Genome-Wide Changes in Peripheral Gene Expression following Sports-Related Concussion

Abstract

We conducted a prospective study to identify genome-wide changes in peripheral gene expression before and after sports-related concussion (SRC). A total of 253 collegiate contact athletes underwent collection of peripheral blood mononuclear cells (PBMCs) before the sport season (baseline). Sixteen athletes who subsequently developed an SRC, along with 16 non-concussed teammate controls, underwent repeat collection of PBMCs within 6 h of injury (acutely). Concussed athletes underwent additional sample collection at 7 days post-injury (sub-acutely). Messenger RNA (mRNA) expression at baseline was compared with mRNA expression acutely and sub-acutely post-SRC. To estimate the contribution of physical exertion to gene changes, baseline samples from athletes who subsequently developed an SRC were compared with samples from uninjured teammate controls collected at the acute time-point. Clinical outcome was determined by changes in post-concussive symptoms, postural stability, and cognition from baseline to the sub-acute time-point. SRC athletes had significant changes in mRNA expression at both the acute and sub-acute time-points. There were no significant expression changes among controls. Acute transcriptional changes centered on interleukins 6 and 12, toll-like receptor 4, and NF-κB. Sub-acute gene expression changes centered on NF-κB, follicle stimulating hormone, chorionic gonadotropin, and protein kinase catalytic subunit. All SRC athletes were clinically back to baseline by Day 7. In conclusion, acute post-SRC transcriptional changes reflect regulation of the innate immune response and the transition to adaptive immunity. By 7 days, transcriptional activity is centered on regulating the hypothalamic-pituitary-adrenal axis. Future efforts to compare expressional changes in fully recovered athletes with those who do not recover from SRC could suggest putative targets for therapeutic intervention.

An investigation of neuroinjury biomarkers after sport-related concussion: from the subacute phase to clinical recovery

“…In view of the latter, injury-induced alterations to hormones produced by both the sympathetic nervous system and hypothalamic-pituitary-adrenal (HPA)-axis can modulate peripheral immune function, altering blood levels of cytokines and chemokines (58)(59)(60). While we did not find differences in blood concentrations of the inflammatory chemokine MCP-1 between concussed and healthy athletes in either the subacute period or at medical clearance, MerchantBorna et al observed that at 7 days after SRC, gene transcription profiles in peripheral blood leukocytes were perturbed, reflecting potential dysregulation of the HPA-axis (25). In addition, we recently demonstrated that acutely elevated levels of peripheral catecholamines after moderate and severe TBI were highly correlated with elevated circulating concentrations of inflammatory cytokines and chemokines (19).…”

“…Indeed, alterations in various circulating indices of brain tissue damage such as glial fibrillary acidic protein (GFAP), s100 calcium-binding protein B (s100B), neuron specific enolase (NSE), αII-spectrin N-terminal fragment (SNTF) (22)(23)(24), and inflammatory genes (25,26) have been observed in the acute and subacute phases after SRC.…”

Systemic Inflammation Persists the First Year after Mild Traumatic Brain Injury: Results from the Prospective Trondheim Mild Traumatic Brain Injury Study

“…8 In sports-related mTBI an immediate activation of the innate immune system (interleukin 6 , IL-12) has been observed with return to baseline after a week. 9 The long-term course of systemic inflammation and type of cytokines present in blood in patients with mTBI has been evaluated sparsely, with one study including 52 patients showing an increase of IL-1b, IL-6, and monocyte chemoattractant protein 1 (MCP-1) over a 3-month period with association of MCP-1 to postconcussion syndrome. 10 Many patients with mild TBI are not admitted to hospitals and are thus possibly underrepresented in clinical studies.…”

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

“…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).…”