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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD048162-04
Application #
7260510
Study Section
Special Emphasis Panel (ZHD1-DSR-R (25))
Program Officer
Nitkin, Ralph M
Project Start
2004-09-24
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$352,012
Indirect Cost
Name
University of Pittsburgh
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Markos, Steven M; Failla, Michelle D; Ritter, Anne C et al. (2017) Genetic Variation in the Vesicular Monoamine Transporter: Preliminary Associations With Cognitive Outcomes After Severe Traumatic Brain Injury. J Head Trauma Rehabil 32:E24-E34
Myrga, John M; Juengst, Shannon B; Failla, Michelle D et al. (2016) COMT and ANKK1 Genetics Interact With Depression to Influence Behavior Following Severe TBI: An Initial Assessment. Neurorehabil Neural Repair 30:920-930
Failla, Michelle D; Juengst, Shannon B; Graham, Kristin M et al. (2016) Effects of Depression and Antidepressant Use on Cognitive Deficits and Functional Cognition Following Severe Traumatic Brain Injury. J Head Trauma Rehabil 31:E62-E73
Myrga, John M; Failla, Michelle D; Ricker, Joseph H et al. (2016) A Dopamine Pathway Gene Risk Score for Cognitive Recovery Following Traumatic Brain Injury: Methodological Considerations, Preliminary Findings, and Interactions With Sex. J Head Trauma Rehabil 31:E15-29
Failla, Michelle D; Conley, Yvette P; Wagner, Amy K (2016) Brain-Derived Neurotrophic Factor (BDNF) in Traumatic Brain Injury-Related Mortality: Interrelationships Between Genetics and Acute Systemic and Central Nervous System BDNF Profiles. Neurorehabil Neural Repair 30:83-93
Ritter, Anne C; Kammerer, Candace M; Brooks, Maria M et al. (2016) Genetic variation in neuronal glutamate transport genes and associations with posttraumatic seizure. Epilepsia 57:984-93
Failla, Michelle D; Juengst, Shannon B; Arenth, Patricia M et al. (2016) Preliminary Associations Between Brain-Derived Neurotrophic Factor, Memory Impairment, Functional Cognition, and Depressive Symptoms Following Severe TBI. Neurorehabil Neural Repair 30:419-30
Failla, Michelle D; Kumar, Raj G; Peitzman, Andrew B et al. (2015) Variation in the BDNF gene interacts with age to predict mortality in a prospective, longitudinal cohort with severe TBI. Neurorehabil Neural Repair 29:234-46
Diamond, Matthew L; Ritter, Anne C; Jackson, Edwin K et al. (2015) Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development. Epilepsia 56:1198-206
Failla, Michelle D; Myrga, John M; Ricker, Joseph H et al. (2015) Posttraumatic Brain Injury Cognitive Performance Is Moderated by Variation Within ANKK1 and DRD2 Genes. J Head Trauma Rehabil 30:E54-66

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