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

酒精影响 MCI 和早期 AD 发展的去甲肾上腺素能机制

• 批准号: 10401937
• 负责人: Chiang-Shan Ray Li
• 金额: $ 36.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10401937
• 关键词: Acute; Address; Adult; Age; Age-associated memory impairment; Aging; Alcohol abuse; Alcohol consumption; Alcohols; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Autopsy; Basal Nucleus of Meynert; Brain; Brain imaging; Brain region; Cells; Cerebral cortex; Cessation of life; Chronic; Clinical; Clinical Research; Clinical assessments; Cognition; Cognitive; Cognitive aging; Cognitive deficits; Data; Development; Early Onset Alzheimer Disease; Emotional; Emotions; Etiology; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Heavy Drinking; Hippocampus (Brain); Image; Impaired cognition; Individual; Intoxication; Lead; Life; Light; Link; Literature; Logistics; Longitudinal Studies; Magnetic Resonance Imaging; Mediating; Memory; Molecular; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Neuropil Threads; Patients; Positron-Emission Tomography; Prefrontal Cortex; Prospective Studies; Reporting; Rest; Risk; Role; Severities; Sex Differences; Signal Transduction; Source; Staging; Structure; System; Thalamic structure; Time; Withdrawal; Woman; abeta deposition; age related; alcohol effect; alcohol exposure; alcohol misuse; burden of illness; cerebral atrophy; chronic alcohol ingestion; cingulate cortex; cognitive control; cognitive function; cognitive performance; cognitive reserve; cognitive testing; dementia risk; density; drinking; entorhinal cortex; epidemiology study; healthy aging; locus ceruleus structure; mild cognitive impairment; modifiable risk; neuroinflammation; neuromelanin; neuron loss; noradrenergic; preclinical study; relating to nervous system; response; social

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.

摘要/总结 滥用酒精会加剧认知老化。前瞻性研究将饮酒问题与风险增加联系起来 以及阿尔茨海默病 (AD) 和相关痴呆 (ADRD) 的早期发病。另一方面，研究 主要是社交饮酒者报告称，饮酒对认知功能没有影响或有减轻影响。因此，饮酒 可能会影响 ADRD 的风险，其影响可能取决于饮酒的严重程度。 鉴于 ADRD 的进展通常被描述为与积累相关的六个阶段 其他研究表明，大脑皮层和海马体中的神经原纤维缠结和神经纤维网线 AD 早期蓝斑 (LC) 的功能和结构变化，包括神经元丢失。液相色谱 退化发生在健康衰老过程中，纵向研究表明 LC 是一个关键的 认知储备结构，支持 LC 去甲肾上腺素能 (NA) 回路功能障碍的发展 ADRD。滥用酒精可能会导致 NA 信号传导发生变化并加速 LC 回路功能障碍 老化期间。大量研究提供了滥用酒精对中枢 NA 影响的证据 神经回路和 NA 功能障碍是连接酒精滥用和 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 与少量饮酒者相比，重度饮酒者随着年龄的增长而迅速增加。此外，前额皮质和其他结构 默认模式网络从 LC 接收大量 NA 投影，也显示出明显更陡峭的结果 重度饮酒者与轻度饮酒者对认知控制和静息状态的反应与年龄相关的变化。 基于这些数据和支持情绪记忆中海马功能的文献，我们建议 结合 MRI 和对 120 名重度饮酒者和非/轻度饮酒者的纵向评估（每人 n=60，一半 女性，年龄匹配），以实现三个目标：1）检查 LC 神经黑色素是否发生与年龄相关的变化 信号随饮酒和认知障碍而变化，以及 LC 信号是否介导相互关系 饮酒与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情况以及连接强度是否相关而变化 具有 LC 神经黑色素信号； 3) 检查 LC 神经黑色素信号和 LC 电路是否以及如何发出信号 连接性预测认知功能的下降以及从健康老龄化到 MCI 的潜在转变或 从 MCI 到 AD 早期。我们还将进行探索性分析来检查性别差异和 其他可改变的痴呆风险因素对 MCI 和 AD 发展的影响。 该研究的总体目标是调查酒精滥用和 NA 功能障碍对 ADRD 的发展。我们相信，这些发现不仅能解决 ADRD 的一个关键机制 而且还揭示了与 NA 功能障碍有关的其他神经退行性疾病的病因。