Military Personnel with Chronic Symptoms Following Blast Traumatic Brain Injury Have Differential Expression of Neuronal Recovery and Epidermal Growth Factor Receptor Genes

Abstract

Objective: Approximately one-quarter of military personnel who deployed to combat stations sustained one or more blast-related, closed-head injuries. Blast injuries result from the detonation of an explosive device. The mechanisms associated with blast exposure that give rise to traumatic brain injury (TBI), and place military personnel at high risk for chronic symptoms of post-concussive disorder (PCD), post-traumatic stress disorder (PTSD), and depression are not elucidated.Methods: To investigate the mechanisms of persistent blast-related symptoms, we examined expression profiles of transcripts across the genome to determine the role of gene activity in chronic symptoms following blast-TBI. Active duty military personnel with (1) a medical record of a blast-TBI that occurred during deployment (n = 19) were compared to control participants without TBI (n = 17). Controls were matched to cases on demographic factors including age, gender, and race, and also in diagnoses of sleep disturbance, and symptoms of PTSD and depression. Due to the high number of PCD symptoms in the TBI+ group, we did not match on this variable. Using expression profiles of transcripts in microarray platform in peripheral samples of whole blood, significantly differentially expressed gene lists were generated. Statistical threshold is based on criteria of 1.5 magnitude fold-change (up or down) and p-values with multiple test correction (false discovery rate <0.05).Results: There were 34 transcripts in 29 genes that were differentially regulated in blast-TBI participants compared to controls. Up-regulated genes included epithelial cell transforming sequence and zinc finger proteins, which are necessary for astrocyte differentiation following injury. Tensin-1, which has been implicated in neuronal recovery in pre-clinical TBI models, was down-regulated in blast-TBI participants. Protein ubiquitination genes, such as epidermal growth factor receptor, were also down-regulated and identified as the central regulators in the gene network determined by interaction pathway analysis.Conclusion: In this study, we identified a gene-expression pathway of delayed neuronal recovery in military personnel a blast-TBI and chronic symptoms. Future work is needed to determine if therapeutic agents that regulate these pathways may provide novel treatments for chronic blast-TBI-related symptoms.

A decade from discovery to therapy: Lingo-1, the dark horse in neurological and psychiatric disorders

“…This is supported by a finding of a 6 Mb deletion at 12p13.3 in 2 patients presenting with attention deficit hyperactivity disorder (one of whom resided in a psychiatric center) encompassing around 50 genes including WNK1 (Madrigal et al, 2012). Differential expression of gene transcripts has been found in military personnel suffering from traumatic brain injury from blast exposure, who also suffer from post-traumatic stress disorder and depression (Heinzelmann et al, 2014). WNK1 was found to be among the genes found to be significantly upregulated in these military personnel compared to controls, further implicating WNK1 in a wider scope of psychiatric disorders.…”

“…Moreover, the EGFR/PI3-K/Akt signaling pathway has also been implicated in autism, post-traumatic and psychosocial stress disorders, as well as depression through a number of genetic and neurobiological studies. EGFR gene regulation was found to be significantly upregulated in the same cohort of military personnel suffering blast traumatic brain injury, post-traumatic stress disorder and depression as those who also had an upregulation of WNK1 (Heinzelmann et al, 2014).…”

Neuronal DNA Methylation Profiling of Blast-Related Traumatic Brain Injury

“…Of note, the Aanat gene showed a 1.2 fold 51 Similar fold changes have been reported with gene expression changes associated with blast in human samples. 52 The Aanat gene encodes aralkylamine Nacetyltransferase and also is known as serotonin N-acetyltransferase. This enzyme is involved in the conversion of serotonin to the circadian hormone melatonin.…”

National Institutes of Health Symptom Science Model sheds light on patient symptoms

“…Gill and her team have recently undertaken studies utilizing gene-expression analyses to understand the comorbid symptoms that have been previously identified in studies of deployed military personnel, including insomnia, PTSD, and depression (Hoge, McGurk et al, 2008; Luxton, Greenburg, et al, 2011), as well as TBI and related neurological symptoms (Heinzelmann, et al, 2014). An example of this line of research is a study by Dr. Gill’s team that used whole genome expression to identify genes that were altered in activity in military personnel with chronic TBI related symptoms.…”