Aging Brain, Cognition, and Dopamine

大脑老化、认知和多巴胺

基本信息

批准号：
8577973
负责人：
William J. Jagust
金额：
$ 72.63万
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8577973
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 Functional Magnetic Resonance Imaging Functional disorder 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 system cohort directed attention dopamine system executive function expectation flexibility instrument interest mild cognitive impairment neurochemistry neuropsychological pre-clinical protein aggregation public health relevance 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，可能涉及 b-淀粉样蛋白 (Ab) 和 tau 等蛋白质的聚集、脑血管疾病以及神经化学功能的改变。虽然许多认知能力下降的老年人可能存在与阿尔茨海默病症状前相关的抗体沉积，但事实上，大多数老年人的大脑中很少或根本没有抗体。该项目将专门解决非淀粉样蛋白形式与年龄相关的认知能力下降与大脑多巴胺系统的改变有关。多巴胺参与执行功能所需的额叶纹状体系统。执行功能障碍是衰老的常见标志，与额纹状体萎缩有关，并且在需要认知控制、转移和注意力的任务中表现得很明显。我们这个项目的具体目标是：（1）招募20-85岁的健康个体样本；老年受试者之前曾接受过 [11C]PIB PET 扫描，并且没有脑抗体的证据。我们将使用神经心理学仪器表征这些个体的执行功能，并使用 PET 示踪剂 [18F]氟偏酪氨酸测量大脑多巴胺合成能力 (2) 使用结构 MRI 评估区域脑萎缩 (3) 使用 MR 检查大规模脑网络之间的相互作用(4) 在设定转换任务期间使用功能磁共振成像研究大脑活动指导这项研究的总体框架是，衰老过程中大脑多巴胺的变化会产生损害适应性的适应。额叶纹状体执行功能并产生认知僵化。我们假设衰老与多巴胺合成增加有关，导致“过度补偿”，从而扰乱认知。我们认为，老年人的前额皮质和纹状体会出现区域性萎缩，而更大的萎缩与多巴胺合成较高和反映执行功能的神经心理学测试表现较差有关。正常年轻人的现有数据表明，额顶控制网络（FPCN）参与将注意力引导到外部或内部刺激，并且它通过在内部处理过程中与默认模式网络（DMN）或背侧注意网络耦合来执行此功能（DAN）在注意外部刺激时。我们假设，在衰老过程中，更多的多巴胺合成会增加 FPCN-DMN 耦合，导致执行功能测试中的表现较差，因为无法响应外部刺激来更新或改变设置。最后，我们提出，在设定转移任务中，要求受试者将注意力从内部刺激转移到外部刺激，老年受试者的表现会受到损害，这与更高的多巴胺合成、任务期间 DMN 失活减少、更大的多巴胺合成有关。 FPCN-DMN耦合，执行功能测试表现较差。这些实验将为与年龄相关的认知衰退提供一种新的神经系统方法，这对潜在机制和治疗具有重大影响。