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

项目负责人/主要研究者（最后，第一，中间）：Teich，Andrew，富兰克林 项目摘要 该补助金的总体目标是使用通过手术切除的老年患者的脑组织和CSF 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 并将这些发现与临床结果相关联。老年慢性脑积水 人群中的腹泻可因多种原因发生，尽管病因通常不清楚。缺乏明确的 根据病因，这些病例中的大多数被归类为"正常压力脑积水"（NPH）。放置 脑室分流术通常对NPH的症状缓解有效。在放置分流管时， 通常在脑进入点获得皮质活检以寻找可能共存的脑病理。也许 毫不奇怪，从老年NPH患者在分流安置时采集的皮质活检显示， 有相对高频率的b-淀粉样蛋白斑块病理和偶尔的痕量tau病理， 因为早期AD可能会导致NPH的一些症状。我们最近 对106例NPH活检进行了RNA-seq，并将结果与b-淀粉样蛋白和 tau和同期认知数据。与现有的人类AD尸检文献相比，我们确定了一个 自稳态小胶质细胞模块，部分复制了自稳态基因的减少， 小鼠AD文献。这些数据表明，我们的NPH活检捕捉到了一些最早的变化， AD生理学，并在这样做可能作为一个概念之间的桥梁，一些早期反应看到 在小鼠文献和人类AD尸检文献中。在这些数据的激励下， 格兰特将测试以下三个假设：1）在我们的批量RNA-seq数据中小胶质细胞模块的变化 反映了小胶质细胞亚型中基因表达的群体变化或变化，2）一种进化的小胶质细胞 患者活检中的反应将与CSF蛋白的改变相关，以及3）小胶质细胞免疫应答将与CSF蛋白的改变相关。 患者活检的反应对认知能力下降具有预测价值， 淀粉样蛋白和tau蛋白在皮质的沉积。该项目的完成将确定CSF蛋白质组学变化， 与小胶质细胞群的变化和小胶质细胞基因表达的变化相关， 在AD病理学背景下活检密度和临床结局的变化。 OMB编号0925 - 0001/0002（2016年3月修订版，批准至2018年10月31日）

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