R01AG073360

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 β-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 β-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.
3) The microglial immune response in patient biopsies has predictive value for cognitive decline that is different or additive to the degree of β-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)
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The Trustees Of Columbia University In The City Of New York

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

New York, New York 10032 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 420% from $809,998 to $4,208,639.