Dopamine Genetic Variants Modulating Recovery After TBI

描述（由申请人提供）：创伤性脑损伤（TBI）导致认知、行为、情感和身体功能障碍。中皮层多巴胺（DA）和皮层下DA系统被认为与工作记忆和执行认知功能（包括目标导向行为，认知活动的启动和动机，以及新的和应用的学习策略）密切相关。我们实验室越来越多的证据表明，DA神经传递的黑质-纹状体-皮质改变在实验TBI后长期发生，并且可能受到性别和治疗干预的影响。 TBI后DA系统在人类中改变的证据主要基于使用DA激动剂（包括多巴胺转运蛋白（DAT）抑制剂哌甲酯（MPD））治疗可以有益于减轻认知缺陷的报道。然而，有证据表明，对MPD或其他DA激动剂的治疗反应是可变的，使得关于这些药物在治疗与TBI相关的后遗症中的使用和有效性的一般性建议变得困难。迄今为止，很少有工作集中在哪些因素可能影响这些药物在TBI中的治疗效果。科学文献已经确定了许多DA能候选基因的变体与一系列认知和精神疾病相关，包括注意缺陷多动障碍（ADHD），抑郁症，冲动和帕金森病（PD）。许多这些疾病和症状与TBI相关的缺陷重叠。 我们实验室正在进行的工作表明，DAT 1基因的遗传变异在严重TBI后介导DA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，很少有工作集中在DA候选基因多态性可能与TBI在其影响的病理生理学，结果，或治疗干预的疗效。该提案的目标是调查潜在相关的DA能候选基因是否影响中度至重度TBI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）TBI对DAT/D2结合和动力学的影响以及DAT/D2基因型在介导受体结合潜在差异中的作用。2)纹状体DAT/D2结合与TBI后认知功能障碍的关系3）DAT/D2基因型在MPD治疗对工作记忆（WM）和执行功能（EF）的疗效中的作用。该提案的长期目标是了解Daergic遗传变异在影响TBI后DA神经传递和结果中的作用。通过神经成像，我们希望更好地了解遗传学如何影响可能受益于相关康复药物治疗策略的人。

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.