title: Identification of serum biomarkers in brain-injured adults: potential for predicting elevated intracranial pressure.
abstract: Brain injury biomarkers may have clinical utility in stratifying injury severity level, predicting adverse secondary events or outcomes, and monitoring the effectiveness of therapeutic interventions. As a biomarker source, serum offers several advantages over cerebrospinal fluid (CSF), including ease of accessibility and reduced risk to the patient. We screened pooled serum samples obtained from 11 severely injured traumatic brain injury (TBI) patients (Glasgow Coma Scale [GCS] <or= 8) and 11 age-, sex- and race-matched volunteers. Two time points-41.5 +/- 4.9 h and 66.3 +/- 6.6 h post-injury-were chosen for the initial screening analysis. Samples were immunodepleted for 12 highly abundant serum proteins, and then labeled with mass-balanced isobaric tags (iTRAQ), and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Identification and quantification of 2455 iTRAQ-labeled peptides that mapped to 160 proteins revealed 31 candidate biomarkers whose serum abundance was altered after injury. Changes in three candidate biomarkers (serum amyloid A, [SAA], c-reactive protein [CRP], retinol binding protein 4 [RBP4]) were verified using independent TBI and healthy volunteer serum samples. Receiver operating characteristic (ROC) curve analysis of CRP and SAA indicated they were robust indicators of injury even at very acute time points. Analysis of serum RBP4 levels at 24-36 h post-injury indicates it may predict subsequent increases in intracranial pressure (ICP) with a sensitivity of 86% and specificity of 88% at 11.6 mug/mL [n = 7, ICP < 20 mm Hg; n = 8, ICP > 25 mm Hg). Our results support the use of serum as a source for discovery of TBI biomarkers, and indicate that serum biomarkers may have utility for predicting secondary pathologies (e.g., elevated ICP) associated with TBI.
authors.affiliation: Vivian L. Smith Center for Neurologic Research, University of Texas Medical School, Houston, TX, USA.
authors.forename: Georgene
authors.initials: G
authors.lastname: Hergenroeder
authors.forename: John B
authors.initials: JB
authors.lastname: Redell
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Moore
authors.forename: William P
authors.initials: WP
authors.lastname: Dubinsky
authors.forename: Robert T
authors.initials: RT
authors.lastname: Funk
authors.forename: John
authors.initials: J
authors.lastname: Crommett
authors.forename: Guy L
authors.initials: GL
authors.lastname: Clifton
authors.forename: Robert
authors.initials: R
authors.lastname: Levine
authors.forename: Alex
authors.initials: A
authors.lastname: Valadka
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Dash
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D001798:Blood Proteins / Q000032:analysis / Q000378:metabolism; D001930:Brain Injuries / Q000097:blood* / Q000503:physiopathology*; D015536:Down-Regulation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007427:Intracranial Pressure / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D054839:Retinol-Binding Proteins, Plasma / Q000032:analysis / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014357:Trypsin / Q000737:chemistry
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D007202:Indicators and Reagents; C101326:RBP4 protein, human; D054839:Retinol-Binding Proteins, Plasma; D014357:Trypsin