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

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。 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。 这项补充申请将从两个主要方面提高家长助学金。首先，它将启用 获得药用甲戊胺(我们的抗胆碱能挑战药物)已变得极其困难 在过去的两年里获得了。 其次，它将增加一种新的体内胆碱能分子成像生物标记物，用于检测胆碱能受体的完整性/功能 胆碱能神经传递系统。这种方法将使用一种新的正电子发射断层扫描(PET) 放射性示踪剂，[18F]氟乙氧基苯并氨基酚([18F]FEOBV)，是为活体脑评估而开发的 胆碱能对突触前囊泡乙酰胆碱表现出高的结合亲和力和特异性 运输船(游艇)。[18F]FEOBV PET成像将极大地增强我们评估 早期临床前AD病理改变对胆碱能完整性与早期认知功能关系的影响 改变和繁殖史。 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。

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.