。这些病理改变可能导致脑束与脑白质交叠区域的白质损伤 β和Ptau沉积，如额叶、颞叶和海马体。鉴于强有力的证据 提示血管疾病和AD病理相互作用加速临床进展，这是可能的 病理在特别脆弱的白质束上施加重叠效应，加速认知 拒绝。这项拟议的研究将检查与年龄相关的动脉僵硬和体内分子生物标志物。 与白质微结构纵向下降有关的AD病理(根据扩散张量进行评估 成像)，为期5年的随访期。分析将检查白色的完整性与 被确定为特别容易受到各种病理和认知衰退影响的物质束。建议数 研究将利用范德比尔特大学范德比尔特记忆和阿尔茨海默氏症中心的丰富资源 影像科学研究所，范德比尔特翻译临床心血管研究组 高级计算研究和教育中心和范德比尔特脑研究所。这项研究将是 由跨学科指导团队指导，其中包括老年神经心理学、阿尔茨海默病、脑 小血管病变、磁共振成像、统计分析、临床异常处理 认知老化和AD分子生物标记物。平行培训计划将有助于应聘者 获得必要的知识和技能来研究异常脑白质病的病因 认知老化，并推动她作为一名独立内科科学家的成功职业生涯。理解 与年龄相关的白质改变的病因学，特别是特定束和 相应的临床结果，将提供关于潜在的神经生物学的关键信息 认知能力下降。研究结果将提供更全面的信息，说明脑白质疾病 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.