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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

基本信息

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
项目类别：
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

项目摘要

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.

我们提出了一种新的方法来诊断早期阿尔茨海默病（AD）和预测进展通过一个强大的生物标志物，捕获系统水平上的“胶质淋巴”途径运输。胶质淋巴脑内信号通路是一个广泛的脑系统，最近发现其作为毒性物质的清除通路发挥作用。脑废物蛋白质包括可溶性淀粉样蛋白β（A β）和tau，类似于经典的全身淋巴系统因此，胶质淋巴通路包括一个以前被忽视的和独特的隔室，脑血管系统，其中脑脊液（CSF）流动并流入脑血管系统的血管周围空间，脑间质液（ISF）空间，从而迫使废物溶质出脑。除了罕见的家族性AD，在大脑中过量的A β产生和沉积显然会导致认知能力下降的情况下，在更常见的散发性AD中的证据表明，大脑中的A β积聚是A β过度产生的结果。在事实上，新出现的证据表明，散发性AD的实质A β积聚是由A β减少驱动的，间隙因此，胶质淋巴通路是将A β的破坏性清除与AD联系起来的主要候选者，并且我们将利用这个机会开发新的工具和计算分析，目的是明确地捕捉这是一种具有全局胶质淋巴通路功能的蛋白质，并可作为新的诊断AD的生物标志物。目前没有可用于捕获胶质淋巴转运的所有复杂和动态成分的方法，特别是，实质转运和清除途径。我们建议整合成像技术，新的计算分析，包括最佳的质量传输，以表征胶质淋巴途径作为一个全脑动态“单元”。拟议研究的最终目标是应用胶质淋巴生物标志物并跟踪其在血管和实质淀粉样病变进展中的破坏。拟议的研究基于新的初步发现，1）胶质淋巴转运可以被视为一个整合系统通过血管周围和间质空间; 2）由特定麻醉剂诱导的状态依赖性变化显著影响胶质淋巴转运的方案可以通过最佳质量转运来捕获分析;和3）脑淀粉样血管病（rTg-SwDI）的新转基因大鼠模型，其将用于在拟定研究中，针对转基因大鼠AD模型（rTgF 344-AD 36）进行特定假设检验。的具体目标如下：（1）开发生物标记物以可视化和功能性地量化宏观的，基于MRI的计算分析和CSF示踪剂的宏观光学成像的胶质淋巴转运在正常的年轻（3个月大）大鼠和（2）以确定如何和何时正常老化和特定的AD样脑血管和实质淀粉样蛋白病变影响脑内胶质淋巴转运，在SA 1中开发的计算流水线。成功完成了极具创新性的实验将产生一个全新的和有前途的生物标志物，以跟踪减少的阿托伐他汀清除通过胶质淋巴途径是CAA和AD传播的关键。