Characterizing enlarged perivascular spaces in Alzheimer's and vascular dementia

项目总结/摘要 我是一名临床神经科学家，在衰老的神经生物学方面接受过博士培训， 磁共振成像（MRI）方法识别神经变性的结构和功能变化。长期 研究目标是了解阿尔茨海默病背景下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区室在连接这些系统中的作用及其潜力 作为治疗目标。脑血管周围空间被很好地证明是用于维持脑的流体流动的路径 体内平衡，并且研究已经显示通过血管周围隔室清除包括淀粉样蛋白的间质废物。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， 脑血管病理学尸检评估将ePVS与血管结合的淀粉样蛋白（以脑淀粉样蛋白的形式）联系起来 血管病（CAA）和实质内淀粉样蛋白负荷增加。体内研究发现， 放射学上可见的（因此扩大的）PVS和阿尔茨海默病、脑小血管病和CAA。而血管周围 间隙处于血管、星形胶质细胞和淀粉样蛋白为基础的病理学的交叉点， ePVS的发展尚不清楚。这部分是由于缺乏敏感的方法来跟踪ePVS的细微差异或变化 临床成像负担和缺乏ePVS的放射学/病理学相关研究。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 预防性或治疗性靶向阿尔茨海默病和相关痴呆。目前的建议是朝着这些目标迈出的第一步。 目标.我组建了一个充满活力和凝聚力的导师和合作者团队，我们一起制定了一个培训计划， 它结合了直接指导培训，实验室会议，部门研讨会，国家和国际科学会议，教学法， 和讲习班。这些活动有助我了解老年痴呆症的临床和病理特征， 血管性痴呆（VaD）以及这些疾病过程如何交叉和相互作用。此外，拟议的计划将使我能够 扩展我的研究工具箱，包括脑血管疾病的体内证据表征方法（灌注MRI和白色 物质高强度负荷）和淀粉样蛋白沉积（淀粉样蛋白正电子发射断层扫描）以及直接定量相关 病理学和感兴趣的蛋白质（免疫组织化学和免疫荧光成像）。最后，在培训结束后， 在此期间，我将熟练地识别阿尔茨海默病和VaD的临床特征，并在管理和 分析多维数据集。这将是同类研究中第一个将体内、死后和靶向联合收割机结合起来的研究。 ePVS的组织病理学表征，缺乏组织病理学表征被认为是理解其临床相关性的关键限制。的 该提案是在一个独特的时间;阿尔茨海默病和脑血管疾病的合并领域汇聚并专注于血管周围 空间通过本培训计划，我将生成一系列数据，阐明ePVS的临床和生物学相关性， 将为旨在更全面地理解ePVS的机械基础的其他建议奠定基础， 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症。

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.