Traumatic brain injury (TBI) is a leading cause of death and disability in children under age, and over five million Americans live with a TBI-related disability. Cognitive deficits, particularly in the domains of memory and attention, are the major source of distress and disability in TBI survivors. However factors influencing cognitive outcome are poorly understood. Specific genetic profiles may contribute in important ways to response to neurotrauma and cognitive outcomes. The neuropathology of TBI, and the neurochemistry of memory and attention suggest that genes that modulate cholinergic and catecholaminergic function, and systems important to neural repair and plasticity are attractive candidate genes. We hypothesize individuals with alleles that reduce central catecholaminergic/cholinergic tone, and that reduce neuronal repair/plasticity will show greater cognitive deficits one month after injury and less improvement in cognitive function one year after injury than those with alternate alleles. We further hypothesize that genotype will influence cerebral activation patterns in response to cognitive challenge tasks. Specifically individuals with alleles that reduce central catecholaminergic/cholinergic tone will show reduced activation in memory and attention network circuitry and this reduced activation will correlate with poorer cognitive performance. 250 consecutive individuals with TBI admitted to two trauma centers will undergo genotyping for an ensemble of 13 candidate alleles impacting on central catecholaminergic/ cholinergic tone and neuronal repair/plasticity. All participants will undergo a standardized neurocognitive assessment one month and one year after injury. A randomly selected subgroup of participants will also undergo fMRI while performing memory, attention, and frontal-executive tasks. A multivariate analysis of co-variance will be used to determine the effects of single and multiple candidate alleles on cognitive function one month after injury and the degree of improvement one year after injury, fMRI will be used to characterize the neural mechanisms underlying the influence of genotype on cerebral activation. This study will yield important information on the genetic underpinnings of cognitive deficits following TBI. Understanding of the genetic factors underlying cognitive outcomes will allow the development of truly individualized pharmacological treatment regimens designed to ameliorate the devastating cognitive sequelae of an enormous public health problem. ? ? ?
Showing the most recent 10 out of 15 publications
