Map Paravascular Fluid Dynamic Signatures of Key Aging and AD Processes Using Dynamics Diffusion-Weighted Imaging

摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种以β淀粉样蛋白（amyloid-beta，Aβ）和tau蛋白（tau蛋白）聚集为特征的疾病 病理学来自临床前研究的越来越多的证据表明， 血管旁脑脊液（pCSF）清除途径（胶质淋巴系统）有助于 Aβ和tau聚集。这些研究进一步强调了pCSF循环依赖于 血管功能，其中自发性高血压导致pCSF流量减少。但据 目前还不清楚人类是否存在类似的现象，以及pCSF动力学如何随着衰老而变化， 原发性高血压和AD。对胶质淋巴系统的人类研究已被证明是 由于缺乏安全的无示踪剂成像方法，这是一个挑战。最近，一种新的临床 一种可行的成像技术，动态弥散加权成像（dDWI），已经开发出来， PI，其产生胶质淋巴细胞内pCSF运动的可再现定量度量 系统定量指标可以同时评估pCSF的体积和动力学 靠近主动脉和软脑膜动脉-胶质淋巴流的流入。作为早期的人类之一 我们对18至82岁年龄组的研究结果显示， 血管旁间隙扩大和pCSF泵送显著改变， 与认知能力下降有关。基于新颖的技术，有趣的初步 结果，以及我们团队在AD研究方面的强大专业知识，该提案的总体目标是绘制 关键老化和AD过程的pCSF特征。我们的核心假设是，尽管衰老 和高血压是pCSF受损的两个罪魁祸首，AD显示疾病特异性pCSF 与发病机制有关的异常。我们会利用最先进的神经成像技术 技术（例如，dDWI，Aβ/tau正电子发射断层扫描[PET]）和我们的大纵向 印第安纳州阿尔茨海默病研究中心（IADRC）的临床数据库，以实现 （1）绘制健康老龄化的pCSF特征图谱。(2)将老化的pCSF特征与 高血压(3)绘制AD的pCSF特征并确定其与Aβ/tau的相关性 聚合来这三个目标的成功与否将决定液体清除功能是否表现出 在健康老龄化、高血压和AD中的相似或不同的改变。这些知识至关重要 用于识别疾病途径和开发新的治疗方法。新的成像技术 有望提供有价值的和翻译的成像生物标志物，用于检测和监测 AD中的液体清除功能障碍，并可应用于研究其他神经退行性疾病， 高临床影响。

Abstract Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) and tau pathologies. Mounting evidence from preclinical studies suggests that disruption of the paravascular cerebrospinal fluid (pCSF) clearance pathway (glymphatic system) contributes to Aβ and tau aggregation. These studies further highlighted a reliance of pCSF circulation on vascular functions, where spontaneous hypertension led to reduced pCSF flow. However, it is unclear whether similar phenomena exist in humans and how pCSF dynamics change with aging, essential hypertension, and AD. Human studies of the glymphatic system have proven to be challenging due to the lack of safe tracer-free imaging approaches. Recently, a novel clinically feasible imaging technique, dynamic diffusion-weighted imaging (dDWI), has been developed by the PI, which yields reproducible quantitative metrics of pCSF movement within the glymphatic system. The quantitative metrics can simultaneously assess the volume and dynamics of pCSF near the major and pial arteries – the influx of the glymphatic flow. As one of the early human studies in this glymphatic pathway, our results of a cohort aged 18 to 82 revealed significantly enlarged paravascular space and remarkably altered pCSF pumping in the older brain, the extent of which is associated with cognitive decline. Built upon the novel technique, intriguing preliminary results, and our team’s strong expertise in AD research, the overall goal of the proposal is to map pCSF signatures of key aging and AD processes. Our central hypothesis is that although aging and hypertension are two culprits of compromised pCSF, AD show disease-specific pCSF abnormalities related to pathogenesis. We will leverage the state-of-the-art neuroimaging techniques (e.g., dDWI, Aβ/tau positron emission tomography [PET]) and our large longitudinal clinical database of the Indiana Alzheimer’s Disease Research Center (IADRC) to achieve the following aims: (1) Map pCSF signatures of healthy aging. (2) Map pCSF signatures of aging with hypertension. (3) Map pCSF signatures of AD and determine their associations with Aβ/tau aggregation. The success of the three aims will determine whether fluid clearance function shows similar or distinct alterations in healthy aging, hypertension, and AD. Such knowledge is critical for identifying disease pathways and developing novel therapeutics. The new imaging technique is expected to provide valuable and translational imaging biomarkers for detecting and monitoring dysfunctional fluid clearance in AD and be applied to study other neurodegenerative diseases of high clinical impact.