021 Poor sleep quality in traumatic brain injury patients is associated with elevated inflammatory biomarkers

Introduction Mild traumatic brain injury (mTBI) and sleep disorders are independently associated with inflammation. Following mTBI, elevated levels of cytokines, such as interleukin-6 (IL-6), 10 (IL-10) and tumor necrosis factor alpha (TNFα), have been observed. These signals are also known to modulate sleep homeostasis. IL-6, IL-10 and TNFα concentrations are typically measured in plasma, but recent work has shown that their measurement in extracellular vesicles (EVs) may hold additional value, as they are shielded from degradation and may be more biologically relevant. We hypothesized that inflammatory biomarkers in chronic mTBI patients would be elevated in poor sleepers. Methods In a cross-sectional cohort of warfighters (n=137 mTBI, 44 controls), the Pittsburgh Sleep Quality Index (PSQI) was compared with EV and plasma IL-6, IL-10, TNFα. Protein quantification was performed with Simoa. Two-tailed tests were used with a type I error of p=10, a published military cutoff) had elevated IL-6 vs. good sleepers (mean [SD] pg/mL, EV: 0.47 [0.63] vs 1.01 [1.54], p=0.04, d=0.44; plasma: 5.00 [13.31] vs 6.88 [13.51], p=0.03, d=0.14). Poor sleepers with mTBI had less EV IL-10 (1.71 [8.18] vs 0.30 [0.54], p=0.017). Comparisons of plasma IL-10 were not significant. No differences in TNFα were observed in mTBI groups. In our model, PSQI was the strongest predictor of EV IL-6 (βstd=0.27, p=0.03) in mTBI patients, whereas only BMI predicted IL-6 in controls. EV IL-6, IL-10, and TNFα correlated with PSQI (R=0.21, p=0.019; R=0.21, p=0.014; R=0.22, p=0.013, respectively), but these relationships were not found with plasma. In controls, no correlations or differences in any biomarker were observed between groups. Conclusion Warfighters who report poor sleep had significantly elevated inflammatory biomarkers after chronic mTBI. Cytokine levels in EVs had greater effect sizes between groups compared to plasma levels suggesting EV measurements may have improved signal. Poor sleep and its association with inflammatory cytokines after mTBI may have therapeutic implications. Support (if any) DoD: Contract W91YTZ-13-C-0015/ HT0014-19-C-0004 with VHA Central Office VA TBI Model Systems Program of Research/DHA Contracting Office (CO-NCR) HT0014