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

项目摘要 在女性中，生殖衰老的标志是卵巢激素分泌的急剧下降， 许多女性报告说记忆力和注意力发生了变化。动物研究提供了强有力的证据， 卵巢激素，特别是17β-雌二醇，在塑造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。的程度 女性生殖衰老导致人类大脑形态的宏观结构变化， 连接，并最终改变认知功能代表了一个重大的知识差距， 尚待充分研究。卵巢激素抑制（OHS），一种广泛用于治疗 子宫内膜异位症，提供了一个独特的临床情况，通过它来研究雌激素的影响， 孕酮对大脑和认知的影响。治疗允许暂时的和可逆的 诱导绝经后样内分泌状态，其作用可以在绝经后的一段时间内观察到。 几个月，并提供了一个人类模拟动物研究，提供了大量的证据， 卵巢激素的神经保护作用及其对神经功能的影响。拟议 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25至40岁），其中一半将 通过促性腺激素释放激素（GnRH）拮抗剂Elagolix进行OHS，其中一半将遵循 一个非激素治疗计划，以获得关键的见解如何消耗卵巢激素， 影响大脑和认知。将在治疗前和基线后6个月对女性进行检查， 描述对OHS反应的变化进展。在目标1中，我们将描述OHS的影响 关于认知功能。我们将采用一个全面的神经心理电池来评估变化， OHS带来的认知。在目标2中，我们将利用最先进的神经成像技术， 描述OHS对大脑结构测量的影响，特别是针对 海马、内嗅皮质和白色物质通路的扩散光谱成像。在目标3中， 我们将使用静息状态和基于任务的功能磁共振成像范例来确定OHS对全球和 大脑区域网络我们假设OHS会影响默认模式下的内在相关性， 额顶叶和边缘系统网络在休息，并改变前额叶皮层的效率在工作记忆。 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改变了OHS对阿尔茨海默病的影响。 大脑和认知多模态认知神经科学方法将使我们能够模拟一个核心方面， 生殖衰老，卵巢激素耗竭，同时保持实足年龄相对固定。这个项目 将阐明卵巢激素在塑造大脑结构和认知功能中的作用， 在认知神经科学的竞技场中，这一领域的研究不足，对妇女的健康有明显的影响。

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.