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Association of Biomarkers of Neuronal Injury and Inflammation With Insomnia Trajectories After Traumatic Brain
J Kent Werner1, Jennifer Albrecht1, Vincent F Capaldi1
1From the Department of Neurology (J.K.W.); Center for Neuroscience and Regenerative Medicine (J.K.W.), Uniformed Services University; Sleep Disorders Center (J.K.W., J.C.), Department of Medicine, Walter Reed National Military Medical Center, Bethesda; Department of Epidemiology and Public Health (J.A.), University of Maryland School of Medicine, Baltimore; Center for Military Psychiatry and Neuroscience (V.F.C., S.G.W.), Walter Reed Army Institute of Research, Silver Spring; Department of Medicine (V.F.C., J.C.), Uniformed Services University of the Health Sciences, Bethesda, MD; Biostatistics Research Center (V.F.C., S.G.W.), Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego; Department of Radiology (S.J., X.S.), School of Medicine, University of California San Francisco; Department of Medicine (P.M.), Alexander T. Augusta Military Medical Center, Fort Belvoir, VA; Department of Psychiatry (S.G.W.), Uniformed Services University of the Health Sciences, Bethesda, MD; Department of Neurology (R.D.-A.), University of Pennsylvania Perelman School of Medicine, Philadelphia; Brain and Spinal Injury Center (G.T.M.); Department of Neurosurgery (G.T.M.); Department of Psychiatry and Behavioral Sciences (A.D.K.); Weill Institute for Neurosciences (A.D.K.), University of California, San Francisco; Sleep Disorders Center (E.W.), Division of Pulmonary and Critical Care Medicine, Department of Medicine; and Department of Psychiatry (E.W.), University of Maryland School of Medicine, Baltimore.
Background And Objectives:
Insomnia affects about one-third of patients with traumatic brain injury and is associated with worsened outcomes after injury. We hypothesized that higher levels of plasma neuroinflammation biomarkers at the time of TBI would be associated with worse 12-month insomnia trajectories.
Methods:
Participants were prospectively enrolled from 18 level-1 trauma centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study from February 26, 2014, to August 8, 2018. Plasma glial fibrillary acidic protein (GFAP), high-sensitivity C-reactive protein (hsCRP), S100b, neuron-specific enolase (NSE), and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) were collected on days 1 (D1) and 14 (D14) after TBI. The insomnia severity index was collected at 2 weeks, 3, 6, and 12 months postinjury. Participants were classified into insomnia trajectory classes based on a latent class model. We assessed the association of biomarkers with insomnia trajectories, controlling for medical and psychological comorbidities and demographics.
Results:
Two thousand twenty-two individuals with TBI were studied. Elevations in D1 hsCRP were associated with persistent insomnia (severe, odds ratio [OR] = 1.33 [1.11, 1.59], p = 0.002; mild, OR = 1.10 [1.02, 1.19], p = 0.011). Similarly, D14 hsCRP elevations were associated with persistent insomnia (severe, OR = 1.27 [1.02, 1.59], p = 0.03). Of interest, D1 GFAP was lower in persistent severe insomnia (median [Q1, Q3]: 154 [19, 445] pg/mL) compared with resolving mild (491 [154, 1,423], p < 0.001) and persistent mild (344 [79, 1,287], p < 0.001). D14 GFAP was similarly lower in persistent (11.8 [6.4, 19.4], p = 0.001) and resolving (13.9 [10.3, 20.7], p = 0.011) severe insomnia compared with resolving mild (20.6 [12.4, 39.6]. Accordingly, increases in D1 GFAP were associated with reduced likelihood of having persistent severe (OR = 0.76 [95% CI 0.63-0.92], p = 0.004) and persistent mild (OR = 0.88 [0.81, 0.96], p = 0.003) compared with mild resolving insomnia. No differences were found with other biomarkers.
Discussion:
Elevated plasma hsCRP and, surprisingly, lower GFAP were associated with adverse insomnia trajectories after TBI. Results support future prospective studies to examine their utility in guiding insomnia care after TBI. Further work is needed to explore potential mechanistic connections between GFAP levels and the adverse insomnia trajectories.
