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

项目1摘要 “压力”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。变稳态是生物体对 压力恢复稳态，参与一系列生理，生化和分子过程， 在音乐会上。当压力过大时，这些反应会在细胞和器官中产生不健康的长期变化 结构和功能，包括大脑。“非稳态负荷”是一个有用的概念， 以及身体和大脑的撕裂，动物和一些人类研究已经提出了许多方法， 慢性应激直接或间接地影响神经元、神经胶质和神经化学，并伴随着区域性的变化。 大脑的连接和功能，这将增加老年痴呆症的脆弱性。解决何时，如何 以及压力和非稳态负荷通过何种机制增加了大脑在晚年对AD/ADRD的脆弱性 需要一个生命周期的观点和一个大的，丰富的表型纵向队列。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 年轻人和中年人更高的压力水平会导致更大的非稳态负荷， 心血管和代谢健康问题。非稳态负荷与高血压、肥胖和胰岛素 耐药性改变了大脑的炎症、血管和代谢环境，增加了AD/ADRD的易感性 老年痴呆症项目1将侧重于青年到中年的过渡，这是成年生活的一个阶段， 压力水平最高，大脑脆弱的最早信号出现。机械地，我们专注于 免疫失调和炎症是慢性应激状态、非稳态负荷 以及淀粉样蛋白、tau蛋白和神经变性的出现。AABC和项目1还扩大了其评估范围， 描述代表性不足的人口中社会不平等和健康差距的独特压力因素， 为了使人们更多地了解这些群体对 AD/ADRD。在目标1中，我们确定应激措施对大脑结构、功能、神经化学 和认知，尤其是在AABC的年轻人到中年参与者中。在目标2中，我们确定了 关于先天免疫失调、非稳态负荷和神经变性生物标志物的应激测量和用途 中介模型，以评估压力，非稳态负荷，大脑脆弱性和认知之间的关系。 目的3探讨社会地位相关因素、压力源和压力体验对个体非稳态的影响 负荷、脑结构、脑功能、神经化学和认知功能。在目标4中，我们将协同 通过研究压力、先天免疫失调和非稳态负荷的影响， 与项目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/抵抗与不成功的老化中表现出脑血管和AD/ADRD疾病。

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.