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.
The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of most watersoluble molecules over 500 Da, is often disrupted after trauma.Post-traumatic BBB disruption may have important implications for prognosis and therapy.Assessment of BBB status is not routine in clinical practice because available techniques are invasive.The gold-standard measure, the cerebrospinal fluide (CSF)-serum albumin quotient (Q A ), requires the measurement of albumin in CSF and serum collected contemporaneously.Accurate, less invasive techniques are necessary.The objective of this study was to evaluate the relationship between Q A and serum concentrations of monomeric transthyretin (TTR) or S100B.Nine subjects with severe traumatic brain injury (TBI; Glasgow Coma Scale [GCS] score 8) and 11 subjects with non-traumatic headache who had CSF collected by ventriculostomy or lumbar puncture (LP) were enrolled.Serum and CSF were collected at the time of LP for headache subjects and at 12, 24, and 48 h after ventriculostomy for TBI subjects.The Q A was calculated for all time points at which paired CSF and serum samples were available.Serum S100B and TTR levels were also measured.Pearson's correlation coefficient and area under the receiver operating characteristic (ROC) curve were used to determine the relationship between the serum proteins and Q A .Seven TBI subjects had abnormal Q A 's indicating BBB dysfunction.The remaining TBI and control subjects had normal BBB function.No significant relationship between TTR and Q A was found.A statistically significant linear correlation between serum S100B and Q A was present (r ¼ 0.432, p ¼ 0.02).ROC analysis demonstrated a significant relationship between Q A and serum S100B concentrations at 12 h after TBI (AUC ¼ 0.800; SE 0.147, 95% CI 0.511-1.089).Using an S100B concentration cutoff of 0.027 ng=ml, specificity for abnormal Q A was 90% or higher at each time point.We conclude that serum S100B concentrations accurately indicate BBB dysfunction at 12 h after TBI.
The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of most water-soluble molecules over 500 Da, is often disrupted after trauma. Post-traumatic BBB disruption may have important implications for prognosis and therapy. Assessment of BBB status is not routine in clinical practice because available techniques are invasive. The gold-standard measure, the cerebrospinal fluide (CSF)-serum albumin quotient (QA), requires the measurement of albumin in CSF and serum collected contemporaneously. Accurate, less invasive techniques are necessary. The objective of this study was to evaluate the relationship between QA and serum concentrations of monomeric transthyretin (TTR) or S100B. Nine subjects with severe traumatic brain injury (TBI; Glasgow Coma Scale [GCS] score ≤ 8) and 11 subjects with non-traumatic headache who had CSF collected by ventriculostomy or lumbar puncture (LP) were enrolled. Serum and CSF were collected at the time of LP for headache subjects and at 12, 24, and 48 h after ventriculostomy for TBI subjects. The QA was calculated for all time points at which paired CSF and serum samples were available. Serum S100B and TTR levels were also measured. Pearson's correlation coefficient and area under the receiver operating characteristic (ROC) curve were used to determine the relationship between the serum proteins and QA. Seven TBI subjects had abnormal QA's indicating BBB dysfunction. The remaining TBI and control subjects had normal BBB function. No significant relationship between TTR and QA was found. A statistically significant linear correlation between serum S100B and QA was present (r = 0.432, p = 0.02). ROC analysis demonstrated a significant relationship between QA and serum S100B concentrations at 12 h after TBI (AUC = 0.800; SE 0.147, 95% CI 0.511–1.089). Using an S100B concentration cutoff of 0.027 ng/ml, specificity for abnormal QA was 90% or higher at each time point. We conclude that serum S100B concentrations accurately indicate BBB dysfunction at 12 h after TBI.
