0045 Diurnal Biomarker Dynamics After Sleep Loss Across Plasma, TEV, and NEV Compartments in Adults with and without mTBI

Abstract Introduction Traumatic brain injury (TBI) has been linked to alterations in neuroinflammatory signaling, synaptic function, glymphatic, and circadian regulatory pathways. Because sleep supports metabolic and glymphatic clearance, sleep loss may amplify neuronal and inflammatory stress signals. Diurnal biomarker patterns across plasma and extracellular vesicle (EV) compartments remain poorly defined. This study examined evening (post–sleep loss, PSL) and morning (post–recovery sleep, PRS) biomarker profiles, with exploratory evaluation of whether mild TBI (mTBI) history modulates these dynamics. Methods Twenty-five adults (mean age 40.3 ± 8.3 years; 9 with mTBI) completed an unsupervised at-home sleep-loss protocol. Blood collected after PSL (PM) and PRS (AM) was analyzed for TNF-α, IL-17, amyloid-β42, and α-synuclein in plasma and EV fractions using MSD platforms. EV subtype analyses quantified total EVs (TEVs), neuron-enriched EVs (NEVs), and NEV:TEV ratios. Diurnal changes, cross-compartment correlations, and exploratory TBI group differences were evaluated using ANOVA, paired comparisons, and regression models. Results TNF-α and Aβ42 were significantly higher in PM than AM, consistent with increased inflammatory drive or reduced evening clearance after sleep disruption. IL-17 and α-synuclein showed clear PM/AM reductions, with α-synuclein demonstrating the largest shift, suggesting partial overnight normalization potentially linked to restored clearance. Plasma–EV correlations were positive across analytes; TNF-α and Aβ42 maintained strong cross-compartment alignment, whereas IL-17 and α-synuclein correlations weakened in the morning. Individuals with mTBI exhibited moderately higher concentrations and larger diurnal changes, but overall temporal patterns were similar across groups. TEVs were dramatically more abundant than NEVs across all conditions, and NEVs represented a small, stable proportion of total EVs (~3–4%) with slight PM elevations. Neither TEV nor NEV concentrations showed meaningful diurnal or TBI-related differences. Conclusion Sleep loss disrupts diurnal inflammatory and neuronal biomarker rhythms, potentially reflecting altered clearance processes, while EV subtype proportions remain stable. Combined plasma and EV profiling offers a scalable framework for identifying physiological stress signatures across both mTBI and non-mTBI populations. Support (if any) Funded by CDMRP Award HU00012020057. The opinions and assertions expressed herein are those of the author(s) and do not reflect the official policy or position of the Uniformed Services University or the Department of War.