Aging Brain, Cognition, and Dopamine

描述（由申请人提供）：脑老化是一个复杂的多因素过程，可能涉及蛋白质（如b-淀粉样蛋白（Ab）和tau蛋白）聚集、脑血管疾病和神经化学功能改变。虽然许多认知能力下降的老年人可能有与症状前阿尔茨海默病相关的Ab沉积，但事实上，大多数老年人的大脑中几乎没有或没有Ab。这个项目将专门针对非淀粉样蛋白形式 与年龄相关的认知能力下降，这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。执行功能障碍是一种常见的衰老标志，与额纹状体萎缩相关，并表现在需要认知控制、设置转换和注意力的任务中。 本项目的具体目标是：（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既往接受过[11 C]PIB PET扫描，并且没有脑Ab的证据。在这些个体中，我们将使用神经心理学仪器表征执行功能，并使用PET示踪剂[18F]氟代酪氨酸测量脑多巴胺合成能力（2）使用结构MRI评估局部脑萎缩（3）使用静息状态功能连接的MR测量检查大规模脑网络之间的相互作用（4）使用fMRI研究一组期间的脑活动-转移任务指导这项研究的总体框架是，大脑多巴胺在衰老过程中的变化产生了损害额-纹状体执行功能并产生认知能力的适应性。我们 假设衰老与多巴胺合成增加有关，导致“过度补偿”，破坏认知。我们认为，老年人会表现出前额皮质和纹状体的区域性萎缩，并且更大的萎缩将与更高的多巴胺合成和反映执行功能的神经心理学测试的表现较差有关。现有的数据表明，正常青年人的额顶叶控制网络（FPCN）参与将注意力引导到外部或内部刺激，它通过耦合到默认模式网络（DMN）在内部处理或背侧注意网络（DAN）在注意外部刺激。我们假设，在老龄化，更多的多巴胺合成增加FPCN-DMN耦合，导致执行功能测试的性能较差，因为无法更新或改变设置响应外部刺激。最后，我们提出，在一个集转移任务，要求受试者转移注意力从内部到外部刺激，将受损的老年受试者，这将与更高的多巴胺合成，减少DMN失活的任务，更大的FPCN-DMN耦合，和执行功能测试性能较差。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，对潜在机制和治疗具有重要意义。

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.