Inflammatory Mediators of Stress and Cognitive Aging

描述(由申请人提供)：随着世界人口老龄化，认知障碍和痴呆症的发病率预计在未来几年将会上升。严重的心理压力(持续几天到几周)会暂时降低认知能力，越来越多的证据表明，慢性压力(持续几个月到几年)会加速长期认知能力的下降。因此，了解压力和对压力(如炎症)的生理反应在认知老化中的作用是至关重要的。慢性应激可引起全身性炎症和夸大的炎症反应，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还不是很清楚。此外，压力导致长期认知衰退的时程动态和方式还没有被描绘出来。我们假设，与压力相关的下丘脑-垂体-肾上腺(HPA)轴的改变和炎症在心理应激和认知表现之间的联系中起中介作用；此外，我们预计慢性应激失调这些相同的生物过程，这种失调增加了认知老化的风险。在这项拟议的研究中，320名年龄在25岁到65岁之间的不同种族的成年人将完成八次半年一次的14次每日评估，以衡量日常压力、情感、沉思和认知功能。我们将在每次发作结束时采集血液，并在每次发作期间收集唾液，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，以及炎症特征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沉思和/或情绪的程度，以及这些因素如何延长压力反应、适度炎症和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、心理与情感、行为、免疫学和内分泌学。来自该项目的数据将提高对压力增加认知衰退风险的生理机制的理解；它还将提供更好的理解，随着时间的推移，在广泛的心理社会背景下，压力、内分泌因素、炎症和认知之间的联系。在这样做的过程中，该项目有望通过识别认知老化的可改变的风险因素来阐明干预的新方法。因为认知衰老可能在老年之前很久就开始了，了解它的前因需要识别和跟踪从成年早期到中年的问题。压力和炎症都是可行的干预目标，并与一系列与衰老相关的生理、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.