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.

我们提出一种新方法来诊断早期阿尔茨海默病 (AD) 并预测进展通过强大的生物标志物捕获系统水平上的“类淋巴”途径运输。途径是一个全脑系统，最近发现它可以作为有毒物质的清除途径大脑废物蛋白，包括可溶性淀粉样蛋白 β (A) 和 tau，与经典的全身淋巴管类似因此，类淋巴通路包含一个以前被忽视的独特的区室。脑血管系统、血管周围空间、脑脊液（CSF）不断流入脑间质液 (ISF) 空间，从而将废物溶质排出大脑，但罕见的家族性 AD 除外。当大脑中过量的 A 产生和沉积明显导致认知能力下降时，有限的在更常见的散发性 AD 中，有证据表明脑内 A 积累是 A In 过量产生的结果。事实上，新出现的证据表明，散发性 AD 中实质 A 积累是由 A 减少驱动的因此，类淋巴通路是将 A 破坏性清除与 AD 联系起来的主要候选途径，并且我们将利用这个机会开发新的工具和计算分析，明确旨在捕获全局类淋巴通路功能并可作为新型 AD 诊断生物标志物。可用于捕获类淋巴运输的所有复杂和动态成分的方法，特别是，我们建议整合成像技术并开发。新颖的计算分析，包括最佳质量运输，以将类淋巴通路表征为拟议研究的最终目标是应用类淋巴生物标志物。并追踪其对血管和实质淀粉样蛋白病理进展的破坏。基于新的初步发现：1）类淋巴运输可以被视为一个综合系统通过血管周围和间质空间；2) 特定麻醉剂引起的状态依赖性变化显着影响类淋巴运输的方案可以通过最佳质量运输来捕获分析；3) 一种新的转基因大鼠脑淀粉样血管病模型（rTg-SwDI），将用于在拟议的研究中针对转基因大鼠 AD 模型 (rTgF344-AD36) 进行特定假设检验。具体目标如下：（1）开发生物标志物以可视化和功能量化宏观、基于 MRI 计算分析和脑脊液示踪剂宏观光学成像的类淋巴运输在正常的年轻（3 个月大）大鼠中，以及（2）确定正常衰老和特定 AD 样的方式和时间脑血管和实质淀粉样蛋白病理通过以下方式影响大脑中的类淋巴运输 SA1 中开发的计算管道成功完成了拟议的高度创新。实验将产生一种全新的、有前途的生物标志物，通过类淋巴通路是 CAA 和 AD 传播的关键。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Optimal Transport for Gaussian Mixture Models

DOI：
10.1109/access.2018.2889838
发表时间：
2017-10
期刊：
IEEE Access
影响因子：
3.9
作者：
Yongxin Chen;T. Georgiou;A. Tannenbaum
通讯作者：
Yongxin Chen;T. Georgiou;A. Tannenbaum

Cerebral amyloid angiopathy is associated with glymphatic transport reduction and time-delayed solute drainage along the neck arteries.

DOI：
10.1038/s43587-022-00181-4
发表时间：
2022-03
期刊：
NATURE AGING
影响因子：
0
作者：
Chen, Xinan;Liu, Xiaodan;Koundal, Sunil;Elkin, Rena;Zhu, Xiaoyue;Monte, Brittany;Xu, Feng;Dai, Feng;Pedram, Maysam;Lee, Hedok;Kipnis, Jonathan;Tannenbaum, Allen;Van Nostrand, William E.;Benveniste, Helene
通讯作者：
Benveniste, Helene

Direct Measurement of Cerebrospinal Fluid Production in Mice.