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.

认知健康对于成功老龄化、独立和幸福至关重要。痴呆症的患病率是 在美国，这种情况正在增加，并且没有有效的疗法来预防认知能力下降或治疗阿尔茨海默病 疾病（AD）和相关的痴呆症。神经炎症，包括全身免疫细胞，有助于 AD 和年龄相关性痴呆中的神经退行性变。来自 AD 动物模型的令人信服的证据 AD 和痴呆成像标记的人类遗传关联研究以及小规模人类病例对照 对 AD 的研究证明了免疫细胞和过程在该疾病中的作用。复杂的关系 在外周免疫系统中，心血管疾病及其危险因素以及认知健康并不重要。 却又明白了。了解循环免疫细胞与认知之间的生物学机制 衰老有可能识别新的基于血液的生物标志物和认知能力下降的新疗法， 痴呆症和AD。我们建议对循环免疫细胞在整个系统中的作用进行全面的研究 以社区为基础的弗雷明汉后代队列中的认知衰老谱。队列很深 表型认知结果，包括纵向痴呆监测和重复的神经 心理 (NP) 测试和脑部 MRI。我们假设我们将发现之间的新关联 促炎和调节途径中的免疫细胞表型以及不良认知事件 结果包括临床痴呆、轻度认知障碍 (MCI) 的发展以及 由 NP 测试和脑 MRI 扫描定义的认知老化。我们将调查是否血管因素 与免疫细胞表型相关的细胞介导这种关系，因为血管因素会增加易感性 到认知老化。我们将通过以下具体目标来检验我们的假设： 目标 1：分析无痴呆和无中风社区样本中的循环免疫细胞表型 对不同年龄范围的男性和女性（n=1000，平均年龄 63，范围 40 至 88）进行了调查，并确定了交叉 免疫细胞表型的截面相关性，包括年龄和性别。 目标 2：确定促炎和调节途径中的循环免疫细胞表型 是事件认知老化结果的危险因素（痴呆症，包括 AD 和认知老化测量 基于 NP 测试和 MRI 脑容量）。我们将测试关联是否因性别和遗传风险而异。 目标 3. 研究目标 2 中确定的认知结果相关免疫细胞表型是否 与已知增加认知衰老易感性的血管因素（包括事件）相关 脑血管疾病、心血管疾病和血管危险因素。 这项工作将揭示循环免疫细胞之间关系的新机制见解 表型和衰老的大脑，识别认知能力下降的新生物标志物，并可能揭示新的 预防和治疗痴呆症的治疗目标与 NIA 的衰老研究战略目标一致。