Effects of Acute Stress Exposure on Plasma beta-amyloid Levels

急性应激暴露对血浆 β-淀粉样蛋白水平的影响

• 批准号: 10575514
• 负责人: MARA MATHER
• 金额: $ 21.36万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575514
• 关键词: Acute; Address; Adrenal Glands; Affect; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Biological Markers; Blood specimen; Brain; Cerebrospinal Fluid; Correlation Studies; Deposition; Development; Disease; Disease Marker; Disease Outcome; Disease Progression; Encephalitis; Endocrine; Etiology; Exposure to; Feedback; Functional disorder; Future; Glucocorticoids; Hand; Hormones; Hour; Human; Hydrocortisone; Hypothalamic structure; Ice; Impairment; Individual; Laboratories; Life; Link; Literature; Measures; Nerve Degeneration; Observational Study; Participant; Pathogenesis; Pathway interactions; Patients; Persons; Physiological; Pituitary Gland; Pituitary-Adrenal System; Plasma; Play; Post-Traumatic Stress Disorders; Process; Production; Reaction; Recording of previous events; Reporting; Research; Role; Salivary; Series; Stress; Stressful Event; System; Testing; Time; Translating; Veterans; Videotape; Water; Woman; Work; acute stress; aged; allostatic load; biological adaptation to stress; disease phenotype; glucose metabolism; heart rate variability; hyperphosphorylated tau; hypothalamic-pituitary-adrenal axis; insight; interstitial; longitudinal analysis; men; middle age; mild cognitive impairment; neuroinflammation; response; restraint stress; social; stressor; theories

PROJECT SUMMARY Stress is theorized to be involved in Alzheimer’s disease (AD) pathogenesis and progression. In animal models, stress hormones can induce states similar to those seen in AD, such as impaired glucose metabolism, inflammation of the brain, and increased -amyloid (A) and hyperphosphorylated tau in the brain. Unfortunately, the effect of stress on AD pathogenesis in humans is more difficult to establish. Currently, the relationship between stress and AD in humans is limited to correlational studies. For instance, individuals with mild cognitive impairment and AD have higher stress hormone (cortisol) levels throughout the day and do not efficiently shut down the stress response. Other work suggests that greater stress system dysfunction is associated with more rapid disease progression. Still other research suggests that veterans with a history of post-traumatic stress disorder had a two-fold increase in AD development, while a series of studies in women suggests that stress in midlife is related to an increased risk of AD diagnosis later in life. These studies suggest there is a long-term and possibly cumulative effect of stress exposure on later AD outcomes, however, these observational studies do not sufficiently address potential mechanisms connecting stress exposure to AD risk. In particular, we lack information about whether stressors influence A levels in humans. This proposal targets this gap by asking, “does acute stress increase A levels in humans?” We will achieve this by measuring the plasma A response to an acute laboratory stressor, the socially evaluated cold pressor test. Thirty-eight women and men aged 18-65 will complete a laboratory stressor involving holding their hand in ice water for an amount of time unknown to the participant while their reactions to the stressor are videotaped. Participants will also complete a non-stressful task in lieu of the stressor in a separate session. At both sessions, stress activation will be measured using changes in salivary free cortisol levels and in heart rate variability, and blood samples will be collected for measuring the A response to stress. We predict that cortisol and plasma A levels will increase, and heart rate variability will decrease, during the stress session but not during the control session. We further predict that the magnitude of change in salivary free cortisol and heart rate variability in response to stress will be related to the magnitude of change of plasma A in response to stress. Understanding how stress may trigger AD-related processes is an important step in understanding how stress contributes to AD development and progression in people. This proposal will address this important gap in the stress-AD literature by translating the effects of acute stress on A production observed in animal models to humans. Findings from this study will help develop a mechanistic pathway for how repeated or cumulative stress increases AD risk and pathogenesis later in life and drive future avenues of research in AD development and AD treatment options, especially during the prodromal stage of the disease when decreasing stress- related A production might protect against AD-pathogenesis and progression.

项目概要 理论上，压力与阿尔茨海默病 (AD) 的发病机制和进展有关。在动物中 模型中，应激激素可以诱发与AD相似的状态，例如葡萄糖代谢受损， 大脑炎症，以及大脑中 -淀粉样蛋白 (A) 和过度磷酸化 tau 蛋白的增加。 不幸的是，压力对人类 AD 发病机制的影响更难以确定。目前， 人类压力与 AD 之间的关系仅限于相关研究。例如，个人有 轻度认知障碍和 AD 在一天中的应激激素（皮质醇）水平较高，并且不会 有效地关闭应激反应。其他研究表明，更大的压力系统功能障碍是 与更快的疾病进展有关。还有其他研究表明，有历史的退伍军人 创伤后应激障碍使AD的发展增加两倍，而一系列针对女性的研究 表明中年压力与晚年诊断 AD 的风险增加有关。这些研究表明 压力暴露对以后的 AD 结局有长期且可能累积的影响，然而，这些 观察性研究没有充分解决压力暴露与 AD 风险之间的潜在机制。 特别是，我们缺乏关于压力因素是否影响人类 A 水平的信息。本提案的目标 通过询问“急性压力是否会增加人类的 A 水平？”来弥补这一差距。我们将通过测量来实现这一目标 血浆 A 对急性实验室应激源的反应，即社会评价的冷加压试验。三十八 18-65 岁的女性和男性将完成一项实验室压力测试，其中包括将手放在冰水中 参与者对压力源的反应被录像时未知的时间长度。参与者将 还可以在单​​独的会议中完成一项无压力的任务来代替压力源。在这两次会议上，压力 激活将通过唾液游离皮质醇水平和心率变异性以及血液的变化来测量 将收集样本用于测量 A 对压力的响应。我们预测皮质醇和血浆 A 在压力训练期间，水平会增加，心率变异性会降低，但在控制期间不会 会议。我们进一步预测唾液游离皮质醇和心率变异性的变化幅度 对应力的响应与等离子体 A 对应力的响应变化幅度有关。 了解压力如何触发 AD 相关过程是了解压力如何触发 AD 相关过程的重要一步 有助于人们 AD 的发展和进展。该提案将解决这一重要差距 应激 AD 文献将动物模型中观察到的急性应激对 A 产生的影响转化为 人类。这项研究的结果将有助于开发一个机制途径来解释如何重复或累积 压力会增加以后生活中的 AD 风险和发病机制，并推动 AD 发展的未来研究途径 和 AD 治疗方案，特别是在疾病的前驱阶段，当减少压力时 相关的 A 产生可能可以预防 AD 发病和进展。