EFFECTS OF STRESS, ALLOSTATIC LOAD, AND SOCIAL INEQUITIES ON BRAIN STRUCTURE, FUNCTION, AND COGNITION IN THE EARLY-TO-MIDLIFE TRANSITION

早期到中年过渡期间压力、动态负荷和社会不平等对大脑结构、功能和认知的影响

• 批准号: 10283068
• 负责人: STEVEN E ARNOLD
• 金额: $ 17.57万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10283068
• 关键词: Address; Adrenal Glands; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Anxiety; Atrophic; Biochemical; Biological Aging; Biological Markers; Blood Vessels; Brain; Brain Diseases; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cells; Chronic Disease; Chronic stress; Clinical; Cognition; Cognitive; Dementia; Diabetes Mellitus; Discrimination; Disease; Education; Elderly; Emotional; Epigenetic Process; Glial Fibrillary Acidic Protein; Growth; Growth Factor; Health; Hippocampus (Brain); Homeostasis; Human; Hypertension; Hypothalamic structure; Immune; Immunomodulators; Impaired cognition; Inflammation; Inflammatory; Insulin Resistance; Latinx; Lead; Life; Light; Longevity; Longitudinal cohort; Measurable; Measures; Mediating; Mediation; Menopause; Mental Depression; Metabolic; Metabolic Diseases; Metabolism; Modeling; Modification; Molecular; Natural Immunity; Nerve Degeneration; Neuroglia; Neurons; Obesity; Organ; Organism; Participant; Pathologic; Pathology; Pattern; Peptide Hydrolases; Phenotype; Physical activity; Physiological; Pituitary Gland; Plasma; Pollution; Poverty; Process; Research; Resistance; Risk; Risk Factors; Signal Transduction; Sleep; Smoking; Socioeconomic Factors; Sterility; Stress; Structure; Synapses; Testing; Tissues; Trauma; Vulnerable Populations; aging brain; allostasis; allostatic load; alpha synuclein; biological adaptation to stress; cerebrovascular; chemokine; childhood adversity; cognitive performance; connectome; cytokine; epidemiological model; experience; health disparity; indexing; interest; lifestyle factors; middle age; modifiable risk; mortality; neural circuit; neurochemistry; neurofilament; neurotransmission; occupational stressor; prevent; racial and ethnic; resilience; social; social determinants; social stressor; stress state; stressor; tau Proteins; tau-1; young adult

ABSTRACT FOR PROJECT 1 "Stress" accelerates biological aging, increases risk for many diseases, including Alzheimer's disease (AD) and AD-related dementias (ADRD), and increases mortality. Allostasis is the process by which an organism responds to stress to regain homeostasis, engaging a host of physiological, biochemical, and molecular processes working in concert. When over-stressed, these responses produce unhealthy long-lasting changes in cell and organ structure and function, including the brain. "Allostatic load" has been a useful construct encompassing such wear and tear in the body and the brain, and animal and some human research have proposed many ways in which chronic stress directly or indirectly affects neurons, glia and neurochemistry, with associated changes in regional brain connectivity and function that would increase vulnerability to dementia in later life. To address when, how and by what mechanisms stress and allostatic load increase the brain's vulnerability to AD/ADRD in later life requires a lifespan perspective and a large, richly phenotyped longitudinal cohort. Project 1 will investigate how stress affects the brain's structure, function and neurochemistry across adulthood. Our overarching model is that higher levels of stress in younger and middle-aged adults leads to greater allostatic load and associated cardiovascular and metabolic health problems in middle age. Allostatic load and hypertension, obesity and insulin resistance alter the inflammatory, vascular and metabolic milieu of the brain, increasing vulnerability to AD/ADRD dementias of later life. Project 1 will focus on the young adult to mid-life transition, a stage of adult life when stress levels are highest and the earliest signals of brain vulnerability emerge. Mechanistically, we focus on immune dysregulation and inflammation as an important early feature of chronic stress states, allostatic load, and the emergence of amyloid, tau and neurodegeneration. AABC and Project 1 also expands its assessments to characterize the distinctive stressors of social inequities and health disparities in under-represented ethnoracial groups in order to increase understanding of the increased vulnerability these groups have for AD/ADRD. In Aim 1, we determine the effects of stress measures on brain structure, function, neurochemistry and cognition, especially in AABC's younger adult to middle-aged participants. In Aim 2, we determine the effects of stress measures on innate immune dysregulation, allostatic load and neurodegeneration biomarkers and use mediation models to evaluate the relationships among stress, allostatic load, brain vulnerability and cognition. Aim 3 investigate the effects of status-related social determinants, stressors and stress experience on allostatic load, brain structure, function and neurochemistry and cognition in ethnoracial groups. In Aim 4, we will synergize with Projects, 2, 3 and 4 by investigating the effects of stress, innate immune dysregulation and allostatic load in relation to physical activity, sleep and resilient lifestyle factors of Project 2, menopause in Project 3, and the manifest cerebrovascular and AD/ADRD diseases in resilient/resistant vs. unsuccessful aging in Project 4.

