Examining the etiology and clinical consequences of perivascular spaces in aging adults

项目摘要 血管周围间隙是脑小血管疾病的一个新的标志，通常被视为充满液体的空间 老年人的磁共振成像（MRI）。本建议的目的是为了更好地了解 血管周围间隙的潜在病因学和临床后果。尤其是，我们将评估年龄- 相关的动脉硬化驱动基底神经节的穿通动脉中更高的血液脉动， 力传递到周围组织，并导致形态学改变的形式扩大 血管周围间隙我们建议应用主动脉脉搏波速度，一个动脉血管的金标准标志物， 硬化，以测试搏动性增加是否与纵向血管周围空间负荷相关， 基底神经节。接下来，我们将检查基线血管周围间隙负荷与 纵向认知轨迹基底神经节与执行功能和信息有关 由额叶皮层下网络介导的处理速度。因此，基底部的血管周围空间 神经节可能导致这些特定领域的认知结果更差。载脂蛋白E（APOE）-β 4是 散发性阿尔茨海默病最强的遗传易感性危险因素， 损害鉴于我们先前的工作表明动脉硬化与APOE-104对大脑健康结果的相互作用， 我们还将评估APOE-104作为效应调节剂。为了实现F31应用程序的研究目标，我们将 利用范德比尔特记忆与阿尔茨海默病中心、范德比尔特记忆与衰老中心的特殊资源， 项目，范德比尔特大学成像科学研究所，范德比尔特转化临床心血管 研究小组，范德比尔特高级计算研究和教育中心，以及范德比尔特 大脑研究所。候选人科里·鲍恩将在一位 跨学科导师团队，包括阿尔茨海默病神经生物学方面的国际专家 和小血管疾病，老年神经心理学，神经科学，心脏和大脑MRI，计算 遗传学和血管周围空间解剖学和生理学。平行培训计划将为候选人提供 具备必要的知识和技能，以完成拟议的研究目标，并发展成为一个 他是一位成功的神经科学家，研究小血管疾病和阿尔茨海默氏症的神经生物学交叉点 疾病这项研究的结果将提供有关病因和临床后果的重要信息 为今后的预防和治疗工作提供信息。

PROJECT SUMMARY Perivascular spaces are an emerging marker of cerebral small vessel disease often seen as fluid-filled spaces on magnetic resonance imaging (MRI) in older adults. The purpose of this proposal is to better understand the underlying etiology and clinical consequences of perivascular spaces. In particular, we will assess if age- related arterial stiffening drives higher blood pulsatility in perforating arteries of the basal ganglia, increasing force transmission to surrounding tissue, and leading to morphological change in the form of enlarged perivascular spaces. We propose to apply aortic pulse wave velocity, a gold-standard marker of arterial stiffening, to test whether increased pulsatility is associated with longitudinal perivascular space burden in the basal ganglia. Next, we will examine associations between baseline perivascular space burden and longitudinal cognitive trajectory. The basal ganglia has been implicated in executive function and information processing speed mediated by frontal-subcortical networks. Therefore, perivascular spaces in the basal ganglia may result in worse cognitive outcomes in these particular domains. Apolipoprotein E (APOE)-ϵ4 is the strongest genetic susceptibility risk factor for sporadic Alzheimer’s disease and a moderator of vascular damage. Given our prior work suggesting arterial stiffness interacts with APOE-ϵ4 on brain health outcomes, we will also assess APOE-ϵ4 as an effect modifier. To fulfill the research aims of this F31 application, we will leverage exceptional resources from the Vanderbilt Memory & Alzheimer’s Center, Vanderbilt Memory & Aging Project, Vanderbilt University Institute of Imaging Science, Vanderbilt Translational Clinical Cardiovascular Research Group, Vanderbilt Advanced Computing Center for Research and Education, and the Vanderbilt Brain Institute. The candidate, Corey Bown, will carry out the proposed research with the support of an interdisciplinary mentorship team, including international experts in the neurobiology of Alzheimer’s disease and small vessel disease, geriatric neuropsychology, neuroscience, cardiac and brain MRI, computational genetics, and perivascular space anatomy and physiology. The parallel training plan will provide the candidate with the necessary knowledge and skillset to complete the proposed research aims and develop into a successful neuroscientist working at the neurobiological intersection of small vessel disease and Alzheimer’s disease. Results from this research will offer crucial information about the etiology and clinical consequences of perivascular spaces to inform future prevention and therapeutic efforts.