Health of the Cholinergic System and Risk for Alzheimer's Disease in Postmenopausal Women

绝经后妇女胆碱能系统的健康和阿尔茨海默病的风险

• 批准号: 10170208
• 负责人: JULIE A DUMAS
• 金额: $ 149.01万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170208
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Anti-Cholinergics; Attention; Biological Markers; Brain; Brain Pathology; Calculi; Clinical; Cognition; Cognitive; Cognitive aging; Cognitive remediation; Dementia; Elderly; Estrogens; Financial compensation; Frontal gyrus; Functional Magnetic Resonance Imaging; Functional disorder; Future; Health; Hippocampus (Brain); Hormonal; Hormonal Change; Hormones; Impaired cognition; Impairment; Individual; Individual Differences; Knowledge; Measures; Medial; Menopausal Symptom; Menopause; Moods; Motor Skills; Nerve Degeneration; Neurobehavioral Manifestations; Neurobiology; Neurotransmitters; Pathologic; Pathology; Performance; Pharmaceutical Preparations; Placebos; Positron-Emission Tomography; Postmenopause; Public Health; Research; Risk; Risk Factors; Role; Short-Term Memory; Sleep; Structure; Symptoms; System; Time; Vasomotor; Withdrawal; Woman; aged; amyloid imaging; associated symptom; basal forebrain; base; blood-based biomarker; cholinergic; cognitive change; cognitive performance; cognitive task; dementia risk; experience; middle age; novel; pathological aging; preclinical study; recruit; response; risk mitigation; tau Proteins

Women are at increased risk for Alzheimer’s disease (AD). Notably at menopause, some women experience a change in cognition. However, not all women experience negative effects of menopause on cognition. The cognitive changes that occur at menopause have not yet been connected to late life risk for pathological aging including AD. Thus, understanding the neurobiological factors related to individual differences in cognition at menopause is critical for understanding normal cognitive aging and for determining risk for pathological aging. The challenge in understanding the role of estrogen loss on the risk for AD is the long lag time between the hormonal changes at menopause and the clinical manifestations of AD. Thus, identifying how the hormone changes after menopause are related to AD risk will alter the risk calculus for postmenopausal women in the future. The novel study proposed here will examine an established AD-related neurotransmitter-based mechanism that may also underlie cognitive changes after menopause. We propose that the change in the hormonal milieu at menopause interacts with the cholinergic system and other brain pathologies to influence a woman’s risk for cognitive decline. Preclinical studies have shown that estrogen is necessary for normal cholinergic functioning and its withdrawal leads to cholinergic dysfunction and cognitive impairment. It is important to determine whether menopause-related cognitive changes correlate with both cholinergic functional integrity and established AD biomarkers that portend increased risk for late-life cognitive impairment or dementia. This study will examine brain functioning following cholinergic blockade to separate individuals into those who are able to compensate for the hormone change after menopause and those who are not. We hypothesize women with poor compensation have increased sensitivity to cholinergic blockade by showing poor performance on a cognitive task, altered brain activation, and decreased basal forebrain cholinergic system (BFCS) volume. These cholinergic markers will be related to menopausal factors associated with poor cognition and biomarkers of AD. Specific Aim 1 is to examine cholinergic functional “integrity” by measuring working memory performance, functional brain activation, and BFCS structure in postmenopausal women. Specific Aim 2 will examine whether individual differences in menopause-relevant symptoms and known AD biomarkers are related to cognition and brain activation after anticholinergic challenge. The public health significance of this study is that it will identify individual difference factors that are associated with cognitive performance changes after menopause and their relationship to structural, functional, and biomarker evidence of risk for later life cognitive dysfunction. Knowledge of these factors will serve to advance personalized future risk-mitigation strategies for women including hormonal, medication, cognitive remediation, etc. that will be the subject of further research.

妇女患阿尔茨海默氏病（AD）的风险增加。特别是在更年期，有些女人经历了 认知的变化。但是，并非所有女性都会遇到更年期对认知的负面影响。这 更年期发生的认知变化尚未与病理衰老的晚期生活风险有关 包括广告。这是了解与认知个体差异有关的神经生物学因素 更年期对于理解正常的认知衰老和确定病理衰老的风险至关重要。 理解雌激素损失对AD风险的作用的挑战是 Menopaus的激素变化和AD的临床表现。那，确定马恩的方式 更年期后与AD风险有关的变化将改变绝经后妇女的风险计算 未来。 此处提出的新研究将检查建立的基于广告相关的神经递质机制 更年期后的认知变化也可能是基础。我们建议荷尔蒙环境的变化 更年期与胆碱能系统和其他脑部病理相互作用，以影响女性的风险 认知能力下降。临床前研究表明，雌激素对于正常的胆碱能功能是必需的 它的提取导致胆碱能功能障碍和认知障碍。确定是否是否 与更年期相关的认知变化与胆碱能功能完整性均相关并建立了AD 预示着预测晚期认知障碍或痴呆症风险的生物标志物。这项研究将检查 胆碱能阻断后的大脑功能，将个体分为能够补偿的人 对于更年期和那些没有的人而改变的马。我们假设妇女有贫穷的妇女 通过表现出认知性能较差的性能，补偿对胆碱能阻断的敏感性提高了 任务，大脑激活改变并改善了基本前脑胆碱能系统（BFCS）体积。这些 胆碱能标记将与与AD的认知不良和生物标志物相关的更年期因素有关。 具体目标1是通过测量工作记忆性能来检查胆碱能功能“完整性”， 绝经后妇女的功能性脑激活和BFCS结构。具体目标2将检查是否 绝经症状和已知的AD生物标志物的个体差异与认知和 抗胆碱能挑战后的大脑激活。 这项研究的公共卫生意义在于，它将确定个体差异因素 与绝经后的认知绩效变化及其与结构，功能，功能， 以及生物标志物具有后来生活认知功能障碍的风险的证据。这些因素的了解将有助于 提前针对包括荷尔蒙，药物，认知在内的女性的个性化降低风险降低策略 修复等将是进一步研究的主题。