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

基本信息

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
项目类别：
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&apos 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

项目摘要

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，冷漠经常在认知障碍前表现阿尔茨海默氏病（AD）的光谱。持续的冷漠在快速功能下降和显着影响AD个人生活质量。然而，神经生物学机制冷漠仍然不清楚。冷漠反映了兴趣或动机的一般维度，缺乏目标指导行为的努力。越来越多的证据在动机和努力中实现了单胺能电路。最近的评论表明多巴胺主要代码以未来奖励并促进奖励指导的行动，但较少对预期的努力敏感。另一方面，努力与加剧的唤醒紧密相关，并与丘脑和前额叶皮层的广泛项目，基因座（LC）可能起着关键作用维持积极进取的行为。这项探索性研究旨在检验这一假设并区分去甲肾上腺素能的作用（NA）和多巴胺能（DA）电路的动机行为以及NA和DA功能障碍如何构成与健康相比 controls.controce，特别是LC是一个很小的结构，很难与常规结构进行定位成像。在先前的研究的基础上，我们利用了LC中的高神经苯胺含量和腹侧段区域/底底NIGRA，PARS CMPSTA（VTA/SNC），并成功开发了一个 LC和VTA/SNC在个人空间中的概率图。通过让参与者参与fMRI 奖励任务我们将询问NA和DA电路如何应对时机，努力的行为以获得奖励和行为结果。我们假设有MCI和早期广告的人将证明 LC中神经丙烷信号对比的降低，LC电路活性和连接性降低至支持动机行为与冷漠的临床严重程度有关。我们建议在30例MCI和AD早期患者以及30岁和性别的患者中检验这一假设匹配的健康对照参与者（HC），有两个特定的目的：1）检查LC和/或VTA/SNC是否与HC相比神经素蛋白对比的减少与冷漠有关。 2）fMRI检查是否LC和/或 VTA/SNC对奖励预期和结果以及LC/VTA-SNC前额叶皮质连通性的响应与HC相比，患有MCI和AD的参与者减少了；以及这些更改是否相关冷漠。我们希望这项研究能够证实去甲肾上腺素电路在冷漠的病因中的作用在广告中。如果成功，该研究也可能对许多其他临床研究具有重要意义暗示动机功能障碍的条件。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.