Structural and diffusion changes of perivascular space in aging, cognitive decline and Alzheimer's disease

项目摘要 血管周围间隙（PVS）是指微动脉、微静脉和毛细血管周围的区域， 通过星形胶质细胞终足上表达的水通道蛋白-4通道清除代谢废物，并参与 血脑屏障转运PVS最近通过在脑间质中的潜在作用而变得突出。 液体引流和废物清除，以及阿尔茨海默病（AD）和其他疾病的发病机制 神经退行性疾病虽然动物研究已经精确地阐明了这一机制，但来自人类的数据 是相对粗糙的，并且限于临床磁共振图像上可见PVS的视觉计数，并且这 限制了我们对人类衰老过程中PVS的形态、生物物理特性和分布的理解， AD.长期目标是了解PVS在大脑健康中的作用以及它在AD中的改变程度。 本项目的目的是绘制PVS流体的形态和扩散特性， 在早期，它是如何改变的。核心假设是， PVS流体特性，例如体积占据和扩散特性，是差异性和选择性的。 与正常衰老相比，认知能力下降和AD的改变。这一建议的基本原理是 PVS的体内非侵入性标测提供了关于AD病理生理学的机制性见解。的 拟议的工作还将开发广泛适用的开放资源，以绘制PVS形态和扩散图 这些特性可以应用于广泛的神经系统疾病。中心假设将通过以下方式进行检验： 追求三个具体目标：1）表征正常衰老个体中PVS流体的变化， AD病理学的下降或证据，并评价图像采集策略对结果的影响 测量; 2）识别认知下降和AD病理个体中的PVS改变;和3）确定 PVS与心血管危险因素和AD病理学的相关程度。我们将继续努力， 目的是通过将创新的基于MRI的计算技术应用于最近可用的正常衰老数据， 来自NIH资助的多项大型研究的认知能力下降患者。计算技术包括 最近开发的神经成像技术对PVS和更成熟的结构图像敏感 分析技术。这项研究对AD的研究具有重要意义，因为它将有助于对AD的理解 因此有助于AD的早期诊断和疾病监测。它 也很重要，因为它将使公共资源可用于研究其他神经系统疾病， 以脑内PVS受损为特征的疾病。结果将产生重要的积极影响 因为他们将首次识别和绘制人类大脑中PVS在衰老过程中的变化， 认知障碍和AD个体。我们的共享PVS成像工具也可以更广泛地应用于 广泛的临床和研究应用，以及其他群体。

PROJECT SUMMARY Perivascular spaces (PVS) are the area around arterioles, venules and capillaries which accommodate the clearance of the metabolic waste via Aquaporin-4 channels expressed on astrocytic endfeet and are involved in blood-brain barrier transport. PVS have come to prominence recently through potential roles in brain interstitial fluid drainage and waste clearance, and in the pathogenesis of Alzheimer’s disease (AD) and other neurodegenerative disorders. While animal studies have precisely clarified this mechanism, data from humans are relatively crude and limited to visual counting of visible PVS on clinical magnetic resonance images, and this limits our understands of the morphology, biophysical properties and distribution of the PVS in human aging and AD. The long-term goal is to understand the role of PVS in brain health and the degree to which it alters in AD. The objective of this project is to map morphologic and diffusion characteristics of the PVS fluid in healthy aging, and how it is altered in the early stages of AD. The central hypothesis is that imaging-derived PVS fluid characteristics, such as volume occupied and diffusion properties, are differentially and selectively altered in cognitive decline and AD in comparison with normal aging. The rationale underlying this proposal is that in vivo noninvasive mapping of the PVS provides mechanistic insight about AD pathophysiology. The proposed work will also develop widely applicable open resources to map PVS morphologic and diffusion properties that can be applied to a wide range of neurological disorders. The central hypothesis will be tested by pursuing three specific aims: 1) Characterize changes in PVS fluid in normal aging individuals with no cognitive decline nor evidence of AD pathology and evaluate the effect of image acquisition strategy on outcome measures; 2) Identify PVS alteration in cognitive decline and in individuals with AD pathology; and 3) Determine the extent to which PVS is associated with cardiovascular risk factors versus AD pathology. We will pursue these aims by applying innovative MRI-based computational techniques on recently available data of normal aging and patients with cognitive decline from multiple large NIH-funded studies. Computational techniques include both recently developed neuroimaging techniques sensitized to the PVS and more established structural image analysis techniques. The proposed research is significant, because it will aid in the understanding of AD pathophysiological mechanisms and consequently assist in the early diagnosis and disease monitoring of AD. It is also significant because it will make public resources available that can be used to study other neurological disorders characterized by impaired PVS in the brain. The results will have an important positive impact immediately because they will identify and map, for the first time, PVS alteration in human brain across aging, cognitively impaired and AD individuals. Our shared PVS imaging tools can also be more broadly applied to a wide range of clinical and research applications by other groups as well.