Elevated Serum Ubiquitin Carboxy-Terminal Hydrolase L1 Is Associated with Abnormal Blood–Brain Barrier Function after Traumatic Brain Injury

Abstract

Serum S100B elevations accurately reflect blood-brain barrier (BBB) damage. Because S100B is also present in peripheral tissues, release of this protein may not be specific to central nervous system (CNS) injury. Ubiquitin C-terminal hydrolase 1 (UCHL1), and phosphorylated neurofilament heavy chain (pNF-H) are found exclusively in neurons, but their relationship to BBB dysfunction has not been determined. The objective of this study was to determine the accuracy of serum UCHL1 and pNF-H as measures of BBB integrity after traumatic brain injury (TBI), to and compare them to S100B. We performed a prospective study of 16 patients with moderate to severe TBI (Glasgow Coma Scale [GCS] score ≤12) and 6 patients with non-traumatic headache who had cerebrospinal fluid (CSF) collected by ventriculostomy or lumbar puncture (LP). Serum and CSF were collected at the time of LP for headache patients and at 12, 24, and 48 h after injury for TBI patients. BBB function was determined by calculating albumin quotients (Q(A)), where Q(A)=[albumin(CSF)]/[albumin(serum)]. S100B, UCHL1, and pNF-H were measured by enzyme-linked immunosorbent assay (ELISA). Pearson's correlation coefficient and area under the receiver operator characteristic (ROC) curve were used to determine relationships between serum markers and Q(A). At 12 hours after TBI, a significant relationship was found between Q(A) and serum UCHL1 concentrations (AUC=0.76; 95% CI 0.55,1.00), and between Q(A) and serum S100B concentrations (AUC=0.794; 95% CI 0.57,1.02). There was no significant relationship found between these markers and Q(A) at other time points, or between pNF-H and Q(A) at any time point. We conclude that serum concentrations of UCHL1 are associated with abnormal BBB status 12 h after moderate to severe TBI. This relationship is similar to that observed between serum S100B and Q(A,) despite the fact that S100B may be released from peripheral tissues after multi-trauma. We conclude that peripheral release of S100B after multi-trauma is probably negligible and that UCHL1 may have some utility to monitor BBB disruption following TBI.

Expression of ovine ubiquitin C-terminal hydroxylase 1, pH and colour of variety meats from head-stunned Dohne Merino sheep

“…Moreover, differences in heritability traits and adaptive response to traumatic brain injury or painful stimuli (hyperalgesia) could play some roles in these results (Arnaoutakis et al, 2011;George et al, 2011). In contrast, Blyth et al (2011) related the elevated level of UCH-L1 mRNA expression to incidence of traumatic brain injury due to abnormal blood-brain barrier function. According to Gottschalk & Smith (2001), the capacity of opioids to bind to signal receptors in the central nervous system could affect the descending pain pathway in the brain and spinal cord.This phenomenon might support the reason that ewes manisfested low pain expression and high bio-impedance than lambs.…”

“…UCH-L1 is highly expressed throughout the central and peripheral nervous systems, but only in tracal quantities in the large intestine, kidney, ovary, and testis (Orr et al, 2011). This marker is involved in protein binding, proteasome-mediated ubiquitination, sensory pain perception, maintenance of the axonal integrity, axon target recognition, neuroendocrine cell protection, proteolysis, neuromuscular process, muscle fibre development, and traumatic brain injury (Papa et al, 2010;Blyth et al, 2011;Wilson et al, 2016). Therefore, the ubiquitin system plays significant roles in the regulation of many cellular and biological processes.…”

Novel Strategies for Discovery, Validation and FDA Approval of Biomarkers for Acute and Chronic Brain Injury

“…A strong correlation between CSF and serum median concentrations and biokinetics, especially during the acute period, and relationships with clinical outcome were observed (Brophy et al 2011). Furthermore, a recent study reported that serum concentrations of UCHL1 were associated with abnormal blood brain barrier (BBB) permeability, suggesting that UCH-L1 might be used to monitor BBB disruption in patients with TBI (Blyth et al 2011). …”

Time-Dependent Changes in Serum Level of Protein Biomarkers after Focal Traumatic Brain Injury

“…It is much dependent on collecting time following trauma and increased serum S100B levels have been found in other conditions and S100B can be of extracranial origin [45,46]. Elevated serum levels of S100B have been shown to correlate with BBB dysfunction albeit but not at late post-injury time point [40,47].…”