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 酒精遗产加剧了认知衰老。前瞻性研究使饮酒与风险增加 以及早期的阿尔茨海默氏病（AD）和相关痴呆症（ADRD）的发作。另一方面，研究 主要是社交饮酒者报告没有或减轻饮酒对认知功能的影响。那是酒精的使用 可能影响ADRD的风险，影响可能取决于饮酒的严重程度。 而ADRD的进展通常分为六个阶段，与积累相关 皮质和海马中的神经原纤维缠结和神经螺纹，其他研究已经实施 早期AD中的位点层基因座（LC）中的功能和结构变化，包括神经元丧失。 LC 在健康衰老期间发生退化，纵向研究表明LC是关键 认知储备的结构，以支持LC甲肾上腺素能（NA）电路功能障碍的发展 adrd。酗酒可能会导致NA信号传导和加速LC电路功能障碍的同性变化 在衰老期间。大量研究为滥用酒精对中央NA的影响提供了证据 电路和NA功能障碍是将酒精滥用和ADRD联系起来的关键机制。 为了支持这种机械链接，我们表明LC神经元素成像信号降低了 与饮酒者相比，随着年龄的增长迅速。此外，前额叶皮层和其他结构 从LC接收重型NA项目的默认模式网络也显示出明显的蒸汽机 与年龄相关的认知控制反应以及重量饮酒者的静止状态的反应变化。 在这些数据和支持情感记忆中海马功能的文献基础上，我们建议 将MRI和120个老人重和非/非/轻/轻/轻/轻度饮用者的MRI和纵向评估结合在一起（n = 60，一半 妇女，年龄匹配）解决三个目标：1）检查LC Neuromelanin与年龄相关的变化是否 信号因酒精使用和认知障碍而异，以及LC是否介导相互关系的信号 在饮酒和认知状况之间； 2）检查LC电路连接是否以及如何响应 认知控制和情感记忆随着酒精的使用而不同，连通性强度是否相关 带有LC神经元素信号； 3）检查LC神经素信号和LC电路是否以及如何 连接性预测认知功能的下降以及从健康衰老到MCI或 从MCI到早期广告。我们还将进行探索性分析以检查性别差异和 痴呆症的其他可修改风险因素的影响对MCI和AD的发展。 该研究的总体目标是研究滥用酒精和NA功能障碍对 Adrd的发展。我们认为，这些发现不仅会解决ADRD的关键机制 而且还阐明了暗示NA功能障碍的其他神经退行性疾病的病因。