Characterizing the glymphatic peri-vascular connectome and its disruption in AD

AD 中类淋巴血管周围连接组的特征及其破坏

• 批准号: 9452462
• 负责人: Helene D Benveniste
• 金额: $ 337.02万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-11 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9452462
• 关键词: Characterizing; glymphatic; peri; vascular; connectome; Characterizing; glymphatic; peri; vascular; connectome

We are proposing a novel approach to diagnosing early Alzheimer’s disease (AD) and predicting progression via a robust biomarker that captures ‘glymphatic’ pathway transport on a systems level. The glymphatic pathway is a brain-wide system, which was recently discovered to function as a clearance pathway for toxic brain waste proteins including soluble amyloid beta (A) and tau similarly to the classical body-wide lymphatic system. As such, the glymphatic pathway comprises a previously overlooked and unique compartment of the brain vasculature, the peri-vascular space wherein cerebrospinal fluid (CSF) is flowing and streaming into the brain interstitial fluid (ISF) space thereby forcing waste solutes out of the brain. Except for rare familial AD, where excessive A production and deposition in the brain clearly drives cognitive decline, there is limited evidence in the more common sporadic AD that cerebral A accumulation is the result of Aoverproduction. In fact, emerging evidence suggests that parenchymal A accumulation in sporadic AD is driven by reduced A clearance. The glymphatic pathway is thus a prime candidate for linking disruptive clearance of A to AD, and we will use this opportunity to develop new tools and computational analysis aimed explicitly at capturing global glymphatic pathway function and serve as a novel diagnostic AD biomarker. Currently there is no method available to capture all of the intricate and dynamic components of glymphatic transport, in particular, parenchymal transport and clearance pathways. We propose to integrate imaging techniques and develop novel computational analysis including optimal mass transport to characterize the glymphatic pathway as a brain-wide dynamic ‘unit’. The ultimate goal of the proposed investigation is to apply the glymphatic biomarker and track its disruption in progressing vascular and parenchymal amyloid pathologies. The proposed studies are based on novel preliminary findings that 1) glymphatic transport can be visualized as an integrative system through perivascular and interstitial spaces; 2) that state dependent changes induced by specific anesthetic regimens which dramatically affect the glymphatic transport can be captured by optimal mass transport analysis; and 3) a new transgenic rat model of cerebral amyloid angiopathy (rTg-SwDI) which will be used for specific hypothesis testing against the transgenic rat AD model (rTgF344-AD36) in the proposed studies. The specific aims are the following: (1) To develop biomarkers to visualize and functionally quantify macroscopic, glymphatic transport based on computational analysis of MRI and macroscopic optical imaging of CSF tracers in normal young (3 month old) rats and (2) to determine how and when normal aging and specific AD-like cerebral vascular and parenchymal amyloid pathologies influence glymphatic transport in the brain using the computational pipeline developed in SA1. Successful completion of the proposed highly innovative experiments will yield an entirely new and promising biomarker to track reduced Aß clearance via the glymphatic pathway which is key to the propagation of CAA and AD.

我们提出了一种诊断早期阿尔茨海默氏病（AD）并预测进展的新方法 通过可靠的生物标志物，该生物标志物在系统级别捕获“胶状”途径的运输。糖 途径是一个大脑的系统，最近被发现作为有毒的间隙途径起作用 脑浪费蛋白包括固体淀粉样β（A）和TAU，类似于经典的身体淋巴类似 系统。因此，糖基途径包括先前被忽视的独特隔室 脑脉管系统，脑血管周围空间，其中脑脊液（CSF）正在流动并流入 大脑间质液（ISF）空间，从而将废物溶液从大脑中迫使废物溶液。除了罕见的家庭广告， 在大脑中超级产生和沉积显然会导致认知能力下降的地方，有限 在更常见的零星广告中，脑A积累是A超产生的结果。在 事实，新出现的证据表明，零星广告中的实质A积累是由A驱动的。 清除。因此 我们将利用这个机会开发新工具和计算分析，旨在捕获 全球胶状途径功能，并充当一种新型的诊断AD生物标志物。目前没有 可用于捕获尤其是糖糖传输的所有复杂和动态组件的方法， 实质运输和清除途径。我们建议整合成像技术并发展 新的计算分析，包括最佳的质量传输，以将乙二长途径表征为 大脑范围的动态“单位”。拟议的调查的最终目标是应用糖基生物标志物 并在进展的血管和副淀粉样蛋白病理中跟踪其破坏。提出的研究 是基于新的初步发现，即1）可以将乙二醇传输视为集成系统 通过血管周和间质空间； 2）特定麻醉诱导的状态依赖性变化 动态影响性糖运输的方案可以通过最佳质量运输来捕获 分析; 3）一种新的大脑淀粉样血管病（RTG-SWDI）的转基因大鼠模型，该模型将用于 在拟议的研究中，针对转基因大鼠AD模型（RTGF344-AD36）的特定假设检验。这 具体目的是：（1）开发生物标志物以可视化和功能量化宏观， 基于MRI的计算分析和CSF示踪剂的宏观光学成像的胶囊传输 在正常的年轻（3个月大）和（2）中，以确定正常衰老和特定广告样的方式 脑血管和副淀粉样淀粉样蛋白病变会使用使用 SA1开发的计算管道。成功完成拟议的高度创新性 实验将产生一个全新的有希望的生物标志物，以通过 Glymphatic途径是CAA和AD传播的关键。