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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1)
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Wise, Bradley C
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Bettcher, Brianne M; Johnson, Sterling C; Fitch, Ryan et al. (2018) Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer's Disease Pathology and Neuronal Damage. J Alzheimers Dis 62:385-397
Casaletto, Kaitlin B; Staffaroni, Adam M; Elahi, Fanny et al. (2018) Perceived Stress is Associated with Accelerated Monocyte/Macrophage Aging Trajectories in Clinically Normal Adults. Am J Geriatr Psychiatry 26:952-963
Casaletto, K B; Elahi, F M; Fitch, R et al. (2018) A comparison of biofluid cytokine markers across platform technologies: Correspondence or divergence? Cytokine 111:481-489
Saloner, R; Casaletto, K B; Marx, G et al. (2018) Performance on a 1-week delayed recall task is associated with medial temporal lobe structures in neurologically normal older adults. Clin Neuropsychol 32:456-467
Staffaroni, Adam M; Brown, Jesse A; Casaletto, Kaitlin B et al. (2018) The Longitudinal Trajectory of Default Mode Network Connectivity in Healthy Older Adults Varies As a Function of Age and Is Associated with Changes in Episodic Memory and Processing Speed. J Neurosci 38:2809-2817
Alioto, Andrea G; Kramer, Joel H; Borish, Sarah et al. (2017) Long-term test-retest reliability of the California Verbal Learning Test - second edition. Clin Neuropsychol 31:1449-1458
Parthasarathy, Vishnu; Frazier, Darvis T; Bettcher, Brianne M et al. (2017) Triglycerides are negatively correlated with cognitive function in nondemented aging adults. Neuropsychology 31:682-688
Lauriola, Mariella; Esposito, Roberto; Delli Pizzi, Stefano et al. (2017) Sleep changes without medial temporal lobe or brain cortical changes in community-dwelling individuals with subjective cognitive decline. Alzheimers Dement 13:783-791
Elahi, Fanny M; Miller, Bruce L (2017) A clinicopathological approach to the diagnosis of dementia. Nat Rev Neurol 13:457-476
Casaletto, Kaitlin B; Elahi, Fanny M; Bettcher, Brianne M et al. (2017) Neurogranin, a synaptic protein, is associated with memory independent of Alzheimer biomarkers. Neurology 89:1782-1788

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