Role of Peripheral Immune Cells in Cognitive Aging: The Framingham Offspring Study

外周免疫细胞在认知衰老中的作用：弗雷明汉后代研究

• 批准号: 10606543
• 负责人: Margaret F. Doyle
• 金额: $ 61.42万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606543
• 关键词: Abeta clearance; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Antibodies; Atherosclerosis; Biological; Biological Markers; Blood; Brain; Brain region; Cardiovascular Diseases; Case/Control Studies; Cell Aging; Cells; Cerebrovascular Disorders; Chronic; Cognition; Cognitive; Cognitive aging; Communities; Complex; Dementia; Diabetes Mellitus; Disease; Etiology; Genes; Genetic Predisposition to Disease; Genetic Risk; Goals; HLA-DR15; Health; Human; Human Genetics; Hypertension; Immune; Immune response; Immune system; Impaired cognition; Inflammation; Inflammatory; Interferon Type II; Investigation; Laboratories; Link; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Molecular; Nerve Degeneration; Neurologic; Neuropsychological Tests; Onset of illness; Outcome; Pathologic; Pathway interactions; Peripheral; Personal Satisfaction; Persons; Phenotype; Play; Population; Predisposition; Prevalence; Prevention; Process; Public Health; Regulatory Pathway; Regulatory T-Lymphocyte; Research; Risk; Risk Factors; Role; Sampling; Science; Senile Plaques; Stroke; T cell infiltration; T-Lymphocyte; Testing; Time; Transgenic Mice; Vascular Cognitive Impairment; Woman; Work; age related; aged; aging brain; apolipoprotein E-4; blood-based biomarker; brain health; brain magnetic resonance imaging; brain volume; cardiovascular disorder epidemiology; cardiovascular disorder risk; cell type; clinical development; clinical diagnosis; cohort; dementia risk; effective therapy; gene function; genetic association; high risk; imaging biomarker; immune checkpoint blockade; improved; insight; men; middle age; mild cognitive impairment; multidisciplinary; neuroimaging marker; neuroimmunology; neuroinflammation; new therapeutic target; novel; novel marker; novel therapeutics; offspring; prevent; programmed cell death protein 1; sex; sex risk; tau Proteins; vascular factor; vascular risk factor; β-amyloid burden

Cognitive health is central to successful aging, independence and well-being. The prevalence of dementia is increasing in the U.S. and there are no effective therapies to prevent cognitive decline or to treat Alzheimer's disease (AD) and related dementia. Neuroinflammation, including systemic immune cells, contributes to neurodegeneration in AD and age-related dementias. Convincing evidence from animal models of AD, large human genetic association studies of AD and dementia imaging markers, and small human case-control studies of AD, demonstrate a role for immune cells and processes in the disease. The complex relationships among the peripheral immune system, cardiovascular disease and its risk factors, and cognitive health are not yet understood. Understanding the biologic mechanisms connecting circulating immune cells and cognitive aging holds the potential to identify new blood based biomarkers and novel therapies for cognitive decline, dementia and AD. We propose a comprehensive investigation of the role of circulating immune cells across the spectrum of cognitive aging in the community-based Framingham Offspring cohort. The cohort is deeply phenotyped for cognitive outcomes, including longitudinal dementia surveillance and repeated neuro- psychological (NP) tests and brain MRI. We hypothesize that we will identify novel associations between immune cell phenotypes in the pro-inflammatory and regulatory pathways and incident adverse cognitive outcomes including development of clinical dementia, mild cognitive impairment (MCI), and measures of cognitive aging defined by NP testing and brain MRI scans. We will investigate whether vascular factors associated with immune cell phenotypes mediate the relationships, as vascular factors increase susceptibility to cognitive aging. We will test our hypotheses with the following Specific Aims: Aim 1: To profile circulating immune cell phenotypes in a dementia and stroke free community based sample of men and women across a wide age range (n=1000, mean age 63, range 40 to 88) and identify cross- sectional correlates of the immune cell phenotypes including age and sex. Aim 2: To identify circulating immune cell phenotypes in the pro-inflammatory and regulatory pathways that are risk factors for incident cognitive aging outcomes (dementia including AD and cognitive aging measures based on NP testing and MRI brain volumes). We will test whether associations differ by sex and genetic risk. Aim 3. To investigate whether the cognitive-outcome related immune cell phenotypes identified in Aim 2 are associated with vascular factors known to increase susceptibility to cognitive aging including incident cerebrovascular disease, cardiovascular disease and vascular risk factors. This work will uncover novel mechanistic insights into the relations between circulating immune cell phenotypes and the aging brain, identify new biomarkers for cognitive decline, and may reveal novel therapeutic targets to prevent and treat dementia consistent with NIAs strategic goals for aging research.

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