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、以证据为基础的干预措施，以补救与正常衰老相关的认知衰退。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，在老年人中受到不同程度的损害。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。Curren的提议旨在定义多巴胺功能改变影响认知灵活性的可能机制：前额叶皮质和纹状体之间的通讯中断。我将在年轻人和老年人中采用受试者内多模式成像方法，其中将包括纹状体内源性多巴胺功能的测量(使用正电子发射断层扫描放射示踪剂6-[18F]氟-L-m-酪氨酸)、纹状体内萎缩的结构测量(使用结构磁共振成像)，以及前额叶皮质和纹状体之间的功能网络测量(使用功能磁共振分析在静止和任务切换期间的连接性)。我们的初步研究表明，综合能力的FMT指标随着年龄的增长而增加。老年人的多巴胺合成增加可能反映了对系统萎缩和其他功能衰退(例如，多巴胺受体和转运体下调)的补偿。然而，合成能力的增强与认知障碍有关，这表明补偿要么不够，要么意味着有害的过度补偿。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。我提议的研究将检验以下假设：(1)更大的认知灵活性将与更大的纹状体体积相关，但这种影响将通过FMT-PET测量的多巴胺功能来调节；(2)老年人在安静时测得的前额叶皮质-纹状体功能连接强度将降低，但多巴胺功能将解释这些年龄差异；(3)与年轻人相比，老年人在任务转换过程中表现出更少的额叶皮质-纹状体功能连接，连接差异将中介多巴胺对认知灵活性的影响。总之，拟议的实验将有助于建立一个模型，确定与年龄相关的结构性萎缩如何导致多巴胺能失调，进而扰乱功能网络活动，导致认知缺陷。这一研究领域很有希望通过最终临床应用于与年龄相关的认知下降以及与多巴胺能功能障碍相关的疾病，如精神分裂症，来影响公共健康。我提议的研究将为我作为一名专注于翻译的多学科研究人员的发展提供不可或缺的培训。在与William Jagust博士一起接受培训期间，我将在PET成像和认知老化研究方面获得宝贵的经验，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提供的丰富学术资源。

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.