An investigation of Alzheimer's Disease pathology, microglial immune response, and CSF proteomics in normal pressure hydrocephalus patients

常压脑积水患者阿尔茨海默病病理学、小胶质细胞免疫反应和脑脊液蛋白质组学的研究

基本信息

批准号：
10475203
负责人：
Guy M McKhann
金额：
$ 81万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-05-31
项目状态：
未结题

项目摘要

Program Director/Principal Investigator (Last, First, Middle): Teich, Andrew, Franklin Project Summary The overall goal of this grant is to use surgically removed brain tissue and CSF from elderly patients presenting for hydrocephalus surgery to characterize the effects of early co-morbid Alzheimer’s disease (AD) pathology on these tissues and correlate these findings with clinical outcomes. Chronic hydrocephalus in the aging population can occur for a variety of reasons, although the etiology is often unclear. In the absence of a clear etiology, most of these cases are categorized as “Normal Pressure Hydrocephalus” (NPH). Placing a ventricular shunt is often effective for symptom relief in the setting of NPH. At the time of shunt placement, a cortical biopsy is often obtained at the brain entry point to look for possible coexistent brain pathology. Perhaps not surprisingly, cortical biopsies taken from elderly NPH patients at shunt placement have been shown to have a relatively high frequency of b-amyloid plaque pathology and occasional trace tau pathology, perhaps because early-stage AD may be causing some of the symptoms attributed to NPH. We have recently performed RNA-seq on 106 NPH biopsies and compared the results to histologic measures of b-amyloid and tau and contemporaneous cognitive data. In contrast to the existing human AD autopsy literature, we identify a homeostatic microglial module that partially replicates the decrease in homeostatic genes that is seen in the mouse AD literature. These data suggest that our NPH biopsies are capturing some of the earliest changes in AD physiology, and in doing so may serve as a conceptual bridge between some of the early responses seen in the mouse literature and the post-mortem human AD literature. Motivated by these data, the goal of this grant is to test the following three hypotheses: 1) Changes in microglial modules in our bulk RNA-seq data reflect population shifts or changes in gene expression in microglial subtypes, 2) An evolving microglial response in patient biopsies will correlate with alterations in CSF proteins, and 3) The microglial immune response in patient biopsies has predictive value for cognitive decline that is different or additive to the degree of b-amyloid and tau deposition in cortex. Completion of this project will identify CSF proteomic changes that correlate with shifts in microglial populations and microglial gene expression changes, and place all of these changes in the context of AD pathology density on biopsy and clinical outcomes. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page

项目总监/首席研究员（最后、第一、中间）：Teich、Andrew、Franklin 项目概要这笔赠款的总体目标是使用通过手术切除的老年患者的脑组织和脑脊液用于脑积水手术，以表征早期共病阿尔茨海默病 (AD) 病理学对患者的影响这些组织并将这些发现与衰老过程中的慢性脑积水相关联。人群发生的原因有多种，但病因往往尚不清楚。根据病因学，大多数病例被归类为“正常压力脑积水”（NPH）。在 NPH 情况下，脑室分流通常可以有效缓解症状。皮质活检通常在大脑入口点进行，以寻找可能共存的大脑病理。毫不奇怪，在分流术中对老年 NPH 患者进行的皮质活检显示，具有相对较高频率的 b-淀粉样斑块病理学和偶尔的微量 tau 病理学，也许因为早期 AD 可能会导致一些 NPH 症状。对 106 个 NPH 活组织检查进行 RNA-seq，并将结果与 b-淀粉样蛋白和与现有的人类 AD 尸检文献相比，我们确定了 tau 和同期认知数据。稳态小胶质细胞模块部分复制了在小鼠 AD 文献。这些数据表明我们的 NPH 活检正在捕获一些最早的变化。 AD 生理学，这样做可以作为一些早期反应之间的概念桥梁在小鼠文献和死后人类 AD 文献中，受这些数据的启发，本研究的目标是。拨款是为了测试以下三个假设：1）我们的批量 RNA-seq 数据中小胶质细胞模块的变化反映小胶质细胞亚型的群体变化或基因表达的变化，2) 不断进化的小胶质细胞患者活检中的反应将与脑脊液蛋白的变化相关，3) 小胶质细胞免疫患者活检中的反应对认知能力下降具有不同或相加程度的预测价值该项目的完成将确定脑脊液蛋白质组的变化。将变化与小胶质细胞群体和小胶质细胞基因表达变化相关联，并将所有这些 AD 病理密度对活检和临床结果的影响。 OMB 编号 0925-0001/0002（修订版 03/16 已批准至 10/31/2018）页面延续格式页面