Noradrenergic mechanisms of alcohol's impact on the development of MCI and early stage AD

摘要/总结 酒精滥用加剧认知老化。前瞻性研究将问题饮酒与风险增加联系起来 以及阿尔茨海默病（AD）和相关痴呆（ADRD）的早期发作。另一方面，研究 主要是社交饮酒者报告说，饮酒对认知功能没有影响或有减轻影响的作用。因此，酒精的使用 可能影响ADRD的风险，影响可能取决于饮酒的严重程度。 而ADRD的进展通常被描述为与累积相关的六个阶段 其他研究表明， 在早期AD中蓝斑（LC）中的功能和结构变化，包括神经元损失。LC 退化发生在健康的老龄化，纵向研究表明，LC作为一个关键的 认知储备结构，支持LC去甲肾上腺素（NA）回路功能障碍， ADRD。酒精滥用可引起NA信号的非稳态变化，加速LC回路功能障碍 在老化过程中。大量的研究为酒精滥用对中枢神经系统的影响提供了证据。 神经回路和NA功能障碍是联系酒精滥用和ADRD的关键机制。 为了支持这种机制联系，我们发现LC神经黑色素成像信号减少更多， 与轻度饮酒者相比，重度饮酒者的年龄增长迅速。此外，前额叶皮层和其他结构， 默认模式网络，它从LC接收大量的NA预测，也显示出明显的陡峭 与年龄相关的变化，在认知控制的反应，并在休息状态下，大量与少量饮酒。 基于这些数据和支持海马在情绪记忆中功能的文献，我们建议 联合收割机和纵向评估的120名老年成人重度和非/轻度饮酒者（n=60，每一半， 女性，年龄匹配），以解决三个目标：1）检查是否年龄相关的变化，LC神经黑色素 信号随饮酒和认知障碍而变化，以及LC信号是否介导了相互关系 酒精使用和认知状态之间的关系; 2）检查LC电路连接是否以及如何响应 认知控制和情绪记忆随饮酒而变化， 与LC神经黑色素信号;和3）检查LC神经黑色素是否以及如何发出信号和LC电路 连接性预测认知功能的下降和从健康老龄化到MCI的潜在转变， 从MCI到早期AD我们还将进行探索性分析，以检查性别差异和 其他可改变的痴呆危险因素对MCI和AD发展的影响。 这项研究的首要目标是调查酒精滥用和NA功能障碍对 ADRD的发展。我们认为，这些发现不仅可以解决ADRD的关键机制， 而且揭示了涉及NA功能障碍的其他神经退行性疾病的病因。

ABSTRACT/SUMMARY Alcohol misuse exacerbates cognitive aging. Prospective studies associate problem drinking to increased risk and earlier onset of Alzheimer’s disease (AD) and related dementia (ADRD). On the other hand, studies of mainly social drinkers reported no or mitigating effects of alcohol use on cognitive functions. Thus, alcohol use may influence the risks of ADRD and the impacts likely depend on the severity of alcohol consumption. Whereas the progression of ADRD is typically described in six stages in correlation with accumulation of neurofibrillary tangles and neuropil threads in the cortex and hippocampus, other studies have implicated functional and structural changes, including neuronal loss, in the locus coeruleus (LC) in early stage AD. LC degeneration occurs during healthy aging, and longitudinal studies have suggested the LC as a critical structure of cognitive reserve, in support of LC noradrenergic (NA) circuit dysfunction in the development of ADRD. Alcohol misuse may cause allostatic changes in NA signaling and accelerate LC circuit dysfunction during aging. A substantial body of studies provide evidence for the impact of alcohol misuse on central NA circuits and NA dysfunction as a critical mechanism linking alcohol misuse and ADRD. In support of this mechanistic link, we showed that LC neuromelanin imaging signals decreased more rapidly with age in heavy as compared to light drinkers. Further, the prefrontal cortex and other structures of the default mode network, which receives heavy NA projections from the LC, also showed significantly steeper age-related changes in responses to cognitive control and during resting state in heavy vs. light drinkers. Building on these data and a literature supporting hippocampal function in emotion memory, we propose to combine MRI and longitudinal assessments of 120 old adult heavy and non/light drinkers (n=60 each, half women, age matched) to address three aims: 1) Examine whether age-related changes in LC neuromelanin signals vary with alcohol use and cognitive impairment and whether LC signals mediate the inter-relationship between alcohol use and cognitive status; 2) Examine whether and how LC circuit connectivities in response to cognitive control and emotional memory vary with alcohol use and whether the connectivity strength correlates with LC neuromelanin signals; and 3) Examine whether and how LC neuromelanin signals and LC circuit connectivities predict the decline in cognitive function and the potential transition from healthy aging to MCI or from MCI to early stage AD. We will also perform exploratory analyses to examine sex differences and the influences of other modifiable risk factors for dementia on the development of MCI and AD. The overarching goal of the study is to investigate the effects of alcohol misuse and NA dysfunction on the development of ADRD. We believe that the findings would not only address a critical mechanism of ADRD but also shed light on the etiologies of other neurodegenerative conditions that implicate NA dysfunction.