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

Traumatic Brain Injury (TBI) triggers an acute systemic inflammatory response, which may impact outcomes. This response may interact with pre-existing factors linked to inflammation, such as age, to influence outcomes. Previous studies have typically measured few cytokines, but high-dimensional proteomic approaches can sensitively detect a broad range of inflammatory markers, to better characterise post-TBI inflammation. We analysed plasma from BIO-AX-TBI study participants (n = 37 acute moderate-severe TBI (Mayo Criteria), n = 22 acute non-TBI trauma (NTT), n = 28 non-injured controls (CON)) using the Alamar NULISA™ panel (>200 inflammatory markers). The NTT group enabled differentiation of TBI-specific versus general injury-related responses. Inflammatory markers were correlated with plasma NFL, GFAP, total tau, UCH-L1 (Simoa®), S100B (Millipore), and subacute (10 days-6 weeks) 3T MRI measures of lesion volume and white matter injury. Differential expression analysis identified four markers elevated specifically in TBI (VSNL1, IL1RN/IL-1Ra, GFAP, IKBKG), while other derangements reflected non-specific injury responses. Higher VSNL1 correlated with greater lesion volume (r_s = 0.53) and higher IL1RN/IL-1Ra with greater white matter injury (r_s = -0.66, both FDR-adjusted p < 0.05). IL33, part of the non-specific injury response was higher in participants with good (GOS-E 5-8) versus poor (GOS-E 1-4) outcomes (W = 47, FDR-adjusted p = 0.0024). Using an Elastic Net model trained on healthy controls, we show that "inflammation age" exceeded chronological age in TBI, particularly in younger participants. In summary, acute post-TBI inflammation includes both TBI-specific and non-specific components, linked to structural brain injury and functional outcome. Age modulates the inflammatory response. VSNL1, IL1RN/IL-1Ra, and IL33 are potential mediators of post-TBI pathophysiology.