Document text
Principal Investigator: Guy M McKhann
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $76,070
Funding agency: National Institute on Aging
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
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