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

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.

A Moderate Blast Exposure Results in Dysregulated Gene Network Activity Related to Cell Death, Survival, Structure, and Metabolism

“…The NF-κB pathway has been implicated in the regulation of proinflammatory cytokines during meningitis (51) and in bloodbrain barrier permeability (52). Moreover, the NF-κB pathway has been found to be dysregulated in clinical studies of acute and subacute TBI (7)(8)(9)(10). Upregulation of AKT1 in this sample suggests activation of the NF-κB pathway; a finding that supports these prior studies, although the specific role of AKT1 in blast effects on the central nervous system remains to be examined.…”

“…Differential gene expression is reported in a small number of clinical TBI studies (7)(8)(9)(10), with few studies relevant to blast TBI (11)(12)(13). Gene expression regulation is imperative to appropriate cellular response to external mechanical, environmental, or biological stimuli, and the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) complex is a main transcription factor of these adaptive gene expression changes (14).…”

“…Within clinical studies of TBI, changes in the NF-κB network are reported in a limited number of studies (7)(8)(9)(10); however, they have not yet been examined in biTBI. Preclinical studies of blast exposures have demonstrated altered gene expression, including cognitive impairment (20,21) and immune function (22).…”

Smoking affects gene expression in blood of patients with ischemic stroke

“…GPR15 and LRRN3 have DNA methylation loci in their promoter regions that are reported to be hypomethylated among smokers which might indicate smoking‐induced epigenetic changes . LRRN3 is an inflammatory regulatory gene related to T‐cell function and immunosenescence whose expression declines with age and smoking, perhaps resulting in a dysregulated immune system prior to and after stroke. Claudin domain‐containing 1 (CLDND1), also known as claudin‐25, plays a role in the development of cerebrovascular disease in stroke‐prone spontaneously hypertensive rats .…”

Identification of Methylated Gene Biomarkers in Patients with Alzheimer’s Disease Based on Machine Learning

“…The expression of TGF-β is up-regulated in brain tissue [61], while down-regulated in the serum of patients with AD [62]. NOG belongs to the transforming growth factor-β superfamily and is associated with neurorecovery and neuroregeneration [63]. Bonaguidi et al and Yousef et al found that NOG signaling changes with age and involved in the age-related neurological impairments and reductions in neuroregeneration [64,65].…”