Inflammatory Mediators of Stress and Cognitive Aging

描述（由申请人提供）：随着世界人口走向老龄化，认知障碍和痴呆症的发病率预计将在未来几年上升。急性心理压力（持续数天到数周）会暂时降低认知能力，越来越多的证据表明，慢性压力（持续数月到数年）会加速长期认知能力下降。因此，了解应激和应激生理反应（如炎症）在认知衰老中的作用是至关重要的。慢性应激可引起全身性炎症和夸张的炎症反应，而全身性炎症与长期认知能力下降有关。然而，将压力与短期和长期认知联系起来的生理机制尚不清楚。此外，压力导致长期认知能力下降的时间过程动态和方法尚未被描述。我们假设压力相关的下丘脑-垂体-肾上腺（HPA）轴和炎症的改变介导了心理压力和认知表现之间的联系；此外，我们预计慢性压力会失调这些相同的生物过程，而这种失调会增加认知衰老的风险。在拟议的研究中，320名年龄在25岁至65岁之间的不同种族的成年人将完成8次半年一次的14次每日评估，以测量日常压力、情绪、反思和认知功能。每次爆发结束时采集血液，每次爆发时采集唾液，从中我们将评估炎症状态、炎症功能和皮质醇唤醒反应（CAR）的变化。我们将确定压力和这些生理系统的变化如何与认知功能的变化相关，以及炎症谱的长期变化如何解释认知能力下降。我们将研究人口因素（如种族、社会经济地位、性别、年龄）在多大程度上调节了这些中介效应。我们还将确定个体随着时间的推移表现出高度反刍和/或情绪的程度，以及这些因素如何延长压力反应，缓和炎症，并加速认知的长期变化。这项研究将由一个跨学科的科学家团队进行，他们专门研究压力与健康、衰老与认知、心理学与情感、行为、免疫学和内分泌学。这个项目的数据将提高对压力增加认知能力下降风险的生理机制的理解；随着时间的推移，它还将更好地理解压力、内分泌因素、炎症和认知之间的联系。在此过程中，该项目有望通过识别认知衰老的可改变风险因素来阐明新的干预方法。由于认知老化可能早在老年之前就开始了，因此了解其起因需要识别和跟踪从成年早期到中年期间出现的问题。应激和炎症都是可行的干预目标，并且与广泛的衰老相关的身体、心理和认知健康结果有关。

DESCRIPTION (provided by applicant): The incidence of cognitive impairment and dementia are expected to rise in upcoming years, as the world population shifts toward aging. Acute psychological stress (lasting days to weeks) can temporarily lower cognitive performance, and there is growing evidence that chronic stress (lasting months to years) can accelerate long-term cognitive decline. Thus, understanding the roles of stress and physiological responses to stress (e.g., inflammation) in cognitive aging is critical. Chronic stress can provoke elevated systemic inflammation and exaggerated inflammatory responses, and systemic inflammation has been linked with long- term cognitive decline. However, the physiological mechanisms linking stress with both short- and long-term cognition are not well understood. In addition, the time-course dynamics and means by which stress results in long-term cognitive decline have not been delineated. We hypothesize that stress-related alterations of both the hypothalamic-pituitary-adrenal (HPA) axis and inflammation mediate connections between psychological stress and cognitive performance; further, we expect that chronic stress dysregulates these same biological processes and that this dysregulation increases the risk for cognitive aging. In the proposed research, 320 racially diverse adults, ages 25 to 65, will complete eight biannual bursts of 14 daily assessments to measure daily stress, affect, rumination, and cognitive function. Blood will be collected at the end of each burst, and saliva during each burst, from which we will assess measures of inflammatory state, inflammatory function, and changes in the cortisol awakening response (CAR). We will determine how alterations in stress and these physiological systems relate to changes in cognitive function, as well as how longer-term changes in inflammatory profiles account for cognitive decline. We will examine the extent to which demographic factors (e.g., race, SES, gender, age) moderate these mediation effects. We will also determine the degree to which individuals exhibit heightened rumination and/or emotion across time, and how these factors may extend stress responses, moderate inflammation, and accelerate long-term changes in cognition. This research will be conducted by an interdisciplinary team of scientists who specialize in stress and health, aging and cognition, psychology and emotion, behavior, immunology, and endocrinology. Data from this project will improve understanding of the physiological mechanisms by which stress increases risk of cognitive decline; it will also provide better understanding of the connections between stress, endocrine factors, inflammation, and cognition within a broad psychosocial context over time. In doing so, this project is expected to elucidate novel approaches for intervention by identifying modifiable risk factors for cognitive aging. Because cognitive aging may begin long before old age, understanding its antecedents requires identifying and tracking issues that manifest in early adulthood to midlife. Both stress and inflammation are viable intervention targets, and relate to a broad range of aging-related physical, psychological, and cognitive health outcomes.