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

项目总监/首席调查员(最后、第一、中间)：Teich、Andrew、Franklin 项目摘要 这笔赠款的总体目标是使用手术切除的脑组织和脑脊液，这些脑组织和脑脊液来自于 用于脑积水手术以表征早期共病阿尔茨海默病(AD)病理对 并将这些发现与临床结果相关联。老年慢性脑积水 人群的发生可能有多种原因，尽管病因往往不清楚。在没有明确规定的情况下 病因学上，这些病例大多被归类为“正常压力脑积水”(NPH)。放置一个 脑室分流术通常是NPH患者缓解症状的有效方法。在放置分流装置时， 皮质活组织检查通常在大脑入口处进行，以寻找可能共存的脑病理。也许吧 毫不奇怪，分流术中取自老年NPH患者的皮质活组织检查显示 可能有较高频率的b-淀粉样斑块病变和偶尔的微量tau病变。 因为早期的阿尔茨海默病可能会导致一些被认为是NPH的症状。我们最近做了 对106例NPH活检组织进行rna-seq，并将其结果与b-淀粉样蛋白和 Tau和同时代的认知数据。与现有的人类AD尸检文献相比，我们发现了一种 动态平衡小胶质细胞模块，部分复制动态平衡基因的减少 小鼠AD文学。这些数据表明，我们的NPH活组织检查捕捉到了一些最早的变化 AD生理学，在这样做的过程中，可以作为一些早期反应之间的概念桥梁 在老鼠文学和死后人类的AD文学中。在这些数据的推动下，这一目标 格兰特将测试以下三个假设：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转移或基因表达的变化，2)进化中的小胶质细胞 患者活检的反应将与脑脊液蛋白的变化相关，以及3)小胶质细胞免疫。 患者活检的反应对认知能力下降有不同程度或相加程度的预测价值 B-淀粉样蛋白和tau蛋白在皮质中的沉积。该项目的完成将确定脑脊液蛋白质组的变化 与小胶质细胞群体的变化和小胶质细胞基因表达的变化相关，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(03/16修订版批准至2018年10月31日)页面续格式页面

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