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: 10629209
• 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/10629209
• 关键词: Acceleration; Acute; Address; 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; Dementia; Development; Early Onset Alzheimer Disease; Elderly; Emotional; Emotions; Etiology; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Heavy Drinking; Hippocampus; Image; Impaired cognition; Individual; Intoxication; Life; Light; Link; Literature; Logistics; Longitudinal Studies; Magnetic Resonance Imaging; Mediating; Memory; Molecular; Neocortex; 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; neural; neuroinflammation; neuromelanin; neuron loss; noradrenergic; preclinical study; 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/摘要 酗酒会加剧认知老化。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)和相关痴呆症(ADRD)的较早发病。另一方面，对 主要是社交饮酒者报告说，饮酒对认知功能没有或减轻了影响。因此，酒精的使用 可能会影响ADRD的风险，其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 大脑皮层和海马区的神经原纤维缠结和神经纤维线，其他研究已经证实 阿尔茨海默病早期蓝斑(LC)的功能和结构改变，包括神经元丢失。LC 退化发生在健康的衰老过程中，纵向研究表明LC是一种关键的 认知储备结构，支持LC去甲肾上腺素(NA)环路功能障碍的发生发展 阿德勒。酒精滥用可能导致NA信号的变态改变，并加速LC电路功能障碍 在衰老过程中。大量研究为酒精滥用对中枢NA的影响提供了证据 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神经黑素成像信号减少得更多。 与饮酒量较少的人相比，随着年龄的增长，饮酒量增加得很快。此外，前额叶皮质和大脑的其他结构 从LC接收重NA投影的默认模式网络也显示出明显的陡度 重度饮酒者与轻度饮酒者在休息状态下对认知控制反应的年龄相关变化。 在这些数据和支持海马体情绪记忆功能的文献的基础上，我们建议 结合MRI和纵向评估120例老年重度饮酒者和非饮酒者/轻度饮酒者(n=60，一半 女性，年龄匹配)，以解决三个目标：1)检查LC神经黑色素是否与年龄相关的变化 信号会因饮酒和认知损害而不同，以及LC信号是否会调节这种相互关系 酒精使用和认知状态之间的关系；2)检查LC电路连接性是否以及如何响应 认知控制和情绪记忆随饮酒以及连接强度是否相关而变化 用LC神经黑素信号；3)检查LC神经黑素信号和LC电路 连接性预测认知功能下降和从健康老龄化到MCI或MCI的潜在转变 从MCI到AD早期。我们还将进行探索性分析，以检查性别差异和 痴呆的其他可改变危险因素对MCI和AD发生的影响。 这项研究的主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，这些发现不仅将解决ADRD的一个关键机制 但也揭示了导致NA功能障碍的其他神经退行性疾病的病因。