Poor Sleep Quality is Linked to Elevated Extracellular Vesicle-Associated Inflammatory Cytokines in Warfighters With Chronic Mild Traumatic Brain Injuries

Abstract

Background: Elevations of inflammatory cytokine levels occur immediately after mild traumatic brain injury (mTBI) and can persist for years. These elevations have been associated with neuropsychological outcomes, including depression and PTSD symptoms. Sleep disorders, another common sequelae of mTBI, are independently associated with inflammation in otherwise healthy individuals. However, whether sleep and inflammation are linked in chronic mTBI has not been reported.Methods: A retrospective cross-sectional cohort of warfighters was used to investigate the hypothesis that inflammation may be linked to sleep quality in chronic mTBI. Clinical history, peripheral blood samples, and sleep quality scores were collected from 182 warfighters (n = 138 mTBI; n = 44 controls) during enrollment in the Chronic Effects of Neurotrauma Consortium study. Biomarkers of inflammation (IL-6, IL-10, TNFα cytokines) from plasma and plasma-derived extracellular vesicles (EVs) were quantified using single molecule array. Relationships between sleep quality and cytokine levels were assessed, controlling for age, sex, and BMI. Using clinical cutoff scores for sleep quality, mTBI patients were then divided into “good” and “poor” sleepers and cytokine levels compared between groups.Results: In mTBI participants, sleep quality was significantly associated with EV levels of IL-10 [ß (SE) = 0.11 (0.04), p = 0.01] and TNFα [ß (SE) = 0.07 (0.03), p < 0.01]. When divided according to “good” versus “poor” sleepers, those reporting poor sleep had significantly elevated EV IL-10 compared to those reporting good sleep [ß (SE) = 0.12 (0.04), p < 0.01]. Plasma-derived associations were not significant. No associations were found between sleep quality and cytokine levels in controls.Conclusion: These results suggest a significant relationship between sleep quality and chronic inflammation in mTBI patients. Clinically, mTBI patients with a high likelihood of sleep disorders demonstrate elevated levels of inflammatory cytokines. Signal from EVs, though smaller in magnitude, may have stronger clinical associations than from plasma. Sleep-focused interventions may also serve to regulate chronic inflammatory processes in these patients. Larger prospective studies are needed to investigate the mechanisms and therapeutic implications of the likely bi-directional relationship between sleep and inflammation following mTBI.

Elevated Serum Tau and UCHL-1 Concentrations Within 12 Months of Injury Predict Neurobehavioral Functioning 2 or More Years Following Traumatic Brain Injury: A Longitudinal Study

“…These findings extend previous cross-sectional research by demonstrating that serum biomarkers associated with the presence of current neurobehavioral dysfunction (eg, postconcussion symptoms, depression, sleep problems, and cognition6–16) may also be associated with neurobehavioral functioning in the chronic phase of recovery. In addition, these findings extend previous longitudinal research by demonstrating an association between elevated serum tau and UCHL-1 within the first 12 months of injury, with the prediction of neurobehavioral status 2 or more years following a TBI.…”

“…T HE ROLE OF BLOOD-BASED biomarkers has received considerable attention in the literature as possible diagnostic and prognostic indicators following traumatic brain injury (TBI) in the acute and postacute period of recovery. To date, the majority of the literature is cross-sectional in design and has focused on establishing the association between protein biomarkers (such as serum tau, neurofilament light chain [NFL], glial fibrillary acidic protein [GFAP], and ubiquitin carboxyl-terminal hydrolase L1 [UCHL-1]) with the presence/absence of TBI, TBI severity, neuroimaging, mortality rates, and disability severity ratings following moderate to severe TBI, [1][2][3][4][5] in addition to more subtle neurobehavioral outcomes commonly associated with the sequelae of mild TBI (eg, postconcussion, anxiety, depression, sleep, and cognition [6][7][8][9][10][11][12][13][14][15][16] ). In other diseases, including cognitive impairments related to dementia, these same protein biomarkers show risk over time for cognitive declines, indicating that there may be a similar link within individuals following TBI.…”

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

“…Indeed plasma-derived EVs from warfighters display increased levels of cytokines like IL-10, which positively correlated to poor sleep quality in TBI patients. 295 Thus, a detailed investigation is needed to delineate further the mechanisms involved in EV-mediated effects on neuroinflammation in TBI.…”

“…It has been shown that the microglia undergo necroptosis in TBI, resulting in expanded patient inflammatory profiles. − Though a direct correlation between EVs and the neuroinflammatory cascade in TBI is underexplored, a correlation is suggestive, given the immunomodulatory roles of EVs. Indeed plasma-derived EVs from warfighters display increased levels of cytokines like IL-10, which positively correlated to poor sleep quality in TBI patients . Thus, a detailed investigation is needed to delineate further the mechanisms involved in EV-mediated effects on neuroinflammation in TBI.…”

Neurological Symptoms and Their Associations With Inflammatory Biomarkers in the Chronic Phase Following Traumatic Brain Injuries

“…Furthermore, another study found that sleep can modify immune system functions by inducing changes in the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system (63). In addition to the aforementioned studies based on non-TBI population, Gottshall et al also investigated the association between sleep quality and cytokines (IL-10, IL-6, and TNF-α) in the plasma and plasma-derived extracellular vesicles (EVs) in chronic mTBI (64). Same to the current study, they also found that plasma IL-6 was positively correlated with sleep quality; however, this association was absent in their study after adjusting for the effect of age, sex, and BMI.…”