Dopamine Genetic Variants Modulating Recovery After TBI

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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.