title: Time course of cerebrospinal fluid inflammatory biomarkers and relationship to 6-month neurologic outcome in adult severe traumatic brain injury.
abstract: OBJECTIVE
  Activation of the inflammatory cascade is a known pathophysiologic process in severe traumatic brain injury (TBI) with yet non-standardized scientific data regarding relationship to outcome. The understanding of the time course of expression of cerebrospinal fluid (CSF) biomarker levels following severe TBI is an important step toward using these biomarkers to measure injury severity and/or early response to therapeutic interventions. The objective of the current study is to report the time course and values of a battery of CSF inflammatory biomarkers following severe TBI in our reasonably sized patient cohort.
  
  
  METHODS
  Our patient cohort consists of 32 consented patients, who met the study's inclusion criteria for data collection from 2000 to 2010. The time course and values of a battery of CSF biomarkers (IL-1β, IL-6, TNF-α, IFN-γ, IL-12p70, IL-10, and IL-8) following severe TBI in this patient cohort was characterized. Additionally, the correlation of biomarker concentration with 6-month neurological outcome was assessed. Serial CSF sampling through an external ventricular drain was performed over the first five days following injury. Concentration of a panel of inflammatory biomarkers (IL-1β, IL-6, TNF-α, IFN-γ, IL-12p70, IL-10, and IL-8) were evaluated using Meso Scale Discovery's Multi-Array technology. Glasgow Outcome Scale (GOS) score at six months following injury was dichotomized into poor outcome (GOS 1-3) and favorable outcome (GOS 4-5). Statistical analyses were performed using Kruskal-Wallis test and linear regression analysis.
  
  
  RESULTS
  The result shows that CSF concentrations of inflammatory biomarkers had a significant association with 6-month neurological outcome (p-values≤0.05 for each marker), with the favorable outcome group having lower concentrations of these biomarkers on average, in comparison to the poor neurologic outcome group over the first five days after TBI. All inflammatory biomarkers decreased to normal levels by post-trauma day 5, except for IL-6 and IL-8. Upregulation and increased expression of key inflammatory markers following severe TBI were significant predictors of worse 6-month neurologic outcome. Additionally, post-trauma day 5 concentrations of IL-6 and IL-8 remained elevated over normal CSF values.
  
  
  CONCLUSIONS
  The study shows that inflammatory biomarkers in CSF are potential biomarkers of injury severity and progression and/or recovery; they could prove beneficial in the future assessment of injury severity and response to therapy after severe TBI.
authors.affiliation: Department of Neurosurgery, University of Pittsburgh Medical Center, 200 Lothrop Street, Suite B-400, Pittsburgh, PA 15213, United States. Electronic address: Nwachukuel@upmc.edu.
authors.forename: Enyinna L
authors.initials: EL
authors.lastname: Nwachuku
authors.affiliation: Department of Neurosurgery, University of Pittsburgh Medical Center, 200 Lothrop Street, Suite B-400, Pittsburgh, PA 15213, United States. Electronic address: puccam@upmc.edu.
authors.forename: Ava M
authors.initials: AM
authors.lastname: Puccio
authors.affiliation: Frank H. Netter MD School of Medicine of Quinnipiac University, 300 Bassett Road, MNH-211K North Haven, CT 06473, United States. Electronic address: Adeolu.adeboye@quinnipiac.edu.
authors.forename: Adeolu
authors.initials: A
authors.lastname: Adeboye
authors.affiliation: Department of Neurosurgery, University of Pittsburgh Medical Center, 200 Lothrop Street, Suite B-400, Pittsburgh, PA 15213, United States. Electronic address: Changy@upmc.edu.
authors.forename: Yue-Fang
authors.initials: YF
authors.lastname: Chang
authors.affiliation: Department of Neurosurgery, University of Pittsburgh Medical Center, 200 Lothrop Street, Suite B-400, Pittsburgh, PA 15213, United States. Electronic address: Jinhokim@pitt.edu.
authors.forename: Jinho
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, University of Pittsburgh Medical Center, 200 Lothrop Street, Suite B-400, Pittsburgh, PA 15213, United States. Electronic address: Okonkwodo@upmc.edu.
authors.forename: David O
authors.initials: DO
authors.lastname: Okonkwo
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000134:cerebrospinal fluid; D000070642:Brain Injuries, Traumatic / Q000134:cerebrospinal fluid*; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D015850:Interleukin-6 / Q000134:cerebrospinal fluid*; D016209:Interleukin-8 / Q000134:cerebrospinal fluid*; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011379:Prognosis
chemical_list: D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8
keywords: Biomarkers; Inflammatory cytokines; Neurological outcome; Therapeutic targets; Traumatic brain injury