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: 7922641
• 负责人: PAUL A. NEWHOUSE
• 金额: $ 52.01万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922641
• 关键词: Affect; Aftercare; Age; Alzheimer' s Disease; Anti-Cholinergics; Apolipoprotein E; Area; Attention; Attention Concentration; Behavior; Behavioral; Biologic Characteristic; Biological; Brain; Brain imaging; Characteristics; Cholinergic Antagonists; Cholinergic Receptors; Clinical; Clinical Trials; Cognition; Cognitive; Data; Dementia; Development; Diagnosis; Disease; Epidemiologic Studies; Epidemiology; Episodic memory; Estradiol; Estrogens; Functional Magnetic Resonance Imaging; Genetic Markers; Genotype; Glean; Goals; Gonadal Steroid Hormones; Grant; Hippocampus (Brain); Hormonal; Hormones; Human; Impaired cognition; Impairment; Individual; Investigation; Knowledge; Left; Lesion; Maintenance; Mammary Gland Parenchyma; Measurable; Measures; Mecamylamine; Medial; Mediating; Medicine; Memory; Menopause; Methodology; Middle frontal gyrus structure; Modeling; Muscarinics; Nature; Neurobiology; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Organ; Ovarian; Parahippocampal Gyrus; Performance; Pharmaceutical Preparations; Pharmacology; Placebos; Postmenopause; Prefrontal Cortex; Process; Production; Prospective Studies; Relative (related person); Reporting; Research; Risk; Role; Scopolamine; Sensory Receptors; Short-Term Memory; Simulate; Speed; Stress; Surveys; System; Task Performances; Technology; Testing; Therapeutic Uses; Time; Treatment outcome; Ursidae Family; Vascular Dementia; Woman; Women' s Health; Work; age effect; age related; base; body system; bone; cholinergic; cholinergic neuron; cognitive function; critical period; density; grasp; gray matter; heuristics; high risk; hormone therapy; improved; model development; neurochemistry; neuroimaging; neuron development; new technology; normal aging; novel strategies; older women; operation; postsynaptic; presynaptic; prevent; prognostic; prophylactic; prospective; public health relevance; research study; response

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.

描述（由申请人提供）：本竞争性延续（更新）提案的主要目标是将临床、认知和神经成像方法学联合收割机结合起来，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。具体而言，第一项研究（1）将研究雌激素对胆碱能系统相关认知能力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在以前的补助期。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（2）中，我们将检查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。公共卫生关系：我们已经确定的证据表明，雌二醇管理，特别是在正常绝经后妇女增强认知操作的影响，包括注意力，精神速度，和情节记忆的中枢胆碱能系统。该提案试图更全面地了解大脑中的雌激素-胆碱能相互作用如何影响注意力和记忆力，并利用新技术（如神经成像）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。最终目标是开发信息，以允许模型的开发，从而潜在地预测哪些女性可能受益于绝经后雌二醇的认知效应。