ESTROGEN EFFECTS ON CHOLINERGIC FUNCTION IN OLDER WOMEN

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH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 中心，不一定是研究者的机构。 研究表明，随着年龄的增长，心理能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丢失可能会加速这种变化。这项研究的目的是测试是否给予激素雌激素会影响系统的大脑使用乙酰胆碱。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。我们将看看我们是否可以通过认知测试，大脑结构的MRI和一种称为功能性MRI（或fMRI，即下文描述的大脑扫描）的测试来检测这种变化。 这些研究的主要目标是结合联合收割机的临床，认知和神经影像学的方法，继续我们的研究雌激素和相关化合物如何影响人类大脑的胆碱能系统的认知功能。 我们将超越我们原来的调查，开始发展的生物学，临床和认知之间的关系，雌激素对胆碱能相关的认知功能的积极或消极的影响，在老年妇女的理解。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，如果在绝经后早期给药，可能会降低患阿尔茨海默病（AD）的风险。 然而，大型前瞻性研究，如妇女健康倡议（WHI）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。在该基金的前五年期间，我们一直表明雌激素治疗对认知功能的益处可能是通过与CNS胆碱能系统的相互作用介导的，通过特异性增强胆碱能敏感的认知操作，包括注意力、精神速度和情景记忆。该建议继续进行下一个逻辑步骤，以更充分地了解雌激素-胆碱能相互作用的性质，并利用新的方法（例如神经影像学），以更好地掌握个体生物学和认知特征与CNS胆碱能系统对E2刺激的反应性之间的关系。 第一项研究将检查雌激素对胆碱能系统相关认知表现的影响与绝经后妇女的个体特征之间的关系，这些个体特征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的模型，短期雌激素治疗和胆碱能拮抗剂的挑战，在正常绝经后妇女成功地利用我们以前的研究。我们将研究主观和客观基线认知功能学、结构脑成像和遗传标记物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。 我们将明确地检查这个版本的“关键期假说”，利用我们建立的雌激素-胆碱能激发模型，并检查与年龄相关的差异，在脑活动与功能磁共振成像与认知差异，雌激素-胆碱能反应。 这项持续的工作将对理解激素丧失对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具有重要意义。 这项研究涉及给予雌激素，然后给予暂时影响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，在研究#2中，我们将检查大脑激活。通过这种方式，我们希望看到雌激素管理是否改变了这些药物的负面影响，因此可能会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。研究#2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.