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

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.

Influence of Blood–Brain Barrier Integrity on Brain Protein Biomarker Clearance in Severe Traumatic Brain Injury: A Longitudinal Prospective Study

“…Even though neither is brain specific, both are highly brain enriched and have been associated with a worse intracranial condition and long-term functional outcome following TBI. [8][9][10] In fact, some centers event utilize one or both in clinical routine work, 11,12 hence making these two ''biomarkers'' of particular interest to the neurotrauma translational research field.…”

Neurofilaments: The C-Reactive Protein of Neurology

“…Being an unspecific marker of neurodegeneration and axonal damage, NF-L is a promising marker of injury in TBI (Table 1). In severe TBI, both CSF and serum NF-L sharply increase over the first 2 weeks compared to healthy controls and appear to be reliable predictors of poor outcome [56][57][58]. Similar predictions may be possible from serum NF-L in mild traumatic injury although care must be taken when patients are over 60 years old or have preexisting neurological disorders [59,60].…”

Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in CADASIL

“…The coefficients of variations for NfL, GFAP, tau and UCHL1 were 5.9%, 5.3%, 16.4%, and 25.7%, respectively, which are consistent with those in a previous study. (19) The lower limits of detection of NfL, GFAP, tau and UCHL1 assays were 0.039, 0.0265, 0.011, and 3.991 pg/mL, respectively, whereas the lower levels of quantification were 0.241, 0.467, 0.053, and 5.45 pg/mL, respectively. Only 63 of 68 CADASIL patients were included in this study because the plasma volume of 1 patient sample was too low for the assay and the remaining 4 samples had considerable interference during the assay due to extremely high fluorescence.…”

“…(16,17) Recently, a panel of ultra-sensitive immunoassays targeting the aforementioned blood-based biomarkers has been developed. (18)(19)(20)(21) It has the advantages of assessing multiple biomarkers at once and comparing their performance based on the clinical interests. We aimed to use this panel to investigate whether these blood-based biomarkers can reflect disease severity, correctly identify stroke event, and predict its incidence in CADASIL patients.…”

“…The blood samples were analyzed through the Neurology 4-Plex assay established by the Simoa platform (Quanterix; Lexington, MA, USA). The assay could quantify the plasma concentrations of NfL, GFAP, tau, and UCHL1simultaneously, and the measurement details are as described previously (18,19). Measurements were performed by board-certified laboratory technicians who were blinded to the clinical groups.…”