Genetic Influences on Outcome Following Traumatic Brain Injury

Abstract

Several genes have been implicated as influencing the outcome following traumatic brain injury (TBI). Currently the most extensively studied gene has been APOE. APOE can influence overall and rehabilitation outcome, coma recovery, risk of posttraumatic seizures, as well as cognitive and behavioral functions following TBI. Pathologically, APOE is associated with increased amyloid deposition, amyloid angiopathy, larger intracranial hematomas and more severe contusional injury. The proposed mechanism by which APOE affects the clinicopathological consequences of TBI is multifactorial and includes amyloid deposition, disruption of cytoskeletal stability, cholinergic dysfunction, oxidative stress, neuroprotection and central nervous system plasticity in response to injury. Other putative genes have been less extensively studied and require replication of the clinical findings. The COMT and DRD2 genes may influence dopamine dependent cognitive processes such as executive/frontal lobe functions. Inflammation which is a prominent component in the pathophysiological cascade initiated by TBI, is in part is mediated by the interleukin genes, while apoptosis that occurs as a consequence of TBI may be modulated by polymorphisms of the p53 gene. The ACE gene may affect TBI outcome via mechanisms of cerebral blood flow and/or autoregulation and the CACNA1A gene may exert an influence via the calcium channel and its effect on delayed cerebral edema. Although several potential genes that may influence outcome following TBI have been identified, future investigations are needed to validate these genetic studies and identify new genes that might influence outcome following TBI.

Impact of traumatic brain injury on dopaminergic transmission

“…Alterations in gene transcription for pathways related to DA transmission after TBI have also been reported. 41,42 For DA neurotransmission, variants linked to DA D2 receptor (DRD2) and ankyrin repeat and kinase domain (ANKK1) genes were found in some individuals with different cognitive recoveries following TBI. Therefore, genetic variation in DRD2 and influences on post-TBI DA transmission may have important implications for cognitive recovery after TBI.…”

Call for an Integrative and Multi-Disciplinary Approach to Traumatic Brain Injury (TBI)

“…With accurate and early assessment of TBI, intervention programs can be initiated to reduce the risk of postconcussive syndrome. Further, genetic screening for alleles that are known to be associated with poor outcomes following TBI (APOE4, BCL2, COMT, and DRD2) should be performed to identify those at greater risk and initiate prevention programs (Diaz-Arrastia & Baxter, 2006;Jordan, 2007). c) Lack of inclusion of racial and ethnic minorities.…”

Mitochondrial DNA and traumatic brain injury

“…Understanding the variability in response to injury between individuals promises to be key to advances in clinical management. Existing studies have demonstrated detrimental outcome associated with the apolipoprotein E ε4 allele,1 and there is evidence for allele‐specific differences in outcome for other genes, including catechol‐o‐methyltransferase ( COMT ), dopamine D2 receptor ( DRD2 ), phosphoprotein p53 ( TP53 ), and the calcium channel alpha‐1 subunit ( CACNA1 ) 2. The mitochondrial genome has received little attention, despite mitochondria playing a central role in the pathophysiology of TBI.…”