Virgin, ovariectomized rats exposed to 2 wk of sequential estradiol (E 2 ) and progesterone (P) followed by P withdrawal have increased hypothalamic oxytocin (OT) mRNA and peptide levels relative to sham-treated animals. This increase is prevented if P is sustained. In the central nervous system, P is metabolized to the neurosteroid allopregnanolone (3α-hydroxy-5α-pregnan-20-one), which exerts effects by acting as a positive allosteric modulator of GABA A receptor/Cl − -channel complexes. In the present study, ovariectomized rats that received sequential E 2 and P for 2 wk followed by P withdrawal were administered allopregnanolone at the time of P withdrawal. Hypothalamic and plasma allopregnanolone concentrations, serum E 2 and P concentrations, and hypothalamic OT mRNA levels were measured at death. Steroid-induced increases in OT mRNA were attenuated in animals treated with allopregnanolone at the time of P withdrawal. The results suggest that allopregnanolone plays an important modulatory role in steroid-mediated increases in hypothalamic OT.
The objective of the current study was to determine the classification accuracy of serum S100B and apolipoprotein (apoA-I) for mild traumatic brain injury (mTBI) and abnormal initial head computed tomography (CT) scan, and to identify ethnic, racial, age, and sex variation in classification accuracy. We performed a prospective, multi-centered study of 787 patients with mTBI who presented to the emergency department within 6 h of injury and 467 controls who presented to the outpatient laboratory for routine blood work. Serum was analyzed for S100B and apoA-I. The outcomes were disease status (mTBI or control) and initial head CT scan. At cutoff values defined by 90% of controls, the specificity for mTBI using S100B (0.899 [95% confidence interval (CI): 0.78-0.92]) was similar to that using apoA-I (0.902 [0.87-0.93]), and the sensitivity using S100B (0.252 [0.22-0.28]) was similar to that using apoA-I (0.249 [0.22-0.28]). The area under the receiver operating characteristic curve (AUC) for the combination of S100B and apoA-I (0.738, 95% CI: 0.71, 0.77), however, was significantly higher than the AUC for S100B alone (0.709, 95% CI: 0.68, 0.74, p=0.001) and higher than the AUC for apoA-I alone (0.645, 95% CI: 0.61, 0.68, p<0.0001). The AUC for prediction of abnormal initial head CT scan using S100B was 0.694 (95%CI: 0.62, 0.77) and not significant for apoA-I. At a S100B cutoff of <0.060 μg/L, the sensitivity for abnormal head CT was 98%, and 22.9% of CT scans could have been avoided. There was significant age and race-related variation in the accuracy of S100B for the diagnosis of mTBI. The combined use of serum S100B and apoA-I maximizes classification accuracy for mTBI, but only S100B is needed to classify abnormal head CT scan. Because of significant subgroup variation in classification accuracy, age and race need to be considered when using S100B to classify subjects for mTBI.
Twenty-eight patients who had survived severe head injury were studied. Although sixteen achieved 'good recovery' status, they, and their families, had to surmount many difficulties, and persisting physical deficits, substantial personality changes, and disruptions to family relationships were distressing continuing problem for many.
The emergency management of cerebral concussion typically centers on the decision to perform a head computed tomography (CT) scan, which only rarely detects hemorrhagic lesions requiring neurosurgery. The absence of hemorrhage on CT scan often is equated with a lack of brain injury. However, observational studies revealing poor long‐term cognitive outcome after concussion suggest that brain injury may be present despite a normal CT scan. To explore this idea further, the authors reviewed the evidence for objective neurologic injury in humans after concussion, with particular emphasis on those with a normal brain CT. This evidence comes from studies involving brain tissue pathology, CT scanning, magnetic resonance image (MRI) scanning, serum biomarkers, formal cognitive and balance tests, functional MRI, positron emission tomography, and single‐photon emission computed tomography scanning. Each section is accompanied by technical information to help the reader understand what these tests are, not to endorse their use clinically. The authors discuss the strengths and weaknesses of the evidence in each case. These reports make a compelling case for the existence of concussion as a clinically relevant disease with demonstrable neurologic pathology. Areas for future emergency medicine research are suggested.
