A noradrenergic mechanism of apathy and motivation deficit in MCI and AD

MCI 和 AD 中冷漠和动机缺陷的去甲肾上腺素能机制

• 批准号: 9895059
• 负责人: Chiang-Shan Ray Li
• 金额: $ 40.43万
• 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: 2020-01-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895059
• 关键词: Age; Age-Years; Aging; Alzheimer' s Disease; Arousal; Attention; Behavior; Behavioral; Brain; Brain imaging; Cell Nucleus; Cerebral cortex; Clinical; Code; Cross-Sectional Studies; Cues; Data; Dementia; Dopamine; Etiology; Exhibits; Feedback; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Human; Image; Imaging Techniques; Impaired cognition; Incentives; Individual; Link; Longitudinal Studies; Magnetic Resonance; Maps; Midbrain structure; Motivation; Outcome; Participant; Patients; Physiological; Play; Positioning Attribute; Prefrontal Cortex; Quality of life; Research; Resolution; Rewards; Risk; Role; Severities; Sex Differences; Signal Transduction; Source; Stimulus; Structure; Substantia nigra structure; Sum; Symptoms; Testing; Thalamic structure; Time; Variant; Ventral Tegmental Area; analog; behavioral outcome; behavioral study; common symptom; financial incentive; functional decline; interest; locus ceruleus structure; mild cognitive impairment; motivated behavior; neurobiological mechanism; neuromelanin; noradrenergic; pars compacta; recruit; relating to nervous system; response; reward anticipation; sex; β-amyloid burden

SUMMARY/ABSTRACT As one of the most common symptoms, apathy frequently manifests before cognitive impairment in the spectrum of Alzheimer’s disease (AD). Persistent apathy plays an important role in rapid functional decline and significantly impacts the quality of life of individuals with AD. Yet, the neurobiological mechanisms underlying apathy remain unclear. Apathy reflects a general diminution of interest or motivation, a lack of effort in goal-directed behavior. A growing body of evidence implicates the monoaminergic circuits in motivation and effort. A recent review suggests that dopamine primarily codes for future reward and promotes reward-directed action but is less sensitive to anticipated effort. On the other hand, effort is tightly linked to heightened arousal and, with extensive projections to the thalamus and prefrontal cortex, the locus coeruleus (LC) likely plays a critical role in sustaining motivated and effortful behavior. This exploratory study aims to examine this hypothesis and distinguish the roles of the noradrenergic (NA) and dopaminergic (DA) circuits in motivated behavior and how NA and DA dysfunction may underlie apathy in individuals with mild cognitive impairment (MCI) and early stage AD, as compared to healthy controls. Specifically, the LC is a very small structure and difficult to localize with conventional structural imaging. Building on previous studies, we have taken advantage of the high neuromelanin content in the LC and ventral tegmental area/substantia nigra, pars compacta (VTA/SNc) and successfully developed a probabilistic map of the LC and VTA/SNc in individuals’ native space. By engaging participants in fMRI of a reward task we will query how the NA and DA circuits respond to timed, effortful behavior to acquire reward and to behavioral outcomes. We hypothesize that individuals with MCI and early stage AD will demonstrate reduction in neuromelanin signal contrast in the LC and diminished LC circuit activities and connectivities to support motivated behavior in link with the clinical severity of apathy. We propose to test this hypothesis in 30 patients with MCI and early stage AD and 30 age and sex matched healthy control participants (HC), with two specific aims: 1) examine whether LC and/or VTA/SNc neuromelanin signal intensity is diminished in participants with MCI and AD as compared to HC and whether the reduction in neuromelanin contrast is associated with apathy; 2) examine with fMRI whether LC and/or VTA/SNc response to reward anticipation and outcome as well as LC/VTA-SNc prefrontal cortical connectivity are reduced in participants with MCI and AD as compared to HC; and whether these changes are associated with apathy. We hope that the study will substantiate the role of noradrenergic circuits in an etiology of apathy in AD. If successful, the study may also have important implications for research of many other clinical conditions that implicate motivation dysfunction.

