ESTROGEN EFFECTS ON CHOLINERGIC FUNCTION IN OLDER WOMEN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 研究表明，随着我们年龄的增长，智力发生的变化可能是大脑中发生的化学变化的结果。女性绝经后发生的雌激素丢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。乙酰胆碱是大脑中一种自然产生的化学物质，已被证明与注意力和记忆有关。我们将看看是否可以使用认知测试、大脑结构的磁共振成像和一种名为功能磁共振成像(或功能磁共振成像，如下所述的大脑扫描)的测试来检测这种变化。 这些研究的主要目标是结合临床、认知和神经成像方法，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。我们将超越我们最初的调查，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，如果在绝经后早期使用雌激素治疗，可以减缓或防止认知功能下降，增强认知功能，并可能降低患阿尔茨海默病(AD)的风险。然而，妇女健康倡议(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。在这笔赠款的前五年期间，我们一直表明，雌激素治疗对认知功能的好处可能是通过与中枢胆碱能系统的相互作用而实现的，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。这一建议进入下一个合乎逻辑的步骤，以更全面地了解雌激素-胆碱能相互作用的性质，并利用新的方法(如神经成像)更好地掌握个体生物学和认知特征与中枢神经系统胆碱能系统对E2刺激的反应性之间的关系。 第一项研究将考察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先前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的模型。我们将考察主客观基线认知症状学、脑结构成像和遗传标记物对雌激素增强胆碱能相关认知功能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。我们将利用我们已建立的雌激素-胆碱能挑战模型，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有关，从而明确地检验这一版本的“关键期假说”。这项持续的工作将对理解激素丢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和风险具有重要意义。 这项研究包括注射雌激素，然后服用暂时影响执行某些精神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，而在研究2中，我们将检查大脑的激活。通过这种方式，我们希望看到雌激素的使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将持续约4-5个月，将招募50名志愿者。第二项研究将持续约10个月，将招募60名志愿者。

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.