Inflammatory Mediators of Stress and Cognitive Aging

描述（由申请人提供）：随着世界人口向老龄化转变，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（持续数天至数周）可以暂时降低认知能力，越来越多的证据表明，慢性压力（持续数月至数年）可以加速长期认知能力下降。因此，理解压力的作用和对压力的生理反应（例如，炎症）在认知老化中至关重要。慢性应激可引起全身炎症升高和炎症反应加剧，全身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没有得到很好的理解。此外，压力导致长期认知能力下降的时程动力学和手段尚未得到描述。我们假设，压力相关的改变下丘脑-垂体-肾上腺（HPA）轴和炎症介导心理压力和认知能力之间的联系;此外，我们预计，慢性压力失调这些相同的生物过程，这种失调增加认知老化的风险。在这项拟议中的研究中，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次一年两次的14次日常评估，以测量日常压力，影响，反刍和认知功能。将在每次爆发结束时收集血液，并在每次爆发期间收集唾液，从中我们将评估炎症状态，炎症功能和皮质醇觉醒反应（CAR）变化的测量。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导致认知能力下降。我们将研究人口因素（例如，种族，社会经济地位，性别，年龄）缓和这些中介作用。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，减轻炎症，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，他们专门研究压力和健康，衰老和认知，心理学和情感，行为，免疫学和内分泌学。该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，它还将在广泛的心理社会背景下更好地理解压力，内分泌因素，炎症和认知之间的联系。在这样做的过程中，该项目预计将阐明新的干预方法，通过识别认知老化的可改变的风险因素。由于认知老化可能在老年之前很久就开始开始，因此了解其前身需要识别和跟踪在成年早期到中年期间表现出来的问题。压力和炎症都是可行的干预目标，并与广泛的衰老相关的身体，心理和认知健康结果有关。 公共卫生相关性：随着全球人口老龄化，痴呆症的早期诊断指标的识别是控制医疗保健成本和提高生活质量的关键挑战。该项目的目标是提高对生理机制和时间过程的理解，通过这些机制和时间过程，成年早期到中期的压力会增加认知能力下降的风险，并更好地确定压力，内分泌因素，炎症和认知变化之间的关系。由于压力和炎症都是可改变的干预目标，这项工作也可能阐明减少或延迟认知老化的新治疗方法。

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. PUBLIC HEALTH RELEVANCE: With an aging world-wide population, the identification of early diagnostic indices of dementia represents a critical challenge to controlling health care costs and improving quality of life. The goals of this project are to improve understanding of the physiological mechanisms and time-course by which stress in early to mid- adulthood increases risk of cognitive decline, and to better determine the relationships between stress, endocrine factors, inflammation, and cognitive change. As stress and inflammation are both modifiable targets for intervention, this work may also elucidate novel therapeutic approaches to reduce or delay cognitive aging.