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: 10018632
• 负责人: JULIE A DUMAS
• 金额: $ 148.33万
• 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/10018632
• 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）的风险更高。尤其是在更年期，一些女性会经历 认知的改变。然而，并非所有女性都会经历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晚年病理性衰老风险相关 包括AD。因此，了解与个体认知差异相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性衰老的风险至关重要。 了解雌激素减少对 AD 风险的影响的挑战在于，雌激素减少与 AD 风险之间存在较长的滞后时间。 更年期荷尔蒙变化和 AD 的临床表现。因此，确定激素如何 绝经后与 AD 风险相关的变化将改变绝经后女性的风险计算 未来。 这里提出的新研究将检查已建立的 AD 相关神经递质机制 这也可能是绝经后认知变化的基础。我们建议改变荷尔蒙环境 在更年期，它与胆碱能系统和其他大脑病理相互作用，影响女性患乳腺癌的风险 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 其戒断会导致胆碱能功能障碍和认知障碍。重要的是要确定是否 更年期相关的认知变化与胆碱能功能完整性和既定 AD 相关 预示晚年认知障碍或痴呆风险增加的生物标志物。这项研究将考察 胆碱能阻断后的大脑功能将个体分为能够代偿的人 对于绝经后和未绝经后激素变化的人。我们假设贫困女性 补偿通过表现出较差的认知表现而增加了对胆碱能阻断的敏感性 任务，改变大脑激活，并减少基础前脑胆碱能系统（BFCS）体积。这些 胆碱能标志物与认知不良和 AD 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的“完整性”， 绝经后妇女的功能性大脑激活和 BFCS 结构。具体目标 2 将检查是否 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认知相关 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 与绝经后认知表现变化及其与结构、功能、 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 为女性推进个性化的未来风险缓解策略，包括激素、药物、认知 修复等，这将是进一步研究的主题。