Chronic inflammation is a major characteristic of the typical aging process. The view that the central nervous system is immunologically privileged, however, is challenged by evidence linking low level, chronic inflammation to neurologic injury, neurodegeneration, and cognitive dysfunction. The degree of risk posed by inflammation and the underlying mechanisms of injury remain unclear. The overarching goal of this proposal is to better define the impact of chronic inflammation on brain structure and function. We propose to study four potential downstream effects of chronic inflammation on the brain: 1) Alzheimer's-related changes; 2) white matter injury; 3) network connectivity; and 4) cognition. We will longitudinally study 150 functionally normal community-dwelling subjects over the age of 65 selected from on-going, well-characterized cohorts at UCSF. We will quantify chronic inflammation using several well established markers in serum, plasma, and cerebrospinal fluid. Innovative MRI and PET molecular neuroimaging methods will measure microstructural integrity of white matter tracts, functional connectivity networks, and Alzheimer's-related deposition of brain amyloid. Cerebrospinal fluid (CSF) obtained on a subset of cases will further our understanding of specific inflammatory profiles in the periphery and brain. The cognitive phenotype(s) associated with chronic inflammation will be defined using methods from cognitive neuroscience, and we will explore potential mechanisms by which chronic inflammation interacts with brain structure and function. Results from this project will potentially guide clinial trials and identify elderly subjects with treatable and reversible risks for adverse neurological and cognitive aging.

Public Health Relevance

Chronic inflammation increases as we age, and has been independently linked to major age-related diseases, including neurodegeneration and cerebrovascular disease. The overarching goal of this proposal is to better define the longitudinal impact of chronic inflammation on brain structure and function in the elderly by employing imaging biomarkers of white matter injury and Alzheimer's disease. Because inflammation is potentially treatable, this study can contribute to public health by establishing te nature and mechanisms of brain changes, and identifying the best biomarkers of inflammation and neurological functioning for clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG048234-04
Application #
9415443
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wise, Bradley C
Project Start
2015-04-15
Project End
2020-01-31
Budget Start
2018-03-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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