A Serum Protein Biomarker Panel Improves Outcome Prediction in Human Traumatic Brain Injury.

Eric Thelin,Fredrik Piehl,Henrik Zetterberg,Harriet Nyström,Bo-Michael Bellander,Kaj Blennow,Faiez Al Nimer,Mikael Svensson,David W Nelson,Arvid Frostell

doi:10.1089/neu.2019.6375

Abstract

Brain-enriched protein biomarkers of tissue fate are being introduced clinically to aid in traumatic brain injury (TBI) management. The aim of this study was to determine how concentrations of six different protein biomarkers, measured in samples collected during the first weeks after TBI, relate to injury severity and outcome. We included neurocritical care TBI patients that were prospectively enrolled from 2007 to 2013, all having one to three blood samples drawn during the first 2 weeks. The biomarkers analyzed were S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), tau, and neurofilament-light (NF-L). Glasgow Outcome Score (GOS) was assessed at 12 months. In total, 172 patients were included. All serum markers were associated with injury severity as classified on computed tomography scans at admission. Almost all biomarkers outperformed other known outcome predictors with higher levels the first 5 days, correlating with unfavorable outcomes, and UCH-L1 (0.260, pseduo-R2) displaying the best discrimination in univariate analyses. After adjusting for acknowledged TBI outcome predictors, GFAP and NF-L added most independent information to predict favorable/unfavorable GOS, improving the model from 0.38 to 0.51 pseudo-R2. A correlation matrix indicated substantial covariance, with the strongest correlation between UCH-L1, GFAP, and tau (r = 0.827–0.880). Additionally, the principal component analysis exhibited clustering of UCH-L1 and tau, as well as GFAP, S100B, and NSE, which was separate from NF-L. In summary, a panel of several different protein biomarkers, all associated with injury severity, with different cellular origin and temporal trajectories, improve outcome prediction models.

Highlights

Traumatic brain injury (TBI) is a devastating disease and one of the most common reasons people are living with acquired disabilities,[1] leading to increasing suffering and societal costs
We aimed to assess the predictive power of a panel of six candidate TBI markers (S100B, neuron-specific enolase (NSE), NF-L, glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), and tau) in serum, both independently and combined, while adjusting for known outcome predictors in a prospective cohort of neurocritical care unit (NCCU) TBI patients
Most patients were unconscious upon admission to the hospital (GCS3–8; 70%)

Summary

Introduction

Traumatic brain injury (TBI) is a devastating disease and one of the most common reasons people are living with acquired disabilities,[1] leading to increasing suffering and societal costs. TBI usually results in a combination of diffuse tissue injuries and a spectrum of focal lesions, as well as a range of subsequent secondary injury responses, making TBI a biologically very complex and heterogenic condition.[2] Analyzing admission parameters have improved outcome prediction in TBI,[3,4] which may provide tools for resource allocation both on the group level, and on individual treatment strategies. Current prediction models is limited and much variance remains unexplained.[5,6]. Serum brain-enriched proteins of tissue fate are increasingly used as biomarkers to manage TBI patients.[7] For example, serum

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