Dopamine Genetic Variants Modulating Recovery After TBI

描述(申请人提供)：创伤性脑损伤(TBI)导致认知、行为、情绪和身体功能障碍。中脑皮层多巴胺(DA)和皮质下DA系统被认为与工作记忆、执行认知功能(包括目标定向行为、认知活动的启动和动机以及新的和应用学习的策略)密切相关。来自我们实验室的越来越多的证据表明，在实验脑损伤后，DA神经传递中的黑质-纹状体-皮质改变是慢性的，可以受到性别和治疗干预的影响。有证据表明，脑损伤后人类的DA系统发生了变化，这主要是基于有报道称，使用DA激动剂，包括多巴胺转运体(DAT)抑制剂哌醋甲酯(MPD)，可以有益于减轻认知障碍。然而，有证据表明，对MPD或其他DA激动剂的治疗反应是不同的，这使得关于这些药物在治疗与脑外伤相关的后遗症方面的使用和疗效的一般性建议变得困难。到目前为止，很少有研究集中于哪些因素可能会影响这些药物在脑外伤中的治疗效果。科学文献已经确定了一些DAR候选基因的变体与一系列认知和精神疾病有关，包括注意力缺陷多动障碍(ADHD)、抑郁症、冲动性和帕金森病(PD)。其中许多疾病和症状与脑损伤相关的缺陷重叠。我们实验室正在进行的工作表明，DAT1基因的遗传变异在严重脑外伤后介导DAR能神经毒性中发挥关键作用，并可能与后来的结果有关。然而，很少有工作关注DA候选基因的多态如何与脑外伤相关，以及它们对病理生理学、结果或治疗干预效果的影响。这项建议的目的是调查潜在相关的DAR候选基因是否会影响中度到重度脑外伤患者的认知和行为结果。此外，我们将使用PET成像技术来研究1)脑损伤对DAT/D2结合的影响和动力学，以及DAT/D2基因在调节受体结合电位差异中的作用。2)纹状体DAT/D2结合与脑损伤后认知功能障碍的关系；3)DAT/D2基因在MPD治疗对工作记忆(WM)和执行功能(EF)影响中的作用。这项建议的长期目标是了解DAIR基因变异在影响脑外伤后DA神经传递和预后中的作用。通过神经成像，我们希望更好地了解遗传学如何影响谁可能受益于相关的基于康复的药物治疗策略。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) results in the disturbance of cognitive, behavioral, emotional, and physical functioning. The mesocortical dopamine (DA) & subcortical DA systems are thought to be critically involved with working memory, & executive cognitive functioning including goal directed behaviors, initiation & motivation for cognitive activities, & strategies for new & applied learning. Growing evidence from our laboratory suggests nigro-striatal-cortical alterations in DA neurotransmission occur chronically after experiment TBI & can be affected by gender & treatment interventions. Evidence that DA systems are altered in humans following TBI is largely based on reports that treatment with DA agonists, including the dopamine transporter (DAT) inhibitor, methylphenidate (MPD), can be beneficial in attenuating cognitive deficits. However, evidence suggests that treatment response to MPD or other DA agonists is variable, making generalizeable recommendations about the use & efficacy of these drugs in treating the sequelae associated with TBI difficult. Little work to date has focused on what factors might influence the therapeutic efficacy of these drugs in TBI. The scientific literature has identified variants for a number of DAergic candidate genes as being associated with a range of cognitive & psychiatric conditions, including Attention Deficit Hyperactivity Disorder (ADHD), depression, impulsivity & Parkinson's Disease (PD). Many of these diseases & symptoms overlap with deficits associated with TBI. Ongoing work from our laboratory suggests that genetic variants for the DAT1 gene, play a key role in mediating DAergic neurotoxicity after severe TBI, & may be linked to later outcome. However, little work has focused on how polymorphisms for DA candidate genes may be relevant to TBI intheir affects on pathophysiology, outcome, or efficacy of treatment interventions. The goal of this proposal is to investigate whether potentially relevant DAergic candidate genes influence cognitive & behavioral outcomes for persons with moderate to severe TBI. Additionally, we will use PET imaging techniques to investigate 1) the effects of TBI on DAT/D2 binding & kinetics & the role of DAT/D2 genotype in mediating potential differences in receptor binding. 2) the relationship between striatal DAT/D2 binding & cognitive deficits post-TBI 3) the role of DAT/D2 genotype in mediating the efficacy of MPD treatment on working memory (WM) & executive function (EF). The long-term goal of this proposal is to understand the role of Daergic genetic variants in affecting DA neurotransmission & outcome after TBI. Through neurolmaging, we hope to better understand how genetics Influences who may benefit from a relevant rehabilitation-based pharmacological treatment strategy.