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The aim of our study was to investigate the biological underpinnings of persistent post-concussion symptoms (PPCS) at 3 months following mild traumatic brain injury (mTBI). Patients ( n  = 192, age 16-60 years) with mTBI, defined as Glasgow Coma Scale (GCS) score between 13 and 15, loss of consciousness (LOC) <30 min, and post-traumatic amnesia (PTA) <24 h were included. Blood samples were collected at admission (within 72 h), 2 weeks, and 3 months. Concentrations of blood biomarkers associated with central nervous system (CNS) damage (glial fibrillary acidic protein [GFAP], neurofilament light [NFL], and tau) and inflammation (interferon gamma [IFNγ], interleukin [IL]-8, eotaxin, macrophage inflammatory protein-1-beta [MIP]-1β, monocyte chemoattractant protein [MCP]-1, interferon-gamma-inducible protein [IP]-10, IL-17A, IL-9, tumor necrosis factor [TNF], basic fibroblast growth factor [FGF]-basic platelet-derived growth factor [PDGF], and IL-1 receptor antagonist [IL-1ra]) were obtained. Demographic and injury-related factors investigated were age, sex, GCS score, LOC, PTA duration, traumatic intracranial finding on magnetic resonance imaging (MRI; within 72 h), and extracranial injuries. Delta values, that is, time-point differences in biomarker concentrations between 2 weeks minus admission and 3 months minus admission, were also calculated. PPCS was assessed with the British Columbia Post-Concussion Symptom Inventory (BC-PSI). In single variable analyses, longer PTA duration and a higher proportion of intracranial findings on MRI were found in the PPCS group, but no single biomarker differentiated those with PPCS from those without. In multi-variable models, female sex, longer PTA duration, MRI findings, and lower GCS scores were associated with increased risk of PPCS. Inflammation markers, but not GFAP, NFL, or tau, were associated with PPCS. At admission, higher concentrations of IL-8 and IL-9 and lower concentrations of TNF, IL-17a, and MCP-1 were associated with greater likelihood of PPCS; at 2 weeks, higher IL-8 and lower IFNγ were associated with PPCS; at 3 months, higher PDGF was associated with PPCS. Higher delta values of PDGF, IL-17A, and FGF-basic at 2 weeks compared with admission, MCP-1 at 3 months compared with admission, and TNF at 2 weeks and 3 months compared with admission were associated with greater likelihood of PPCS. Higher IL-9 delta values at both time-point comparisons were negatively associated with PPCS. Discriminability of individual CNS-injury and inflammation biomarkers for PPCS was around chance level, whereas the optimal combination of biomarkers yielded areas under the curve (AUCs) between 0.62 and 0.73. We demonstrate a role of biological factors on PPCS, including both positive and negative effects of inflammation biomarkers that differed based on sampling time-point after mTBI. PPCS was associated more with acute inflammatory processes, rather than ongoing inflammation or CNS-injury biomarkers. However, the modest discriminative ability of the models suggests other factors are more important in the development of PPCS.

Innate immune activation has been attributed a key role in traumatic brain injury (TBI) and successive morbidity. In mild TBI (mTBI), however, the extent and persistence of innate immune activation are unknown. We determined plasma cytokine level changes over 12 months after an mTBI in hospitalized and non-hospitalized patients compared with community controls; and examined their associations to injury-related and demographic variables at admission. Prospectively, 207 patients presenting to the emergency department (ED) or general practitioner with clinically confirmed mTBI and 82 matched community controls were included. Plasma samples were obtained at admission, after 2 weeks, 3 months, and 12 months. Cytokine levels were analysed with a 27-plex beads-based immunoassay. Brain magnetic resonance imaging (MRI) was performed on all participants. Twelve cytokines were reliably detected. Plasma levels of interferon gamma (IFN-γ), interleukin 8 (IL-8), eotaxin, macrophage inflammatory protein-1-beta (MIP-1β), monocyte chemoattractant protein 1 (MCP-1), IL-17A, IL-9, tumor necrosis factor (TNF), and basic fibroblast growth factor (FGF-basic) were significantly increased at all time-points in patients compared with controls, whereas IFN-γ-inducing protein 10 (IP-10), platelet-derived growth factor (PDGF), and IL-1ra were not. IL-17A and FGF-basic showed significant increases in patients from admission to follow-up at 3 months, and remained increased at 12 months compared with admission. Interestingly, MRI findings were negatively associated with four cytokines: eotaxin, MIP-1β, IL-9, and IP-10, whereas age was positively associated with nine cytokines: IL-8, eotaxin, MIP-1β, MCP-1, IL-17A, IL-9, TNF, FGF-basic, and IL-1ra. TNF was also increased in those with presence of other injuries. In conclusion, mTBI activated the innate immune system consistently and this is the first study to show that several inflammatory cytokines remain increased for up to 1 year post-injury.