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

项目总结 衰老与身体和认知能力的衰退都有关。内分泌方面，下丘脑受损- 据报道，垂体-肾上腺轴异常，包括昼夜皮质醇浓度升高。 地塞米松治疗后皮质醇抑制，唾液皮质醇增加。上一首 研究报告皮质醇浓度较高与整体认知表现较差之间存在关联 以及大脑的结构变化，伴有皮质和海马体萎缩，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，主要是 集中在皮质醇(只有1%的类固醇代谢物)。正如我们在初步数据中显示的那样，类固醇 代谢组(由一种新的类固醇图谱分析评估)随年龄变化，女性与 男性，雄激素减少，糖皮质激素代谢物增加，随着年龄的增长而增加 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，更年期会加速血液的表观遗传老化，而自然衰老的晚年 更年期与死亡率的降低有关。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老化 多种疾病的发病率，最明显的是心血管疾病、认知能力下降和死亡率增加。 正如我们的初步数据所显示的，类固醇代谢组最显著的变化发生在女性 更年期。我们进一步表明，更年期妇女中的类固醇代谢异常与 执行功能、处理速度和工作记忆下降。在我们提议的研究中，我们的 假说是肾上腺老化(通过24小时尿类固醇代谢物来衡量)随着 更年期；BSO加速肾上腺衰老，进而影响认知功能和大脑结构。在……里面 我们建议的研究，我们将利用正在进行的研究在梅奥诊所专门中心 关于性别差异的研究卓越(评分)，以评估卵巢激素的突然丧失是如何导致的 BSO影响肾上腺衰老(目标1)。此外，通过机器学习分析，我们建议确定 类固醇代谢异常是否与认知功能减退和AD脑结构改变有关 成像(目标2)。 该项目将深入了解类固醇代谢组中与BSO相关的变化，并将估计 肾上腺老化对阿尔茨海默病认知改变和脑成像结构改变的影响。一种特殊的类固醇 签名将被确定为潜在的衰老和认知衰退的生物标记物。

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.