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: 10558589
• 负责人: Irina Bancos
• 金额: $ 15.44万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10558589
• 关键词: Acceleration; 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; Postmenopause; Process; Recording of previous events; Reporting; Research; Salivary; Salpingo-Oophorectomy; Sex Differences; Short-Term Memory; Specialized Center; Steroids; Structure; 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的下降有关。内分泌方面，下丘脑受损- 垂体-肾上腺轴已报告，包括昼夜皮质醇浓度升高，异常 地塞米松给药后皮质醇抑制和唾液皮质醇增加。先前 研究报告称，皮质醇浓度较高与整体认知能力较差有关 和脑结构变化，皮质和海马萎缩，以及阿尔茨海默病（AD） 发展然而，这些研究使用了肾上腺类固醇代谢组的次优评估，主要 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显示的那样，类固醇 代谢组（通过一种新的类固醇分析法评估）随年龄变化，女性与 男性，雄激素减少，糖皮质激素代谢产物增加，随年龄增长而增加 糖皮质激素/雄激素比率和类固醇比率的变化提示皮质醇的组织暴露增加。 以前的研究报告说，更年期加速了血液的表观遗传老化， 绝经与死亡率降低有关。接受双侧输卵管卵巢切除术的女性 (BSO)在自然绝经年龄之前经历更高程度的加速衰老， 多发病率，最明显的心血管疾病，认知能力下降，死亡率增加。 正如我们的初步数据所示，类固醇代谢组的最显著变化发生在女性中， 绝经我们进一步表明，绝经期妇女类固醇代谢组异常与 执行功能、处理速度和工作记忆下降。在我们的研究中，我们 假设肾上腺老化（通过24小时尿类固醇代谢组测定）加速， 绝经期; BSO加速肾上腺老化，这反过来会影响认知功能和大脑结构。在 我们的研究计划，我们将利用正在进行的研究，在马约诊所专业中心， 卓越研究（SCORE）的性别差异，以评估如何突然失去卵巢激素造成的 BSO影响肾上腺老化（目的1）。此外，通过机器学习分析，我们建议确定 类固醇代谢组异常是否与认知功能下降和AD脑结构改变有关 成像（Aim 2）。 该项目将深入了解BSO相关的类固醇代谢组学变化，并将估计 肾上腺老化对AD认知功能改变和脑影像结构改变的影响。一种特殊的类固醇 将鉴定标记以潜在地用作衰老和认知衰退生物标志物。