ESTROGEN EFFECTS ON CHOLINERGIC FUNCTION IN OLDER WOMEN

雌激素对老年女性胆碱能功能的影响

• 批准号: 8166991
• 负责人: PAUL A. NEWHOUSE
• 金额: $ 0.17万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166991
• 关键词: Acetylcholine; Affect; Age; Alzheimer' s Disease; Attention; Behavior; Biological; Brain; Brain imaging; Brain scan; Characteristics; Chemicals; Cholinergic Antagonists; Clinical; Cognition; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Enrollment; Episodic memory; Estrogens; Functional Magnetic Resonance Imaging; Funding; Genetic Markers; Goals; Grant; Hormonal; Hormones; Human; Impaired cognition; Individual; Institution; Investigation; Magnetic Resonance Imaging; Mediating; Memory; Menopause; Methodology; Modeling; Nature; Performance; Pharmaceutical Preparations; Postmenopause; Prospective Studies; Psyche structure; Research; Research Personnel; Resources; Risk; Source; Speed; Structure; System; Testing; United States National Institutes of Health; Ursidae Family; Woman; Women' s Health; Work; age effect; age related; cholinergic; cognitive function; critical period; design; grasp; hormone therapy; neuroimaging; novel strategies; older women; operation; performance tests; prevent; volunteer

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Studies have suggested that changes that occur in mental abilities as we age may be a result of chemical changes that occur in the brain. The loss of estrogen that occurs after menopause in women may accelerate this change. This study is designed to test whether giving the hormone estrogen will affect the system of the brain that uses acetylcholine. Acetylcholine is a naturally occurring chemical in the brain that has been shown to be associated with attention and memory. We will see if we can detect this change using cognitive testing, MRI of brain structure, and a test called functional MRI (or fMRI which is a brain scan described below). The primary goal of these studies is to combine clinical, cognitive and neuroimaging methodologies to continue our investigations of how estrogen and related compounds influence the cognitive functions of the cholinergic systems of the human brain. We will move beyond our original investigations to begin to develop an understanding of the biological, clinical, and cognitive relationships between positive or negative effects of estrogen on cholinergic-related cognitive functioning in older women. There is evidence that the postmenopausal estrogen treatment may slow or prevent cognitive decline, enhance cognitive functioning, and may lower the risk of developing Alzheimer's disease (AD) if administered in the early postmenopausal period. However, large prospective studies such as the Women's Health Initiative (WHI) have suggested that under certain circumstances, hormone therapy may actually increase the risk for cognitive dysfunction. In the first five year period of this grant, we have consistently shown that benefits of estrogen treatment on cognitive functioning may be mediated through interactions with CNS cholinergic systems by specifically enhancing cholinergic-sensitive cognitive operations including attention, psychomotor speed, and episodic memory. This proposal proceeds to the next logical steps to more fully understand the nature of the estrogen-cholinergic interactions and utilize new approaches (e.g. neuroimaging) to develop a better grasp of the relationships between individual biological and cognitive characteristics and the responsiveness of the CNS cholinergic system to E2 stimulation. The first study will examine the relationship between the effects of estrogen on cholinergic system-related cognitive performance and individual characteristics of postmenopausal women that may bear a relationship on whether estrogen has cognitively enhancing effects. This study will involve our model of short-term estrogen treatment and cholinergic antagonist challenge in normal postmenopausal women successfully utilized in our prior studies. We will examine the influence of subjective and objective baseline cognitive symptomatology, structural brain imaging, and genetic markers on the relationship between the ability of estrogen to enhance cholinergic-related cognitive function. In the second study, we will examine the relationship between age and potential benefit to cholinergic-related cognitive performance. We will explicitly examine this version of the "critical period hypothesis" by utilizing our established estrogen-cholinergic challenge model and examining for age-related differences in brain activity with fMRI that are associated with cognitive differences in estrogen-cholinergic responsivity. This continued work will have important implications for understanding of the effects of hormonal loss on brain function and the potential benefits versus risks of postmenopausal hormone therapy on cognition and behavior. This study involves administering estrogen and then giving medications that temporarily affect the ability to perform certain mental and performance tests. In study #1 we will examine performance through cognitive assessments and in study #2, we will examine brain activation. In this way, we hope to see if estrogen administration changes the negative effects of these medications and therefore may act to alter the effects of aging on brain functioning. Study #1 will last approximately 4-5 months and 50 volunteers will be enrolled. Study #2 will last approximately 10 months and 60 volunteers will be enrolled.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 研究表明，随着年龄的增长，智力发生的变化可能是大脑中发生化学变化的结果。女性绝经后雌激素的流失可能会加速这种变化。这项研究旨在测试给予雌激素是否会影响使用乙酰胆碱的大脑系统。乙酰胆碱是大脑中天然存在的化学物质，已被证明与注意力和记忆力有关。我们将看看是否可以使用认知测试、大脑结构 MRI 以及功能性 MRI（或下文所述的 fMRI，即脑部扫描）测试来检测这种变化。 这些研究的主要目标是结合临床、认知和神经影像学方法，继续研究雌激素和相关化合物如何影响人脑胆碱能系统的认知功能。 我们将超越最初的研究，开始了解雌激素对老年女性胆碱能相关认知功能的积极或消极影响之间的生物学、临床和认知关系。有证据表明，绝经后雌激素治疗可以减缓或预防认知能力下降，增强认知功能，如果在绝经后早期进行治疗，还可以降低患阿尔茨海默病 (AD) 的风险。 然而，女性健康倡议 (WHI) 等大型前瞻性研究表明，在某些情况下，激素治疗实际上可能会增加认知功能障碍的风险。在这笔拨款的前五年中，我们一致表明，雌激素治疗对认知功能的益处可能是通过与中枢神经系统胆碱能系统的相互作用来介导的，具体是通过增强胆碱能敏感的认知操作，包括注意力、精神运动速度和情景记忆。该提案继续进行下一个逻辑步骤，以更全面地了解雌激素-胆碱能相互作用的本质，并利用新方法（例如神经影像学）更好地掌握个体生物和认知特征与中枢神经系统胆碱能系统反应性之间的关系E2刺激。 第一项研究将探讨雌激素对胆碱能系统相关认知表现的影响与绝经后女性的个体特征之间的关系，这可能与雌激素是否具有认知增强作用有关。 这项研究将涉及我们在之前的研究中成功使用的正常绝经后妇女的短期雌激素治疗和胆碱能拮抗剂挑战模型。我们将研究主观和客观基线认知症状、结构脑成像和遗传标记对雌激素增强胆碱能相关认知功能的能力之间关系的影响。在第二项研究中，我们将研究年龄与胆碱能相关认知表现的潜在益处之间的关系。 我们将利用我们建立的雌激素-胆碱能挑战模型，并通过功能磁共振成像检查与年龄相关的大脑活动差异，这些差异与雌激素-胆碱能反应性的认知差异相关，来明确检验这个版本的“关键期假说”。 这项持续的工作将对理解激素损失对大脑功能的影响以及绝经后激素治疗对认知和行为的潜在益处与风险产生重要影响。 这项研究涉及服用雌激素，然后给予暂时影响执行某些心理和表现测试能力的药物。在研究#1 中，我们将通过认知评估来检查表现，在研究#2 中，我们将检查大脑激活。通过这种方式，我们希望了解雌激素的施用是否会改变这些药物的负面影响，从而可能改变衰老对大脑功能的影响。研究 #1 将持续大约 4-5 个月，将招募 50 名志愿者。研究 #2 将持续大约 10 个月，将招募 60 名志愿者。