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

Abstract

Brain protein biomarker clearance to blood in traumatic brain injury (TBI) is not fully understood. The aim of this study was to analyze the effect that a disrupted blood-brain barrier (BBB) had on biomarker clearance. Seventeen severe TBI patients admitted to Karolinska University Hospital were prospectively included. Cerebrospinal fluid (CSF) and blood concentrations of S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) were analyzed every 6-12 h for *1 week. Blood and CSF albumin were analyzed every 12-24 h, and BBB integrity was assessed using the CSF:blood albumin quotient (Q A ). We found that time-dependent changes in the CSF and blood levels of the two biomarkers were similar, but that the correlation between the biomarkers and Q A was lower for NSE (q = 0.444) than for S100B (q = 0.668). Because data were longitudinal, we also conducted cross correlation analyses, which indicated a directional flow and lagtime of biomarkers from CSF to blood. For S100B, this lag-time could be ascribed to BBB integrity, whereas for NSE it could not. Upon inferential modelling, using generalized least square estimation (S100B) or linear mixed models (NSE), Q A ( p = 0.045), time from trauma ( p < 0.001), time from trauma 2 ( p = 0.023), and CSF biomarker levels ( p = 0.008) were independent predictors of S100B in blood. In contrast, for NSE, only time from trauma was significant ( p < 0.001). These findings are novel and important, but must be carefully interpreted because of different characteristics between the two proteins. Nonetheless, we present the first data that indicate that S100B and NSE are cleared differently from the central nervous system, and that both the disrupted BBB and additional alternative pathways, such as the recently described glymphatic system, may play a role. This is of importance both for clinicians aiming to utilize these biomarkers and for the pathophysiological understanding of brain protein clearance, but warrants further examination.

Fluid Proteomics of CSF and Serum Reveal Important Neuroinflammatory Proteins in Blood-Brain Barrier Disruption and Outcome Prediction Following Severe Traumatic Brain Injury: A Prospective, Observational Study

“…The Q A reference interval is de ned for lumbar albumin (36), and due to the CNS rostro-caudal gradient, the amount of ventricular albumin comprises ~ 40% that of lumbar albumin under homeostasis (66). As one would expect the rostro-caudal gradient to be inverted following a supratentorial trauma with ventricular albumin consequently higher than the lumbar ditto, we did not attempt any rostro-caudal correction for the Q A reference interval, in line with our previous work (12,15). A few control subjects exhibited pathological Q A values (Table 1), in accordance with previous work where ~ 15% of healthy subjects exhibit a pathological Q A in the absence of neurological disorder (67).…”

“…Through the Karolinska University Hospital TBI Database, additional clinical data is collected prospectively. For the current study, clinical data collection comprised neurological variables, injury severity score variables, radiological variables, and outcome data, described in detail elsewhere (12). Functional outcome data (Glasgow Outcome Score, GOS) was collected at 6-12 months following hospital discharge, through structured questionnaires, or follow-up assessments in the outpatient clinic at the Neurosurgical Department.…”

“…An increased Q A indicates albumin leakage due to loss of BBB integrity. Following TBI, Q A has shown to be associated with both structural (12), and neuroin ammatory (13)(14)(15) proteins, of importance as albumin per se does not confer information on the underlying pathophysiology. Yet, as these studies included only a small selection of proteins, they potentially miss out on important biological information, pertaining to protein families and protein pathways that might confer joint or discrepant functions within the CNS.…”

Peripheral, Interictal Serum S100B Levels are Not Increased in Chronic Migraine Patients

“…This hypothesis, however, seems improbable as such disruption has not been convincingly demonstrated in migraineurs 26,27 and the Gasser trigeminal ganglion, where TVS glial cells are concentrated, does not have blood‐brain barrier 28 . Even though data are controversial, 29,30 it has been proposed that removal of brain S100B could depend on the glymphatic system, 29 which functions in the clearance of central nervous system waste molecules, 31 and this system could play a role in migraine pathophysiology 32 . Alternatively, an increase in S100B levels could also represent an acute phase reactant in migraine, conceptually similar to intracellular c‐fos for neurons, but reflecting a transient glial hyperactivity in the case of migraine due to TVS activation, 10,33 In contrast to previous data, however, we did not observe differences (either increase or decrease) in the serum values of S100B protein in patients with CM.…”

Does acute soccer heading cause an increase in plasma S100B? A randomized controlled trial

“…The prolonged time for expression and translocation to the bloodstream could suggest that the mechanism by which S100B from astrocyte activation increases in the periphery is predominantly through clearance by the glymphatic system rather than blood-brain barrier (BBB) disruption [ 17 ]. The presumable low level of neural damage from a short bout of soccer heading may not be sufficient to disrupt the BBB as seen with more severe head injuries [ 66 , 67 ]. The glymphatic system, which is more active during sleep [ 68 ], could be the predominant avenue by which S100B is cleared from the interstitial space through paravenous space after 10 subconcussive head impacts in the form of controlled soccer headers, explaining why we observed an increase when participants returned the next day for the 24h post-intervention blood sample collection.…”