项目 1 摘要 “压力”会加速生物衰老，增加许多疾病的风险，包括阿尔茨海默病 (AD) 和 AD 相关痴呆 (ADRD)，并增加死亡率。动态平衡是有机体做出反应的过程 压力以恢复体内平衡，参与一系列生理、生化和分子过程的工作 在音乐会中。当压力过大时，这些反应会导致细胞和器官发生不健康的长期变化 结构和功能，包括大脑。 “静态负载”是涵盖此类磨损的有用结构 身体和大脑中的泪水，动物和一些人类研究提出了许多方法 慢性应激直接或间接影响神经元、神经胶质和神经化学，并伴有区域性的相关变化。 大脑连接和功能会增加晚年患痴呆症的可能性。解决何时、如何 压力和调节负荷通过何种机制增加大脑在晚年患 AD/ADRD 的脆弱性 需要生命周期的视角和大量、表型丰富的纵向队列。项目1将调查 压力如何影响成年期的大脑结构、功能和神经化学。我们的总体模型 年轻人和中年人的压力水平较高会导致更大的非稳态负荷和相关的 中年心血管和代谢健康问题。稳态负荷与高血压、肥胖和胰岛素 抵抗力改变大脑的炎症、血管和代谢环境，增加 AD/ADRD 的脆弱性 晚年痴呆症。项目 1 将重点关注年轻人到中年的过渡，这是成年生活的一个阶段， 压力水平最高，大脑脆弱性的最早信号就会出现。从机制上来说，我们重点关注 免疫失调和炎症是慢性应激状态、稳态负荷的重要早期特征， 以及淀粉样蛋白、tau蛋白和神经变性的出现。 AABC 和 Project 1 也扩大了评估范围 描述代表性不足的社会不平等和健康差异的独特压力源 族裔群体，以加深对这些群体日益脆弱的了解 AD/ADRD。在目标 1 中，我们确定压力测量对大脑结构、功能、神经化学的影响 和认知，尤其是 AABC 的年轻到中年参与者。在目标 2 中，我们确定效果 对先天免疫失调、稳态负荷和神经退行性变生物标志物的压力测量及其使用 中介模型评估压力、稳态负荷、大脑脆弱性和认知之间的关系。 目标 3 研究与地位相关的社会决定因素、压力源和压力经历对稳态的影响 种族群体的负荷、大脑结构、功能以及神经化学和认知。在目标 4 中，我们将发挥协同作用 通过研究压力、先天免疫失调和稳态负荷的影响，进行项目 2、3 和 4 项目 2 中的体力活动、睡眠和弹性生活方式因素、项目 3 中的更年期以及 在项目 4 中，在弹性/抵抗与不成功的衰老中表现出脑血管和 AD/ADRD 疾病。