Aging Brain, Cognition, and Dopamine

描述(申请人提供)：大脑老化是一个复杂的、多因素的过程，可能涉及b-淀粉样蛋白(Ab)和tau等蛋白质的聚集、脑血管疾病和神经化学功能的改变。虽然许多认知功能减退的老年人可能有与症状前阿尔茨海默病有关的抗体沉积，但事实上，大多数老年人大脑中的抗体很少或根本没有。该项目将专门针对一种非淀粉样蛋白。 与大脑多巴胺系统改变有关的年龄相关性认知衰退。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，并在需要认知控制、定势转移和注意力的任务中表现出来。 我们这个项目的具体目标是：(1)招募年龄在20-85岁之间的健康个体样本；年龄较大的受试者将以前接受过[11C]PIB的正电子发射计算机断层扫描，将没有脑抗体的证据。在这些个体中，我们将使用神经心理学工具表征执行功能，并使用PET示踪剂[18F]flrometatyroine测量脑多巴胺合成能力(2)通过结构磁共振评估局部脑萎缩(3)使用静息状态功能连接性的MR测量来检查大规模脑网络之间的相互作用，以及(4)使用功能磁共振技术研究在集转移任务期间的大脑活动本研究的总体框架是，在衰老过程中，大脑多巴胺的变化会产生损害额纹状体执行功能并产生认知灵活性的适应。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，老年人会出现前额叶皮质和纹状体的区域性萎缩，更严重的萎缩将与多巴胺合成增加和反映执行功能的神经心理测试表现较差有关。现有的数据表明，额顶控制网络(FPCN)参与引导注意到外部或内部刺激，它通过在注意外部刺激时耦合到默认模式网络(DMN)或在注意到外部刺激时耦合到背侧注意网络(DAN)来执行此功能。我们假设，在衰老过程中，更多的多巴胺合成增加了FPCN-DMN偶联，导致在执行功能测试中表现较差，因为无法更新或改变SET对外部刺激的反应。最后，我们提出，在要求受试者将注意力从内部刺激转移到外部刺激的集合转移任务中，老年受试者的表现将受到损害，这将与任务中更高的多巴胺合成、更少的DMN失活、更大的FPCN-DMN耦合以及执行功能测试中更差的表现有关。这些实验将提供一种新的神经系统方法来治疗与年龄相关的认知下降，这对潜在的机制和治疗具有重大意义。

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.