Sex hormones, inflammation, and cognitive decline in older men and women

老年男性和女性的性激素、炎症和认知能力下降

• 批准号: 10017865
• 负责人: CHRISTOPHER G ENGELAND
• 金额: $ 19.98万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017865
• 关键词: Accounting; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Anti-Inflammatory Agents; Antiinflammatory Effect; Biological Assay; Biological Markers; Blood; Blood specimen; Cognition; Cognitive; Data; Dementia; Development; Disease; Early Intervention; Elderly; Endocrine; Enrollment; Estradiol; Estrogens; Estrone; Future; Gender; Gonadal Steroid Hormones; Growth; Health Care Costs; Human; Impaired cognition; Individual; Inflammation; Inflammatory; Inflammatory Response; Intervention; Investigation; Link; Longevity; Longitudinal cohort; Longitudinal cohort study; Measurement; Measures; Mediating; Medical; Menopause; Modeling; Neuropsychology; Outcome; Pathogenesis; Pathway interactions; Postmenopause; Prevalence; Research; Risk; Risk Factors; Role; Route; Sampling; Signal Transduction; Societies; Stress; Testing; Testosterone; Time; Translating; Woman; Work; age related; aged; cognitive change; cognitive development; cognitive function; cytokine; effective therapy; gender difference; immune function; inflammatory marker; innovation; intervention cost; men; mild cognitive impairment; novel strategies; older men; older women; pre-clinical; preclinical development; prevent; protective effect; protective factors; psychosocial; response; sex

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common form of dementia in older adults, has no known cure, and increasingly impacts society in terms of its human toll and healthcare costs. AD disproportionately affects women, even when accounting for women’s greater longevity and other sex-linked factors. This research focuses on the predominant sex hormones in older women and men (estradiol, estrone, testosterone) as protective factors against pre-clinical cognitive decline and mild cognitive impairment (MCI), which may be prodromal states of AD. Sex hormones reduce risk for AD and protect against cognitive decline in women and men and may do so through associations with reduced pro-inflammatory and increased anti-inflammatory signaling. Research rarely studies women and men concurrently and rarely examines the effects of ‘opposite- sex’ hormones (i.e., estrogens in men, testosterone in women) to compare the relative strength of sex hormones’ protective effects. Research on cognitive decline likewise has ignored age-related changes in estrone, the predominant estrogen in older women that may represent a separate protective pathway against cognitive decline. Moreover, studies linking sex hormones to cognitive decline lack rigorous assessments of inflammation as a pathway by which testosterone exerts its protective effects. This project investigates sex hormones’ (estradiol, estrone, and testosterone) influence on cognitive outcomes in adults aged 70+ years (n = 610) who are enrolled as part of the Einstein Aging Studies (EAS), an ongoing longitudinal cohort study. The EAS examines cognitive functioning via highly sensitive ambulatory assessments (6/day, 14 days/wave) across 3 annual waves, and via MCI prevalence at Wave 1. Blood collected before and after each assessment burst is assayed for a panel of pro- and anti-inflammatory cytokines, including basal circulating levels and stimulated responses. We propose to assay sex hormones from these same blood samples. We hypothesize that sex hormones will relate to better cognitive outcomes in Wave 1 in men and women, and that levels of pro- and anti-inflammatory biomarkers will partly mediate this effect. Similarly, we expect sex hormones will protect against cognitive decline and may do so via their effects on inflammation. This research broadens the impact of the ongoing, longitudinal EAS by linking sex hormones to sensitive measurement of cognitive states associated with AD. We will also examine sex hormones association with inflammatory load across the full two- week burst, and with individuals’ inflammatory responses in blood, which may be a more sensitive measure for the development of AD. The work is a necessary and timely investigation of sex hormones’ links to cognitive decline and MCI, which may be part of the long prodromal periods inherent to AD. Integrating this proposal into the EAS will provide a pipeline of new data that will inform and invigorate new research on the routes by which sex hormones influence cognitive decline, and may translate to future approaches to treat or prevent cognitive decline and dementia.

项目总结/摘要 阿尔茨海默病（AD）是老年人中最常见的痴呆形式，没有已知的治愈方法， 在人员伤亡和医疗保健成本方面对社会的影响越来越大。AD不成比例地影响 即使考虑到女性更长寿和其他与性别有关的因素，本研究 重点关注老年女性和男性的主要性激素（雌二醇，雌酮，睾酮）， 预防临床前认知功能下降和轻度认知功能障碍（MCI）的保护因素， AD的前驱状态。性激素降低AD风险，防止女性认知能力下降， 男性，并可能通过与减少促炎和增加抗炎 发信号。研究很少同时研究女性和男性，也很少研究“相反”的影响。 性激素（即，男性的雌激素，女性的睾丸激素）来比较性的相对强度 荷尔蒙的保护作用关于认知能力下降的研究同样忽略了与年龄相关的变化， 雌酮，老年妇女中占主导地位的雌激素，可能代表一种单独的保护途径， 认知能力下降此外，将性激素与认知能力下降联系起来的研究缺乏严格的评估， 炎症是睾酮发挥其保护作用的途径。这个项目调查性 激素（雌二醇、雌酮和睾酮）对70岁以上成年人认知结果的影响（n = 10） 610)这些人被纳入爱因斯坦衰老研究（EAS），这是一项正在进行的纵向队列研究。的 EAS通过高度敏感的动态评估（6天/天，14天/波）检查认知功能 在3个年度波中，以及通过第1波的MCI患病率。每次评估前后采集的血液 测定爆发的一组促炎和抗炎细胞因子，包括基础循环水平， 刺激的反应。我们建议从这些相同的血液样本中检测性激素。我们假设 性激素将与男性和女性在第一波中更好的认知结果有关， 并且抗炎生物标志物将部分介导该效应。同样，我们期望性激素能保护 对抗认知能力下降，并且可能通过其对炎症的影响来实现这一目的。这项研究扩大了 通过将性激素与认知状态的敏感测量联系起来， 与AD有关。我们还将研究性激素与炎症负荷的关系，在整个两个- 周爆发，并与个人的血液中的炎症反应，这可能是一个更敏感的措施， AD的发展。这项工作是对性激素与认知能力之间联系的必要和及时的调查。 衰退和MCI，这可能是AD固有的长前驱期的一部分。将该提案纳入 EAS将提供一条新数据管道，为有关路线的新研究提供信息和动力， 性激素影响认知能力下降，并可能转化为未来治疗或预防认知能力下降的方法。 衰退和痴呆。