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.

女性患阿尔茨海默病 (AD) 的风险增加，尤其是在更年期，一些女性会出现这种情况。 然而，并非所有女性都会经历更年期对认知的负面影响。 更年期发生的认知变化尚未与晚年病理性衰老风险相关 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 风险的影响所面临的挑战是，雌激素减少与 AD 风险之间存在较长的滞后时间。 更年期荷尔蒙的变化和AD的临床表现因此，确定荷尔蒙是如何变化的。 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。 这里提出的新研究将检查已建立的 AD 相关神经递质机制 我们认为这也可能是绝经后认知变化的原因。 更年期时，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 临床前研究表明，雌激素对于正常的胆碱能功能是必需的。 确定其停药是否会导致胆碱能功能障碍和认知障碍很重要。 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。 该补充申请将从两个主要方面增强家长补助金：首先，它将启用。 获取药用美加明（我们的抗胆碱能挑战药物）已变得极其困难 近两年获得的。 其次，它将添加一种新颖的体内胆碱能分子成像生物标志物，用于表征胆碱能的完整性/功能。 该方法将使用新型正电子发射断层扫描（PET）。 放射性示踪剂，[18F]氟乙氧基苯并维萨米考 ([18F]FEOBV)，专为大脑体内评估而开发 胆碱能功能，因为它对突触前囊泡乙酰胆碱表现出高结合亲和力和特异性 [18F]FEOBV PET 成像将用于大大增强我们评估 早期临床前 AD 病理对胆碱能完整性、早期认知之间关系的影响 变化和生殖史。 这项研究的公共卫生意义在于它将确定个体差异因素 与绝经后认知表现变化及其与结构、功能、 对这些因素的了解将有助于了解晚年认知功能障碍风险的生物标志物证据。 针对女性的个性化未来风险缓解策略，包括激素、药物、认知 修复等，这将是进一步研究的主题。