Systemic inflammation and its associations in acute moderate-severe Traumatic Brain Injury: a cross-sectional study

ABSTRACT Traumatic Brain Injury (TBI) triggers an acute systemic inflammatory response, which may contribute to poor long-term outcomes. Additionally, pre-existing factors associated with increased inflammation, such as age, may interact with this acute post-TBI inflammation to influence outcomes. Previous investigations of post-TBI inflammation have typically assessed small numbers of cytokines, but novel high-dimensional proteomic approaches can sensitively detect a broad range of inflammatory markers and more fully characterise post-TBI inflammation. We analysed plasma from 84 participants in the BIO-AX-TBI cohort [ n =37 acute, moderate– severe TBI (Mayo Criteria), n =22 acute non-TBI trauma (NTT), n =28 non-injured controls (CON)] on the Alamar NULISA™ Inflammation panel, assessing >200 inflammatory markers. The NTT group allowed differentiation of TBI-specific from general injury-related acute inflammatory responses. Inflammatory markers were correlated with plasma levels of NFL (neurofilament light), GFAP, total tau, UCH-L1 (all Simoa®) and S100B (Millipore); and subacute (10 days to 6 weeks post-injury) 3T MRI measures of lesion volume and white matter injury (fractional anisotropy). Differential expression analysis identified 4 markers showing TBI-specific elevations in plasma levels (VSNL1, IL1RN/IL-1Ra, GFAP, IKBKG), whilst derangements in other inflammatory markers likely reflected a non-specific injury response. Higher VSNL1 levels were associated with greater lesion volume (r s =0.53), and higher IL1RN/IL-1Ra levels were associated with more white matter injury (r s =-0.66, both FDR-adjusted p<0.05). The non-specific injury response was associated with functional outcome at 6-months – higher IL33 levels in those with good (Glasgow Outcome Scale-Extended, GOS-E, 5-8) versus poor (GOS-E 1-4) outcomes (W=47, FDR-corrected p=0.0024). To assess age-related effects, we calculated “inflammation age” by applying an Elastic Net model trained on a public healthy control dataset. The “age gap” (“inflammation age” minus calendar age) was greater in TBI than CON, and also greater in young participants. In summary, the acute post-TBI inflammatory response is comprised of both TBI-specific and non-specific injury components. These inflammatory responses are associated with structural brain injury measures and overall functional outcome. We additionally find that age influences the acute inflammatory response. Our study highlights VSNL1, IL1RN/IL-1Ra and IL33 as potential inflammatory mediators of post-TBI pathophysiology.