Poor sleep quality predicts plasma markers of neurodegeneration and cognitive deficits in warriors with mild traumatic brain injury

Abstract Introduction Increasing evidence links neurodegeneration to traumatic brain injury (TBI), and a separate body of literature links neurodegeneration to sleep dysfunction, implicating increased toxin production and decreased glymphatic clearance. Sleep disorders affect 50% of TBI patients, yet the sleep-neurodegeneration connection in these patients remains unexplored. We hypothesized that warfighters with TBI and sleep dysfunction would have increased neuronal injury, revealing potential mechanistic underpinnings for TBI outcomes. We measured plasma biomarkers, cognitive function and sleep surveys for correlation analysis. Methods In a retrospective cross-sectional study of warfighters (n=113 chronic mild TBI patients), the Pittsburgh sleep quality index (PSQI) was compared with amyloid β42 (Aβ42), neurofilament light (NFL), tau, and phospho-tau (threonine 181) isolated from plasma and exosomes. Executive function was tested with the categorical fluency test. Exosomes were precipitated from plasma. Proteins were measured with the Single Molecule Array (Quanterix). Linear models were adjusted for age, ApoE, and number of TBIs. Results Poor sleepers with TBI (PSQI>8) had elevated NFL compared to good sleepers in plasma (p=0.007) and exosomes (p=0.00017), and PSQI directly correlated with NFL (plasma: Beta=0.23, p=0.0079; exosomes: Beta=2.19, p=0.0013) stronger than any other marker of neurodegeneration. Poor sleepers also showed higher obstructive sleep apnea (OSA) risk compared to good sleepers by STOP-BANG scores (3.6, SD=1.6 vs 2.8, SD=1.74; p=0.0014) as well as decreased categorical fluency (20.7, SD=4.1) (18.3, SD=4.6, p=.0067). Plasma tau and Aβ42 also correlated with PSQI (Beta=0.64, p=0.028, and Beta=0.40, p=0.049 respectively). Conclusion This is the first reported data correlating markers of neuronal injury and cognitive deficits with sleep complaints and OSA risk in patients with TBI - possibly identifying treatable pathophysiological mediators of TBI neurodegeneration. Limitations include a small sample size, lack of objective sleep measures, and inability to establish directionality due to cross-sectional design. Prospective trials will be required to further explore our proposed hypothesis. If confirmed, these findings would call for targeting sleep disorders in the TBI population to mitigate risk of neurodegeneration. Support This work was supported by grant funding from: Department of Defense, Chronic Effects of Neurotrauma Consortium (CENC) Award W81XWH-13-2-0095 and Department of Veterans Affairs CENC Award I01 CX001135.