Impact of menopause associated adrenal aging on cognitive function and Alzheimer dementia neuroimaging biomarkers

更年期相关肾上腺老化对认知功能和阿尔茨海默氏痴呆神经影像生物标志物的影响

• 批准号: 10371283
• 负责人: Irina Bancos
• 金额: $ 16.92万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371283
• 关键词: Adrenal Glands; Affect; Age; Aging; Alzheimer' s Disease; Androgens; Bilateral; Biological Assay; Biological Markers; Blood; Brain; Brain imaging; Cardiovascular Diseases; Centers of Research Excellence; Clinic; Data; Development; Dexamethasone; Endocrine; Environment; Epigenetic Process; Genetic; Glucocorticoids; Hormonal; Hydrocortisone; Impaired cognition; Impairment; Inflammation; Machine Learning; Measures; Menopause; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Ovarian hormone; Play; Postmenopause; Process; Recording of previous events; Reporting; Research; Role; Salivary; Salpingo-Oophorectomy; Sex Differences; Short-Term Memory; Specialized Center; Steroids; Structure; Suggestion; Techniques; Tissues; Urine; Woman; cerebral atrophy; cognitive change; cognitive function; cognitive performance; executive function; experience; hippocampal atrophy; hypothalamic-pituitary-adrenal axis; insight; men; metabolome; mortality; neuroimaging marker; novel; premature; processing speed

PROJECT SUMMARY Aging is associated with both physical and cognitive decline. Endocrine-wise, impairment in the hypothalamic- pituitary-adrenal axis has been reported, including elevated diurnal cortisol concentrations, abnormal suppression of cortisol following dexamethasone administration, and increased salivary cortisol. Previous studies reported association between higher cortisol concentrations and poor overall cognitive performance and structural changes in the brain, with cortical and hippocampal atrophy, as well as Alzheimer Disease (AD) development. However, these studies used suboptimal assessment of adrenal steroid metabolome, mainly concentrating on cortisol (only 1% of steroid metabolome). As we show in our preliminary data, steroid metabolome (as assessed by a novel steroid profiling assay) changes with age, differentially in women versus men, with decreased androgens and increased glucocorticoid metabolites, increasing with age glucocorticoid/androgen ratio, and steroid ratio changes suggestive of increased tissue exposure of cortisol. Previous studies reported that menopause accelerates epigenetic aging of blood, and that later age of natural menopause is associated with decreased mortality. Women undergoing bilateral salpingo-oophorectomy (BSO) prior to the age of natural menopause experience a higher degree of accelerated aging with increased rates of multiple morbidities, most notably cardiovascular disease, cognitive decline, and increased mortality. As shown in our preliminary data, most significant change in steroid metabolome occurs in women after menopause. We further show that abnormal steroid metabolome in menopausal women is associated with decline in executive function, processing speed, and working memory. In our proposed research, our hypothesis is that adrenal aging (as measured by the 24h urine steroid metabolome) is accelerated with menopause; BSO accelerates adrenal aging which, in turn, impacts cognitive function and brain structures. In our proposed research, we will take advantage of the ongoing study in the Mayo Clinic Specialized Center of Research Excellence (SCORE) on sex differences to assess how abrupt loss of ovarian hormones caused by BSO affects adrenal aging (Aim 1). In addition, through a machine learning analysis, we propose to determine whether abnormal steroid metabolome is associated with cognitive decline and AD structural changes on brain imaging (Aim 2). This project will deliver the insight into BSO-related changes in steroid metabolome and will estimate the impact of adrenal aging on cognitive changes and structural changes of AD on brain imaging. A specific steroid signature will be identified to potentially serve as biomarker of aging and cognitive decline.

项目摘要 衰老与身体和认知能力下降有关。在内分泌方面，下丘脑障碍 据报道垂体 - 肾上腺轴，包括昼夜皮质醇浓度升高，异常 地塞米松给药后皮质醇的抑制，并增加唾液皮质醇。以前的 研究报道了较高的皮质醇浓度与总体认知性能差之间的关联 以及大脑的结构变化，具有皮质和海马萎缩，以及阿尔茨海默氏病（AD） 发展。但是，这些研究使用了肾上腺类固醇代谢组的次优评估，主要是 集中于皮质醇（仅占类固醇代谢组的1％）。正如我们在初步数据中所显示的那样，类固醇 代谢组（通过新型类固醇分析测定法评估）随着年龄的增长而变化，在女性中与 男性，雄激素减少和增加的糖皮质激素代谢产物，随着年龄的增长而增加 糖皮质激素/雄激素比，类固醇比的变化暗示了皮质醇组织暴露增加。 先前的研究报告说，更年期加速了血液的表观遗传衰老，而自然的年龄 更年期与死亡率降低有关。妇女正在接受双边salpingo-opophoropophortormosy （BSO）在自然更年期之前 多种病毒率，最著名的是心血管疾病，认知能力下降和死亡率增加。 如我们的初步数据所示，类固醇代谢组的最显着变化发生在女性之后 绝经。我们进一步表明，更年期女性的类固醇代谢异常与 执行功能，处理速度和工作记忆的下降。在我们提出的研究中 假设是肾上腺衰老（通过24h尿液类固醇代谢组测量）随着 绝经; BSO加速了肾上腺衰老，从而影响认知功能和大脑结构。在 我们提出的研究，我们将利用Mayo诊所专业中心正在进行的研究 性别差异的研究卓越研究（得分），以评估卵巢激素突然损失是如何造成的 BSO会影响肾上腺衰老（AIM 1）。此外，通过机器学习分析，我们建议确定 异常类固醇代谢组是否与认知能力下降和大脑的AD结构变化有关 成像（目标2）。 该项目将洞悉类固醇代谢组的BSO相关变化，并将估计 肾上腺衰老对AD的认知变化和结构变化对脑成像的影响。特定的类固醇 签名将被确定为有可能成为衰老和认知能力下降的生物标志物。