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

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