Dopaminergic modulation of networks mediating cognitive flexibility in older adul

描述（由申请人提供）：拟议研究的长期目标是开发有效的、基于证据的干预措施，以纠正与正常衰老相关的认知能力下降。认知灵活性是执行功能的一个组成部分，允许在任务之间动态切换，老年人的认知灵活性受损程度不同。大脑的多巴胺系统与认知灵活性有关，该系统的功能随着年龄的增长而下降。目前的建议旨在确定多巴胺功能改变影响认知灵活性的可能机制：前额皮质和纹状体之间的通信中断。我将在年轻人和老年人中采用受试者内部多模态成像方法，包括纹状体中多巴胺功能的内源测量（使用正电子发射断层扫描（PET）放射性示踪剂6-[18F]氟- l -m-酪氨酸（FMT）），纹状体中萎缩的结构测量（使用结构磁共振成像（MRI）），以及前额皮质和纹状体之间的功能网络测量（在休息和任务切换期间使用功能性MRI连接分析）。我们的初步研究表明，FMT的综合能力随年龄的增长而增加。老年人多巴胺合成增加可能反映了对系统萎缩和其他功能下降（如多巴胺受体和转运蛋白下调）的补偿。然而，合成能力的增加与认知障碍有关，这表明补偿要么不够，要么表明有害的过度补偿。目前的实验是制定未来治疗干预措施的必要的第一步，因为它们将确定与年龄相关的多巴胺合成增加的功能意义。我提出的研究将检验以下假设：(1)更大的认知灵活性与更大的纹状体体积有关，但这种影响将由FMT-PET测量的多巴胺功能介导；(2)老年人在休息时测量的前额叶皮层-纹状体功能连通性强度降低，但多巴胺功能可以解释这些年龄差异；(3)老年人在任务转换过程中相对于年轻人表现出更少的前额叶皮层-纹状体功能连通性。这种连通性差异调节了多巴胺对认知灵活性的影响。总之，这些实验将有助于建立一个模型，确定与年龄相关的结构萎缩如何导致多巴胺能失调，而多巴胺能失调反过来又破坏功能性网络活动，导致认知缺陷。这一研究领域对影响公众健康有着巨大的希望，通过最终临床应用于与年龄相关的认知能力下降，以及与多巴胺能功能障碍相关的疾病，如精神分裂症。我提出的研究将为我提供培训，使我成为一名专注于翻译的多学科研究人员。在接受William Jagust博士的培训期间，我将获得PET成像和认知衰老研究方面的宝贵经验，并将利用劳伦斯伯克利国家实验室和加州大学伯克利分校丰富的学术资源。

DESCRIPTION (provided by applicant): The long-range goal of the proposed research is to develop effective, evidenced-based interventions for remediating cognitive decline associated with normal aging. Cognitive flexibility, a component of executive function that allows dynamic switching between tasks, is differentially impaired in older adults. The brain's dopamine system has been linked to cognitive flexibility, and function of this system declines with age. The curren proposal aims to define a possible mechanism by which altered dopamine function influences cognitive flexibility: disrupted communication between prefrontal cortex and striatum. I will employ a within-subjects multimodal imaging approach in young and older adults that will include endogenous measures of dopamine function in striatum (using positron emission tomography (PET) radiotracer 6-[18F]fluoro-L-m-tyrosine (FMT)), structural measures of atrophy within striatum (using structural magnetic resonance imaging (MRI)), and functional network measures between prefrontal cortex and striatum (using functional MRI connectivity analyses at rest and during task-switching). Our preliminary research indicates FMT measures of synthesis capacity increase with age. Increased dopamine synthesis in older adults may reflect compensation to counteract atrophy and other functional declines in the system (e.g. dopamine receptor and transporter downregulation). However, increased synthesis capacity is associated with disrupted cognition, suggesting compensation is either not sufficient or indicates detrimental overcompensation. The current experiments are a necessary first step in prescribing future therapeutic interventions, as they will define the functional significance of age-related increases in dopamine synthesis. My proposed research will test the following hypotheses: (1) Greater cognitive flexibility will be related to greater striatal volume, but this effect will be mediated by dopamine function as measured by FMT-PET, (2) Older adults will have decreased prefrontal cortex-striatal functional connectivity strength measured at rest, but that dopamine function will account for these age differences, and (3) Older adults will show less prefrontal cortex-striatal functional connectivity during task switching relative to young adults, and that connectivity differences mediate the effect of dopamine on cognitive flexibility. Together, the proposed experiments will contribute to a model establishing how age-related structural atrophy leads to dopaminergic dysregulation, which, in turn, disrupts functional network activity to cause cognitive deficits. This research area holds great promise for impacting public health, through eventual clinical applications for age-related cognitive decline as well as disorders associated with dopaminergic dysfunction such as schizophrenia. My proposed research will provide me with training integral to my development as a translationally-focused, multidisciplinary researcher. I will gain valuable experience in PET imaging and in cognitive aging research during my training with Dr. William Jagust, and will take advantage of the rich academic resources available through Lawrence Berkeley National Laboratory and UC Berkeley.