Validation of Serum Markers for Blood-Brain Barrier Disruption in Traumatic Brain Injury

Abstract

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 (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 < or =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 QA. 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 QA was found. A statistically significant linear correlation between serum S100B and Q(A) was present (r = 0.432, p = 0.02). ROC analysis demonstrated a significant relationship between Q(A) 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 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.

Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans

“…Consistent with observations in animal models, evidence of acute BBB permeability following severe TBI in humans is provided by reports of elevations in CSF to serum albumin quotient (50)(51)(52)(53) and in serum S100² levels (50-53) after injury. Of note, such evidence of acute BBB disruption following TBI might predict a population of patients with poor longterm outcome (52).…”

Biomarkers in children with traumatic brain injury

“…В качестве нормальных величин использовали данные литературы [2,[9][10][11][14][15][16][17][18][19][20][21][22], а также указанные фирмой-разработчиком нормати-вы и наши собственные неопубликованные данные, полу-ченные при обследовании детей без неврологической и другой патологии внутренних органов. Верхней границей нормы для NSE считали 13 мкг/л, для S100B -0,090-0,125 мкг/л cыворотки крови.…”

“…Белок S100B является наиболее изученным маркером при нарушениях мозгового кровообращения и ЧМТ [9][10][11][14][15][16][17][18][19][20][21][22]. Он синтезируется астроцитами в сером веще-стве мозга и олигодендроцитами в белом веществе [10,18,19].…”

“…Authors determined the levels of glial protein S100B, neuronspecific enolase (NSE), autoantibodies (aAb) to glutamate receptors and natural autoantibodies (nAb) to S100B and brain-derived neurotrophic factor (BDNF) in serum/plasma of children with different outcomes of TBI. All parameters were analyzed in the 1-3 rd , 7-8 th , [14][15] th and 20-23 rd days after TBI, and, in some cases of severe brain injury and long stay patients in hospital, in 11-12 months after TBI. The severity and outcome of TBI were assessed according the Glasgow coma scale (GCS) and the Glasgow outcome scale (GOS), respectively.…”

“…Она должна основываться на выборе таких биохимических маркеров повреждения и репарации мозга, которые могут отражать структурно-функциональные изменения ключевых мишеней повреж-дения при ЧМТ. Такими мишенями могут быть функцио-нально значимые белки: нейронспецифическая энолаза (NSE) [9][10][11][12][13][14][15], глиальный белок S100B [9][10][11][14][15][16][17][18][19][20][21][22], ре-цепторы глутамата (GluRc) [5,[23][24][25][26][27], мозговой нейро-трофический фактор (BDNF) [28][29][30][31]. В настоящей рабо-те были проанализированы полученные нами данные об изменениях содержания указанных биохимических био-маркеров в крови детей в динамике посттравматического периода ЧМТ.…”