Impact of ovarian hormone suppression on regional and global brain architecture and cognition

项目总结 在女性中，生殖衰老的标志是卵巢激素分泌急剧下降，这是一段时间 当许多女性报告记忆力和注意力发生变化时。动物研究提供了强有力的证据 卵巢激素，特别是17β-雌二醇，在形成卵巢的形态和功能方面起着关键作用。 大脑区域是高级认知过程和认知老化的中心。在多大程度上 女性生殖衰老导致人脑形态的宏观结构变化，大脑的变化 连通性，最终认知功能的变化代表着一种显著的知识鸿沟，它具有 还有待充分研究。卵巢激素抑制(OHS)是一种广泛使用的治疗方法 子宫内膜异位症，提供了一个独特的临床场景，通过它来研究雌激素和 黄体酮会对大脑和认知产生影响。这种治疗允许暂时和可逆的 诱导一种类似绝经后的内分泌状态，其影响可以在 几个月，并提供了对动物研究的人体模拟，这些研究为 卵巢激素的神经保护作用及其对神经功能的影响。在建议的 观察性研究，我们将检查200名患有子宫内膜异位症的成年女性(年龄在25岁到40岁之间)，其中一半将 通过促性腺激素释放激素(GnRH)拮抗剂Elagolix进行OHS，其中一半人将跟随 一项非激素治疗计划，以获得对卵巢激素如何枯竭的批判性见解 影响大脑和认知。妇女将在治疗前和基线后6个月接受检查 描述应对OHS的变化的进程。在目标1中，我们将描述OHS的影响 关于认知功能。我们将使用一个全面的神经心理学电池来评估 OHS带来的认知。在目标2中，我们将利用最新的神经成像技术来 描述OHS对结构性大脑测量的影响，特别是针对 使用扩散光谱成像技术研究海马体、内嗅皮层和白质通路。在《目标3》中， 我们将使用静息状态和基于任务的fMRI范例来确定OHS对全球和 区域大脑网络。我们假设OHS将在缺省模式下影响固有关联， 在工作记忆过程中，额顶叶、额叶和边缘网络处于静止状态，并改变前额叶皮质的效率。 最后，在目标4中，我们将测试阿尔茨海默病的多基因风险是否会改变OHS对 大脑和认知。多模式认知神经科学方法将使我们能够模拟 生殖老化、卵巢激素耗竭，同时保持年龄相对固定。这个项目 将阐明卵巢激素在塑造大脑结构和认知功能方面的作用，严重 在认知神经科学领域研究不足，对女性健康有明显影响。

PROJECT SUMMARY In women, reproductive aging is marked by a dramatic decline in ovarian hormone production, and is a time when many women report changes in memory and attention. Animal studies provide powerful evidence that ovarian hormones, in particular 17β-estradiol, play a critical role in shaping the morphology and function of brain regions that are central to higher order cognitive processes and cognitive aging. The degree to which female reproductive aging leads to macrostructural changes in human brain morphology, changes in brain connectivity, and ultimately changes in cognitive functioning represents a significant knowledge gap that has yet to be adequately examined. Ovarian hormone suppression (OHS), a widely used treatment for endometriosis, offers a unique clinical scenario through which to study the impact of estrogen and progesterone changes on the brain and cognition. The treatment allows for the temporary and reversible induction of a postmenopausal-like endocrine status, the effects of which can be observed over the course of a few months, and offers a human analogue of animal studies that have provided substantial evidence for the neuroprotective effects of ovarian hormones and their influence on neural function. In the proposed observational study, we will examine 200 adult women with endometriosis (ages 25 to 40), half of whom will undergo OHS via the gonadotropin releasing hormone (GnRH) antagonist Elagolix, and half of whom will follow a non-hormonal treatment plan, in order to gain critical insights into how the depletion of ovarian hormones impacts the brain and cognition. Women will be examined pre-treatment and at 6 months post-baseline to characterize the progression of changes in response to OHS. In Aim 1, we will characterize the effects of OHS on cognitive functioning. We will employ a comprehensive neuropsychological battery to assess changes in cognition brought on by OHS. In Aim 2, we will utilize state-of-the-field neuroimaging techniques to characterize the impact of OHS on structural brain measures, specifically targeting subfields of the hippocampus, the entorhinal cortex, and white matter pathways using diffusion spectrum imaging. In Aim 3, we will use resting state and task-based fMRI paradigms to determine the effects of OHS on global and regional brain networks. We hypothesize that OHS will impact intrinsic correlations in the default mode, frontoparietal, and limbic networks at rest, and alter prefrontal cortex efficiency during working memory. Finally, in Aim 4, we will test whether polygenic risk for Alzheimer’s disease modifies the effects of OHS on the brain and cognition. The multimodal cognitive neuroscience approach will allows us to model a core aspect of reproductive aging, ovarian hormone depletion, while holding chronological age relatively fixed. This project will clarify the role of ovarian hormones in shaping brain architecture and cognitive functioning, a severely understudied arena in cognitive neuroscience with clear implications for women’s health.