Elucidating the role of endocrine aging as a risk factor for Alzheimer's Disease

阐明内分泌衰老作为阿尔茨海默病危险因素的作用

• 批准号: 10560381
• 负责人: Laura Pritschet
• 金额: $ 3.73万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2023-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10560381
• 关键词: Address; Adult; Affect; Age; Age-associated memory impairment; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Amyloid deposition; Animals; Architecture; Area; Attention; Award; Biological; Biological Markers; Brain; Brain imaging; Brain region; Chronology; Cognitive; Communities; Complex; Data; Deposition; Disease Progression; Endocrine; Estradiol; Exhibits; Female; Fogs; Framingham Heart Study; Functional Magnetic Resonance Imaging; Gonadal Steroid Hormones; Hippocampus (Brain); Hormonal; Hormone Receptor; Human; Imaging Techniques; Impaired cognition; Individual; Investigation; Knowledge; Laboratories; Life; Liquid substance; Medial; Memory; Menopause; Methods; Molecular; Morphology; Nerve Degeneration; Neuroendocrinology; Neurologic; Neurosecretory Systems; Ovarian; Ovarian hormone; Participant; Pathologic; Pathology; Perimenopause; Phase; Play; Population; Positron-Emission Tomography; Postmenopause; Predisposition; Prefrontal Cortex; Premenopause; Prevalence; Production; Progesterone; Registries; Research; Research Personnel; Research Project Grants; Resolution; Rest; Risk; Role; Sampling; Shapes; Signal Transduction; Site; Structure; Systems Analysis; Temporal Lobe; Training; Venipunctures; Wisconsin; Woman; Women' s Health; Work; age related; aging brain; anatomic imaging; base; biomarker panel; brain morphology; cingulate cortex; cognitive neuroscience; cohort; dementia risk; dentate gyrus; hormone regulation; human old age (65+); imaging study; improved; insight; middle age; neural circuit; neuroimaging; neuroimaging marker; neuropathology; relating to nervous system; reproductive; reproductive senescence; response; sex; skills; symposium; tau Proteins

Project Summary Women constitute two-thirds of the Alzheimer’s disease (AD) population. While the sex-specific biological mechanisms underlying women’s increased prevalence are unclear, accumulating evidence points to menopause as a neurological transition state that may influence AD risk. Over the last quarter century, the vast majority of brain imaging studies have studied the neural basis of age-related cognitive decline in adults aged 65 and older. This convention overlooks one of the most significant neuroendocrine changes in a woman’s life— the transition to menopause—and leaves a gap in our understanding of the aging brain during the critical midlife years. The menopausal transition is marked by a sweeping decline in the production of sex hormones—up to 90% in the case of 17b-estradiol and progesterone. Animal studies provide powerful evidence that estradiol and progesterone play a neuroprotective role in brain regions vulnerable to neurodegeneration, including the prefrontal cortex and medial temporal lobes. However, the degree to which female reproductive aging leads to changes in human brain morphology, intrinsic brain network connectivity, and susceptibility to increased AD prevalence represents a significant knowledge gap that has yet to be adequately examined. This proposal will establish whether the decline in sex steroid hormones over the menopausal transition relates to vulnerability in brain circuits implicated in AD. In the F99 phase (Aim 1), I will probe the effects of reproductive aging on the brain in healthy women (N=90, ages 45–55), investigating the endocrine basis of neural aging in midlife. The well-characterized sample is enriched to include a balanced distribution of pre, peri, and post-menopausal women across a limited age range in order to isolate the effects of reproductive aging from chronological aging. I will first determine how the depletion of sex hormones in midlife alters large-scale functional brain networks using resting-state fMRI and computational approaches from complex systems analysis. I will then use high- resolution anatomical imaging of the hippocampus and surrounding medial temporal lobe to determine whether the depletion of sex hormones impacts specific hippocampal subfields (CA1-3, dentate gyrus, subiculum) and entorhinal, perirhinal, and parahippocampal cortices, regions enriched with sex hormone receptors. In the K00 phase (Aim 2), I will take the skills and insights gained from the F99 phase, including fundamental training in neuroendocrinology and brain imaging, and use them to establish the relationship between female reproductive aging and pathological AD biomarkers (b-amyloid, tau). To do this, I will leverage two large community cohorts (N~620, 60% female) that provide relevant hormonal, cognitive, and molecular positron emission tomography (PET) data from midlife subjects (ages 40-65) and build a neuroendocrine model of AD risk. Together, this proposal will identify the role menopause plays in contributing to female-specific vulnerability to Alzheimer’s disease, a severely understudied area in cognitive neuroscience with clear implications for women’s health.

项目概要 女性占阿尔茨海默病 (AD) 人群的三分之二。虽然具有性别特异性的生物 女性患病率增加的机制尚不清楚，但越来越多的证据表明 更年期作为一种可能影响 AD 风险的神经过渡状态。在过去四分之一个世纪里，巨大的 大多数脑成像研究都研究了老年人与年龄相关的认知能力下降的神经基础 65 岁及以上。这一惯例忽视了女性一生中最重要的神经内分泌变化之一—— 向更年期的过渡——并且在我们对关键的中年时期大脑老化的理解上留下了空白 年。更年期过渡的特点是性激素产生的全面下降——最多 17b-雌二醇和黄体酮的情况下为 90%。动物研究提供了强有力的证据表明雌二醇和 黄体酮在易发生神经退行性变的大脑区域中发挥神经保护作用，包括 前额皮质和内侧颞叶。然而，女性生殖衰老的程度 人脑形态、内在脑网络连接性和 AD 易感性的变化 流行率代表了一个尚未得到充分审查的重大知识差距。该提案将 确定绝经过渡期间性类固醇激素的下降是否与脆弱性有关 AD 涉及的大脑回路。在F99阶段（目标1），我将探讨生殖衰老对 健康女性（N = 90，年龄 45-55）的大脑，调查中年神经老化的内分泌基础。这 充分表征的样本得到丰富，包括绝经前、围绝经期和绝经后的均衡分布 研究人员对有限年龄范围内的女性进行了研究，以便将生殖衰老与时间衰老的影响区分开来。 我将首先确定中年性激素的消耗如何改变大规模的功能性大脑网络 使用静息态功能磁共振成像和复杂系统分析的计算方法。然后我将使用高 海马和周围内侧颞叶的分辨率解剖成像，以确定是否 性激素的消耗会影响特定的海马亚区（CA1-3、齿状回、下托） 内嗅皮质、嗅周皮质和海马旁皮质，这些区域富含性激素受体。在K00 阶段（目标 2），我将利用从 F99 阶段获得的技能和见解，包括基础培训 神经内分泌学和脑成像，并利用它们建立女性生殖之间的关系 衰老和病理性 AD 生物标志物（b-淀粉样蛋白、tau）。为此，我将利用两个大型社区群体 （N~620，60%女性）提供相关的激素、认知和分子正电子发射断层扫描 (PET) 中年受试者（40-65 岁）的数据并建立 AD 风险的神经内分泌模型。在一起，这个 该提案将确定更年期在女性特有的阿尔茨海默病易感性方面所起的作用 疾病是认知神经科学中一个严重不足的领域，对女性健康有着明显的影响。