Estrogen Effects on Cholinergic Function in Older Women

描述（由申请人提供）：这个竞争性延续（更新）提案的主要目标是结合临床，认知和神经影像学方法，继续我们对雌激素和相关化合物如何影响人脑胆碱能系统认知功能的研究。我们将超越我们最初的研究，开始了解雌激素对老年妇女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防止认知能力下降，增强认知功能，并可能降低患阿尔茨海默病（AD）的风险，如果在绝经后早期给予。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。在本研究的前5年，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中枢神经系统胆碱能系统的相互作用介导的，通过特异性地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。本研究将进一步深入了解雌激素-胆碱能相互作用的本质，并利用新方法（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。具体而言，第一项研究(1)将研究雌激素对绝经后妇女胆碱能系统相关认知表现的影响与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。这项研究将包括我们的短期雌激素治疗和胆碱能拮抗剂挑战的正常绝经后妇女的模型，成功地在先前的资助期使用。我们将研究主客观基线认知症状学、脑结构成像和遗传标记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(2)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，明确地检验这一版本的“关键时期假说”，并利用fMRI检查与雌激素-胆碱能反应的认知差异相关的脑活动的年龄相关差异。这项持续的工作将对理解激素丢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和风险具有重要意义。公共卫生相关性：我们已经确定的证据表明，正常绝经后妇女服用雌二醇可特别增强受中枢胆碱能系统影响的认知功能，包括注意力、精神运动速度和情景记忆。本研究旨在更全面地了解大脑中雌激素-胆碱能相互作用如何影响注意力和记忆，并利用新技术（如神经影像学）了解老年妇女的个体、时间、生物学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。最重要的目标是开发信息，允许开发模型，以潜在地预测哪些女性可能从绝经后雌二醇的认知效果中受益。

DESCRIPTION (provided by applicant): The primary goal of this competing continuation (renewal) proposal 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. Specifically, the first study (1) 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 the prior grant period. 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 (2), 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. PUBLIC HEALTH RELEVANCE: We have established evidence that estradiol administration in normal postmenopausal women specifically enhances cognitive operations that are influenced by central cholinergic systems including attention, psychomotor speed, and episodic memory. This proposal attempts to more fully understand how estrogen-cholinergic interactions in the brain affect attention and memory and develop an understanding of the relationships between individual, chronological, biological, and cognitive characteristics of older women and the responsiveness of the CNS cholinergic system using new technologies (e.g. neuroimaging). The over arching goal is to develop information to allow the development of models to potentially predict which women may benefit from the cognitive effects of estradiol after menopause.