Older Age Results in Differential Gene Expression after Mild Traumatic Brain Injury and Is Linked to Imaging Differences at Acute Follow-up.

Young-Eun Cho,Chen Lai,Jessica Gill,Dan Wang,L Christine Turtzo,Ann Cashion,Whitney S Livingston,Christiana Martin,Hyungsuk Kim,Lawrence L Latour,Anlys Olivera

doi:10.3389/fnagi.2016.00168

Abstract

Older age consistently relates to a lesser ability to fully recover from a traumatic brain injury (TBI); however, there is limited data to explicate the nature of age-related risks. This study was undertaken to determine the relationship of age on gene-activity following a TBI, and how this biomarker relates to changes in neuroimaging findings. A young group (between the ages of 19 and 35 years), and an old group (between the ages of 60 and 89 years) were compared on global gene-activity within 48 h following a TBI, and then at follow-up within 1-week. At each time-point, gene expression profiles, and imaging findings from both magnetic resonance imaging (MRI) and computed tomography were obtained and compared. The young group was found to have greater gene expression of inflammatory regulatory genes at 48 h and 1-week in genes such as basic leucine zipper transcription factor 2 (BACH2), leucine-rich repeat neuronal 3 (LRRN3), and lymphoid enhancer-binding factor 1 (LEF1) compared to the old group. In the old group, there was increased activity in genes within S100 family, including calcium binding protein P (S100P) and S100 calcium binding protein A8 (S100A8), which previous studies have linked to poor recovery from TBI. The old group also had reduced activity of the noggin (NOG) gene, which is a member of the transforming growth factor-β superfamily and is linked to neurorecovery and neuroregeneration compared to the young group. We link these gene expression findings that were validated to neuroimaging, reporting that in the old group with a MRI finding of TBI-related damage, there was a lesser likelihood to then have a negative MRI finding at follow-up compared to the young group. Together, these data indicate that age impacts gene activity following a TBI, and suggest that this differential activity related to immune regulation and neurorecovery contributes to a lesser likelihood of neuronal recovery in older patients as indicated through neuroimaging.

Highlights

Traumatic brain injuries (TBIs) occur in about 5% of individuals over 60 years of age, and place them at a far greater risk for morbidity and mortality following traumatic brain injury (TBI) compared to younger cohorts (Ghorbani et al, 2014)
At 48 h post-TBI, we found 56 transcripts annotated to 42 genes that were significantly upregulated in the young group, which include: leucine-rich repeat neuronal 3 (LRRN3), NOG, and tumor necrosis factor receptor superfamily, member 17 (TNFRSF17; Table 3)
At 1-week postTBI, we found 48 transcripts annotated to 28 genes that were significantly upregulated in the young group, including 19 genes that were upregulated at the 48 h time period (67.86%; Table 3)

Summary

INTRODUCTION

Traumatic brain injuries (TBIs) occur in about 5% of individuals over 60 years of age, and place them at a far greater risk for morbidity and mortality following TBI compared to younger cohorts (Ghorbani et al, 2014). Previous studies suggest that peripheral blood gene expression changes relate to TBIs. In the only known study to examine the impact of age in relation to TBI recovery and role of genetic predisposition, polymorphisms in brain-derived neurotrophic factor interacted with age following severe TBI and related to mortality risk (Failla et al, 2015); genefunction was not determined. In the only known study to examine the impact of age in relation to TBI recovery and role of genetic predisposition, polymorphisms in brain-derived neurotrophic factor interacted with age following severe TBI and related to mortality risk (Failla et al, 2015); genefunction was not determined These studies did not explicate the association between gene expression and tissue recovery evidenced in imaging scans, and even fewer studies compare processes in young and old patients, thereby limiting our ability to develop improved diagnostics, therapeutic screenings, and interventions for older patients with TBI (Mellergard et al, 2012). Total scores can range from 0 to 88, with 88 being the most severe (Vanderploeg et al, 2015)

MATERIALS AND METHODS

RESULTS

DISCUSSION