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

项目总结 血管周围间隙(PVS)是小动脉、小静脉和毛细血管周围的区域，它们容纳了 通过星形细胞终足表达的水通道蛋白-4清除代谢废物，并参与 血脑屏障运输。PVS最近通过在脑间质中的潜在作用而变得突出起来 液体排出和废物清除，以及在阿尔茨海默病(AD)和其他疾病的发病机制中 神经退行性疾病。虽然动物研究已经准确地阐明了这种机制，但来自人类的数据 相对粗糙，仅限于临床磁共振图像上可见的PVS的视觉计数，而这 限制了我们对PVS的形态、生物物理性质和分布在人类衰老和 广告。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。 本项目的目标是绘制PVS流体的形态和扩散特征图 健康的衰老，以及在AD的早期阶段它是如何改变的。中心假设是成像派生的 PVS流体特性，如体积占有率和扩散特性，是有区别和选择性的 与正常衰老相比，认知功能减退和阿尔茨海默病的改变。这项提议背后的理由是 体内无创性的PVS标测提供了对AD病理生理学的机械性洞察。这个 拟议的工作还将开发广泛适用的开放资源，以绘制PVS的形态和扩散图 可应用于多种神经性疾病的特性。核心假设将通过以下方式进行检验 追求三个具体目标：1)描述没有认知能力的正常老年个体PVS液体的变化 拒绝AD病理证据，评估图像采集策略对预后的影响 测量；2)确定认知减退和AD病理个体的PVS改变；以及3)确定 与AD病理相比，PVS与心血管危险因素的关联程度。我们将致力于实现这些目标 旨在将创新的基于MRI的计算技术应用于最近可获得的正常衰老和 由美国国立卫生研究院资助的多项大型研究发现的认知功能减退患者。计算技术包括这两种 新近发展的对PVS和更多已建立的结构图像敏感的神经成像技术 分析技术。这项拟议的研究具有重要意义，因为它将有助于理解AD 因此有助于AD的早期诊断和疾病监测。它 这也很重要，因为它将提供可用于研究其他神经学的公共资源 以脑内PVS受损为特征的疾病。这一结果将产生重要的积极影响 因为他们将第一次识别和绘制出人类大脑中PVS在衰老过程中的变化， 认知障碍和阿尔茨海默病患者。我们的共享PVS成像工具还可以更广泛地应用于 广泛的临床和研究应用，其他群体也是如此。

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.