Aging Brain, Cognition, and Dopamine

大脑老化、认知和多巴胺

基本信息

批准号：
8932645
负责人：
William J. Jagust
金额：
$ 70.63万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8932645
关键词：
Address Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease Amyloid Amyloid deposition Applications Grants Atrophic Attention Behavior Behavioral Biological Markers Biological Neural Networks Brain Cerebrovascular Disorders Cognition Cognitive Complex Corpus striatum structure Coupling Data Deposition Dopamine Dorsal Episodic memory Etiology Executive Dysfunction Functional Magnetic Resonance Imaging Health Impaired cognition Individual Label Laboratories Lead Link Magnetic Resonance Imaging Measures Mediating Memory Neuropsychological Tests Outcome Pathologic Processes Pathology Pattern Performance Pittsburgh Compound-B Positron-Emission Tomography Prefrontal Cortex Process Recruitment Activity Research Resources Rest Sampling Stimulus Stress Structure System Temporal Lobe Testing Tracer Update age related aging brain amyloid imaging amyloid pathology base behavior measurement brain volume cerebral atrophy cognitive control cognitive function cognitive process cognitive system cohort directed attention dopamine system executive function expectation flexibility instrument interest mild cognitive impairment neurochemistry neuropsychological pre-clinical protein aggregation relating to nervous system research study response tau Proteins

项目摘要

DESCRIPTION (provided by applicant): Brain aging is a complex, multifactorial process that can involve aggregation of proteins such as b-amyloid (Ab) and tau, cerebrovascular disease, and alterations in neurochemical function. While many older people with cognitive decline may have Ab deposition related to presymptomatic Alzheimer's disease, in fact the majority of older people have little or no Ab in the brain. This project will specifically address a non-amyloid form of age- related cognitive decline that is associated with alterations in the brain's dopamine system. Dopamine is involved in frontal-striatal systems required for executive function. Executive dysfunction is a frequent hallmark of aging that is associated with fronto-striatal atrophy and which is manifest in tasks that require cognitive control, set-shifting, and attention. Our specific aims for this project are: (1) To recruit a sample of healthy individuals spanning ages 20-85; older subjects will have previously undergone PET scanning with [11C]PIB and will have no evidence of brain Ab. In these individuals we will characterize executive function with neuropsychological instruments and measure brain dopamine synthesis capacity using the PET tracer [18F]flurometatyrosine (2) To assess regional brain atrophy with structural MRI (3) To examine the interactions between large scale brain networks using MR measures of resting state functional connectivity and (4) To study brain activity using fMRI during a set-shifting task The overall framework guiding this study is that alterations in brain dopamine in aging produce adaptations that impair frontal-striatal executive function and produce cognitive inflexibility. We hypothesize that aging is associated with increased dopamine synthesis, resulting in "overcompensation" that disrupts cognition. We propose that older people will show regional atrophy in prefrontal cortex and striatum, and that greater atrophy will be associated with higher dopamine synthesis and poorer performance on neuropsychological tests reflecting executive function. Existing data in normal young people show that a frontoparietal control network (FPCN) is involved in directing attention to external or internal stimuli, and that it performs thi function by coupling to the default mode network (DMN) during internal processing or the dorsal attention network (DAN) during attention to external stimuli. We hypothesize that in aging, greater dopamine synthesis increases FPCN-DMN coupling, resulting in poorer performance on tests of executive function because of an inability to update or shift set in response to external stimuli. Finally, we propose that performance during a set-shifting task, requiring subjects to shift attention from internal to external stimuli, will be impaired in older subjects, and that thi will be associated with higher dopamine synthesis, reduced DMN deactivation during the task, greater FPCN-DMN coupling, and poorer performance on tests of executive function. These experiments will provide a new, neural systems approach to age-related cognitive decline that has major implications for underlying mechanisms and therapy.

描述（由申请人提供）：大脑衰老是一个复杂的多因素过程，可以涉及蛋白质（例如B-淀粉样蛋白（AB）和TAU），脑血管疾病以及神经化学功能的改变。尽管许多认知下降的老年人可能患有与预症状的阿尔茨海默氏病有关的AB沉积，但实际上，大多数老年人在大脑中几乎没有AB。该项目将专门解决非淀粉样式与大脑多巴胺系统改变有关的年龄相关认知下降。多巴胺参与执行功能所需的额叶系统。执行功能障碍是衰老的常见标志，与额叶萎缩有关，并且在需要认知控制，设定转移和注意力的任务中表现出来。我们对该项目的具体目标是：（1）招募跨越20-85岁的健康个体的样本；较老的受试者以前将使用[11C] PIB进行PET扫描，并且没有脑AB的证据。在这些人中，我们将使用PET示踪剂[18F] Flurometatyrosine（2）来表征执行功能，并用神经心理学工具来测量脑多巴胺合成能力，以评估与结构MRI（3）的区域脑萎缩（3）相互作用，以检查大规模脑网络使用MR进行静止型脑连接性和（4）在for the in seting ins intervient in a for f i f i for f m的相互作用（4）衰老中脑多巴胺的改变会导致损害额叶执行功能并产生认知僵化的适应性。我们假设衰老与多巴胺合成的增加有关，从而导致“过度补偿”破坏了认知。我们建议老年人将在前额叶皮层和纹状体中表现出区域性萎缩，并且在反映执行功能的神经心理学测试中，更大的萎缩将与较高的多巴胺合成和较差的性能相关。普通年轻人的现有数据表明，额心控制网络（FPCN）参与了将注意力引向外部或内部刺激，并且在内部处理期间或在注意力刺激期间，它通过与默认模式网络（DMN）耦合来执行功能。我们假设在衰老中，更多的多巴胺合成会增加FPCN-DMN耦合，导致执行功能测试的性能较差，因为无法响应外部刺激而更新或换档。最后，我们建议在固定转移任务期间的表现，要求受试者将注意力从内部刺激转移到外部刺激，将在较旧的受试者中受损，并且THI将与多巴胺合成较高的合成，降低DMN在任务，更大的FPCN-DMN coupling和较差的执行功能测试方面降低DMN。这些实验将为与年龄相关的认知下降提供一种新的神经系统方法，对基本机制和治疗具有重大影响。