总结/摘要 作为最常见的症状之一，冷漠经常在认知障碍之前表现出来， 阿尔茨海默病（AD）的症状。持续性冷漠在快速功能衰退中起着重要作用， 显著影响AD患者的生活质量。然而，潜在的神经生物学机制 冷漠仍不清楚。 冷漠反映了兴趣或动机的普遍减少，缺乏目标导向行为的努力。 越来越多的证据表明，单胺能回路与动机和努力有关。最近一次审查 表明多巴胺主要编码未来的奖励，并促进奖励导向的行动，但 对预期的努力很敏感。另一方面，努力与高度的唤醒密切相关， 蓝斑（LC）向丘脑和前额叶皮层的广泛投射可能起着关键作用 保持积极和努力的行为。 这项探索性研究的目的是检验这一假设，并区分去甲肾上腺素能神经元的作用。 (NA)和多巴胺能（DA）电路的动机行为，以及如何NA和DA功能障碍可能是基础 轻度认知障碍（MCI）和早期AD患者与健康人相比， 对照具体地，LC是非常小的结构，并且难以用常规结构定位。 显像在以前研究的基础上，我们利用LC中神经黑色素含量高的优势， 和腹侧被盖区/黑质，丘脑腹侧部（VTA/SNc），并成功地开发了一个 个人原生空间中LC和VTA/SNc的概率地图。通过让参与者参与功能磁共振成像， 在奖励任务中，我们将询问NA和DA回路如何对定时的、努力的行为做出反应以获得奖励。 和行为结果之间的关系。我们假设患有MCI和早期AD的个体将表现出 LC中神经黑色素信号对比度降低，LC回路活动和与 支持与冷漠临床严重程度相关的动机行为。 我们建议在30例MCI和早期AD患者中测试这一假设， 匹配的健康对照参与者（HC），具有两个具体目的：1）检查LC和/或VTA/SNc 与HC相比，MCI和AD参与者的神经黑色素信号强度降低， 神经黑色素对比度的减少与冷漠有关; 2）用fMRI检查LC和/或 VTA/SNc对奖励预期和结果的反应以及LC/VTA-SNc前额叶皮层连接 与HC相比，MCI和AD参与者的发病率降低;以及这些变化是否相关 冷漠无情我们希望这项研究将证实去甲肾上腺素能回路在冷漠病因学中的作用 在AD中。如果成功，这项研究也可能对许多其他临床研究产生重要影响。 动机障碍的症状

项目成果

Altered multimodal magnetic resonance parameters of basal nucleus of Meynert in Alzheimer's disease.

• DOI: 10.1002/acn3.51176
• 发表时间: 2020-10
• 期刊: Annals of clinical and translational neurology
• 影响因子: 5.3
• 作者: Zheng W;Li H;Cui B;Liang P;Wu Y;Han X;Li CR;Li K;Wang Z
• 通讯作者: Wang Z

The effects of age on the severity of problem drinking: Mediating effects of positive alcohol expectancy and neural correlates.

年龄对饮酒问题严重程度的影响：正酒精预期和神经相关因素的中介作用。

• DOI: 10.1111/adb.13278
• 发表时间: 2023
• 期刊: Addiction biology
• 影响因子: 3.4
• 作者: Chaudhary,Shefali;Chen,Yu;Zhornitsky,Simon;Le,ThangM;Zhang,Sheng;Chao,HertaH;Dominguez,JacquelineC;Li,Chiang-ShanR
• 通讯作者: Li,Chiang-ShanR

Shared and distinct neural activity during anticipation and outcome of win and loss: A meta-analysis of the monetary incentive delay task.

• DOI: 10.1016/j.neuroimage.2022.119764
• 发表时间: 2022-12-01
• 期刊: NEUROIMAGE
• 影响因子: 5.7
• 作者: Chen, Yu;Chaudhary, Shefali;Li, Chiang-Shan R.
• 通讯作者: Li, Chiang-Shan R.

Age-Related Structural and Functional Changes of the Hippocampus and the Relationship with Inhibitory Control.

• DOI: 10.3390/brainsci10121013
• 发表时间: 2020-12-19
• 期刊: Brain sciences
• 影响因子: 3.3
• 作者: Hu S;Li CR
• 通讯作者: Li CR