Health of the cholinergic system and risk for Alzheimer's disease in post-menopausal women

绝经后女性胆碱能系统的健康和阿尔茨海默病的风险

• 批准号: 10588361
• 负责人: JULIE A DUMAS
• 金额: $ 21.27万
• 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/10588361
• 关键词: Administrative Supplement; Affect; Affinity; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Anti-Cholinergics; Attention; Binding; Biological Markers; Brain; Brain Pathology; Calculi; Clinical; Cognition; Cognitive; Cognitive aging; Cognitive remediation; Dementia; Elderly; Estrogens; Exhibits; Functional disorder; Future; Health; Hippocampus (Brain); Hormonal; Hormonal Change; Hormones; Impaired cognition; Impairment; Individual; Individual Differences; Knowledge; Measures; Mecamylamine; Menopausal Symptom; Menopause; Moods; Motor Skills; Nerve Degeneration; Neurobiology; Neurotransmitters; Parents; Pathologic; Performance; Pharmaceutical Preparations; Placebos; Positron-Emission Tomography; Postmenopause; Public Health; Reproductive History; Research; Risk; Risk Factors; Role; Short-Term Memory; Sleep; Specificity; Structure; Symptoms; System; Time; Vasomotor; Withdrawal; Woman; acetylcholine transporter; base; blood-based biomarker; cholinergic; cognitive change; cognitive performance; dementia risk; experience; fluoroethoxy-benzovesamicol; imaging biomarker; in vivo; middle age; molecular imaging; neurotransmission; novel; parent grant; pathological aging; pre-clinical; preclinical study; presynaptic; radiotracer; 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. 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 supplemental application will enhance the parent grant in two primary ways. First it will enable the acquisition of medicinal mecamylamine (our anticholinergic challenge drug) that has become exceedingly difficult to obtain in the last two years. Second, it will add a novel in-vivo cholinergic molecular imaging biomarker of the integrity/function of the cholinergic neurotransmission system. This approach will use a novel positron emission tomography (PET) radiotracer, [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV), that was developed for in-vivo assessment of brain cholinergic function as it exhibits high binding affinity and specificity for the presynaptic vesicular acetylcholine transporter (VAChT). [18F]FEOBV PET imaging will be used to greatly enhance our abilities to evaluate the impact of early preclinical AD pathologies on the relationship between cholinergic integrity, early cognitive alterations, and reproductive history. 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 更年期后的变化与AD风险有关，将改变绝经后妇女的风险计算。 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。 此补充应用将以两种主要方式增强父母赠款。首先，它将启用 获得非常困难的药物甲基胺（我们的抗胆碱能挑战药物） 在过去的两年中获得。 其次，它将添加一种新型的体内胆碱能分子成像生物标志物的完整性/功能 胆碱能神经传递系统。这种方法将使用新颖的正电子发射断层扫描（PET） Radiotracer，[18F]氟乙氧基苯甲酰基木糖（[[18F] feOBV），用于大脑的体内评估 胆碱能功能，因为它表现出高结合亲和力和突触前乙酰胆碱的特异性 转运蛋白（VACHT）。 [18F] FEOBV PET成像将用于大大增强我们评估的能力 早期临床前AD病理学对胆碱能完整性，早期认知之间关系的影响 改变并复制历史。 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。