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: 10408737
• 负责人: JULIE A DUMAS
• 金额: $ 149.64万
• 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/10408737
• 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.

女性患阿尔茨海默病(AD)的风险增加。尤其是在更年期，一些女性会经历 认知上的改变。然而，并不是所有的女性都会经历更年期对认知的负面影响。这个 发生在更年期的认知变化尚未与病理性衰老的晚年风险相关联。 包括公元。因此，了解与个体认知差异有关的神经生物学因素 更年期对于理解正常的认知老化和确定病理性衰老的风险至关重要。 理解雌激素丢失对阿尔茨海默病风险的作用的挑战是 更年期激素变化与阿尔茨海默病的临床表现因此，确定荷尔蒙如何 绝经后的变化与AD风险有关会改变绝经后妇女的风险计算 未来。 这里提出的新研究将检验已建立的基于AD相关神经递质的机制 这也可能是绝经后认知变化的基础。我们认为荷尔蒙环境的变化 更年期与胆碱能系统和其他大脑病理相互作用，影响女性患上 认知能力下降。临床前研究表明，雌激素是正常胆碱能功能所必需的。 停药会导致胆碱能功能障碍和认知功能障碍。重要的是要确定是否 更年期相关认知改变与胆碱能功能完整性和已确诊的阿尔茨海默病相关 预示晚年认知障碍或痴呆症风险增加的生物标志物。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代偿的个体 对于绝经后荷尔蒙的变化和那些没有绝经的人。我们假设有贫穷的女性 补偿增加了对胆碱能阻断的敏感性，因为在认知能力上表现不佳 任务，改变脑激活，减少基底前脑胆碱能系统(BFCS)的体积。这些 胆碱能标志物可能与认知不良的绝经因素有关，也与AD的生物标志物有关。 具体目标1是通过测量工作记忆表现来检查胆碱能功能的完整性， 绝经后妇女的功能性脑激活和BFCS结构。《特定目标2》将考察 更年期相关症状和已知AD生物标志物的个体差异与认知和 抗胆碱能攻击后的脑激活。 这项研究的公共卫生意义在于，它将确定以下个人差异因素 绝经后认知功能改变及其与结构、功能和功能的关系 以及晚年认知功能障碍风险的生物标志物证据。了解这些因素将有助于 为女性提供个性化的未来风险缓解策略，包括激素、药物、认知 补救等，这将是进一步研究的主题。