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.

摘要/摘要 作为最常见的症状之一，冷漠常在认知障碍之前表现出来 阿尔茨海默病(AD)的谱系。持续的冷漠在快速的功能衰退和 严重影响阿尔茨海默病患者的生活质量。然而，潜在的神经生物学机制 人们的冷漠态度仍不明朗。 冷漠反映了兴趣或动机的普遍减弱，即在目标导向的行为上缺乏努力。 越来越多的证据表明，单胺类神经回路与动机和努力有关。最近的一篇评论 这表明多巴胺主要编码未来的奖赏，并促进奖赏导向的行动，但 对预期的努力很敏感。另一方面，努力与更高的唤醒密切相关， 蓝斑(LC)广泛投射到丘脑和前额叶皮质，可能起着关键作用。 在维持有动力和努力的行为方面。 这项探索性研究旨在检验这一假说，并区分去甲肾上腺素能 动机行为中的(NA)和多巴胺(DA)环路以及NA和DA功能障碍可能的基础 轻度认知障碍(MCI)和早期阿尔茨海默病(AD)患者与健康人的冷漠 控制。具体地说，LC是一个非常小的结构，很难用传统的结构进行局部化 成像。在先前研究的基础上，我们利用了LC中高神经黑色素含量的优势 和腹侧被盖区/黑质、致密部(VTA/SNC)，并成功地发展了 个体自然空间中LC和VTA/SNC的概率图。通过让参与者参与 奖赏任务我们将询问NA和DA回路如何对计时的努力行为做出反应以获得奖赏 以及行为结果。我们假设患有MCI和早期AD的个体将会表现出 LC中神经黑素信号对比度的降低以及LC回路活动和与 支持动机行为与临床冷漠的严重程度相关。 我们建议在30名MCI和早期AD患者以及30名年龄和性别的患者中检验这一假设 匹配的健康对照参与者(HC)，有两个特定目的：1)检查LC和/或VTA/SNC 与HC相比，MCI和AD患者的神经黑色素信号强度降低，以及 神经黑色素对比度的降低与冷漠有关；2)用功能磁共振检查LC和/或 VTA/SNC对奖励预期和结果的反应以及LC/VTA-SNC前额叶皮质连接 与HC相比，患有MCI和AD的参与者减少了；以及这些变化是否相关 带着冷漠。我们希望这项研究将证实去甲肾上腺素能回路在冷漠的病因中的作用。 在公元后。如果成功，这项研究也可能对许多其他临床研究具有重要意义 导致动机障碍的情况。

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