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

我们提出了一种新的方法来诊断早期阿尔茨海默病(AD)并预测病情进展 通过一个强大的生物标记物，捕捉系统水平上的“淋巴”途径运输。《歌舞者》 通路是一个全脑系统，最近被发现起到清除毒素的作用。 脑废物蛋白包括可溶性淀粉样β蛋白(A)和tau，类似于经典的全身淋巴管 系统。因此，舌管通路包括一个先前被忽视的独特的 脑血管系统，脑脊液(CSF)在其中流动和流入血管周围的空间。 大脑间质液体(ISF)空间，从而迫使废物溶质从大脑中排出。除了罕见的家族性AD， 在大脑中过度产生和沉积A明显会导致认知能力下降的情况是有限的 在更常见的散发性AD中，有证据表明大脑A积聚是A过度生产的结果。在……里面 事实，新的证据表明，散发性AD的实质A积聚是由A减少驱动的 通行证。因此，淋巴通路是将A的破坏性清除与AD联系起来的最佳候选途径，并且 我们将利用这个机会开发新的工具和计算分析，明确地旨在捕获 全球淋巴通路的功能，并作为一种新的诊断AD的生物标志物。目前没有 可用于捕获淋巴运输的所有复杂和动态组件的方法，尤其是， 实质运输和清除途径。我们建议整合成像技术并开发 新的计算分析，包括最优质量传输，以表征淋巴途径为 全脑的动态‘单位’。拟议调查的最终目标是应用淋巴生物标记物。 并追踪其在血管和实质淀粉样蛋白病理进展中的破坏。建议进行的研究 基于新的初步发现，1)淋巴运输可以被视作一个整合的系统 通过血管周围和间质间隙；2)特定麻醉剂引起的状态依赖改变 显著影响淋巴传输的方案可以通过最佳质量传输来捕获 分析；以及3)一种新的转基因大鼠脑淀粉样血管病模型(RTG-Swdi)，将用于 本研究针对转基因大鼠AD模型(rTgF344-AD36)进行特异性假设检验。这个 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淋巴转运 在正常年轻(3月龄)大鼠和(2)确定如何以及何时正常衰老和特定的AD样 脑血管和实质淀粉样蛋白病变通过影响脑内淋巴转运 在SA1中开发的计算管道。圆满完成拟议的极具创新性的 实验将产生一种全新的、有希望的生物标记物，通过 淋巴通路是CAA和AD传播的关键。

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.