Characterizing enlarged perivascular spaces in Alzheimer's and vascular dementia

项目摘要/摘要 我是一名专注于临床的神经科学家，在衰老神经生物学方面接受过博士培训，博士后培训在 核磁共振成像(MRI)方法，以确定神经退行性变的结构和功能变化。一个长期的 研究目标是了解阿尔茨海默病背景下大脑和血管功能之间的动态关系 病理生理学，特别侧重于阐明血管周围间隔在连接这些系统及其潜力中的作用 作为治疗的靶点。脑血管周围的空间被很好地证明是维持大脑的液体流动的通道。 动态平衡，研究表明，包括淀粉样蛋白在内的间质废物通过血管周围隔室清除。那里 越来越多的证据表明，这个空间的扩大(EPVS)与阿尔茨海默病的临床和诊断特征有关，以及 脑血管病理学。死后评估表明ePVS与脑部淀粉样蛋白的血管结合淀粉样蛋白有关 血管病变(CAA)和实质内淀粉样蛋白负荷增加。在体内的研究已经发现， 放射学上可见(并因此放大)PVS和阿尔茨海默病、脑小血管疾病和CAA。而血管周围 空间处于血管、星形胶质细胞和淀粉样蛋白基础病理的交叉点，相对和/或协同作用对 对ePVS的发展还不了解。这在一定程度上是因为缺乏跟踪ePVS中细微差异或变化的敏感方法 临床影像的负担，以及缺乏对ePVS的放射学/病理学相关性研究。我的目标是应用创新、 多方面的方法来了解ePVS的临床相关性和病因，长期目标是确定一种新的 阿尔茨海默病和相关痴呆症的预防或治疗目标。目前的提议是朝着这些目标迈出的第一步 目标。我已经组建了一个由导师和合作者组成的充满活力和凝聚力的团队，我们共同制定了培训计划 它结合了直接指导培训、实验室会议、部门研讨会、国内和国际科学会议、教学、 和研讨会。这些活动将有助于我了解阿尔茨海默病的临床和病理特征以及 血管性痴呆(VAD)以及这些疾病过程是如何交叉和相互作用的。此外，拟议的计划将使我能够 扩展我的研究工具箱，包括表征脑血管疾病活体证据的方法(灌注MRI和白 物质高强度负荷)和淀粉样沉积(淀粉样正电子发射断层扫描)和相关的直接定量 病理和感兴趣的蛋白质(免疫组织化学和免疫荧光成像)。最后，在完成这次培训后， 在此期间，我将熟练地识别阿尔茨海默病和vad的临床特征，并管理和 分析多维数据集。这将是第一次将活体、死后和靶向相结合的同类研究 EPVS的组织病理学特征被认为是理解其临床相关性的关键限制。这个 建议出现在一个独特的时间；阿尔茨海默氏症和脑血管疾病的合并领域汇聚在一起，专注于血管周围 太空。通过这个培训计划，我将生成一系列数据来阐明ePVS的临床和生物学相关性， 将构成其他提案的基础，旨在更全面地了解ePVS和 探索新的诊断和治疗方法，以预防和治疗阿尔茨海默病和相关痴呆。

Project Summary/Abstract I am a clinically focused neuroscientist with doctoral training in the neurobiology of aging and post-doctoral training in magnetic resonance imaging (MRI) methods of identifying structural and functional changes in neurodegeneration. A long-term research goal is to understand the dynamic relationship between brain and vascular function in the setting of Alzheimer's disease pathophysiology, with a specific focus on elucidating the role of the perivascular compartment in linking these systems and its potential as a therapeutic target. The brain perivascular space is well demonstrated to be a route of fluid flow serving to maintain brain homeostasis, and studies have shown clearance of interstitial wastes including amyloid by way of the perivascular compartment. There is mounting evidence that enlargement of this space (ePVS) is associated with clinical and diagnostic features of Alzheimer's disease and cerebrovascular pathology. Post mortem evaluation has linked ePVS with vessel-bound amyloid in the form of cerebral amyloid angiopathy (CAA) and with increased amyloid burden within the parenchyma. In vivo work has identified a strong correlation between radiologically visible (and thus enlarged) PVS and Alzheimer's disease, cerebral small vessel disease, and CAA. While the perivascular space is at the intersection of vascular, astro-glial, and amyloid-based pathologies, the relative and/or synergistic contribution to the development of ePVS is not understood. This is due in part to lack of sensitive methods to track subtle differences or changes in ePVS burden in clinical imaging and the lack of radiological/pathological association studies of ePVS. My objective is to apply innovative, multi-faceted approaches to understanding the clinical relevance and etiology of ePVS, with the long-term goal of identifying a novel preventative or therapeutic target to Alzheimer's disease and related dementias. The current proposal is a first step towards those goals. I have assembled a dynamic and cohesive team of mentors and collaborators and together we have developed a training plan that combines direct mentored training, lab meetings, departmental seminars, national and international scientific meetings, didactics, and workshops. These activities will facilitate my understanding the clinical and pathological features of Alzheimer's disease and vascular dementia (VaD) and how these disease processes intersect and interact. In addition, the proposed plan will allow me to expand my research toolbox to include methods characterizing in vivo evidence of cerebrovascular disease (perfusion MRI and white matter hyperintensity burden) and of amyloid deposition (amyloid positron emission tomography) and direct quantification of related pathologies and proteins of interest (immunohistochemistry and immunofluorescent imaging). Finally, at the completion of this training period, I will have developed proficiency in identifying the clinical features of Alzheimer's disease and VaD and in managing and analyzing multi-dimensional datasets. This would be the first study of its kind to combine in vivo, post mortem, and targeted histopathological characterization of ePVS, the lack of which is regarded as a key limitation to understanding their clinical relevance. The proposal comes at a unique time; the merging fields of Alzheimer's and cerebrovascular disease converge and focus on the perivascular space. Through this training plan, I will generate a body of data that will elucidate the clinical and biological correlates of ePVS, which will form the foundation for additional proposals aimed at more completely understanding the mechanistic underpinnings of ePVS and to explore novel diagnostic and therapeutic approaches to prevent and treat Alzheimer's disease and related dementias.