Dataset Information

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 (QA). 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 QA was lower for NSE (??=?0.444) than for S100B (??=?0.668). Because data were longitudinal, we also conducted cross correlation analyses, which indicated a directional flow and lag-time 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), QA (p?=?0.045), time from trauma (p?

SUBMITTER: Lindblad C

PROVIDER: S-EPMC7249468 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Lindblad Caroline C Nelson David W DW Zeiler Frederick A FA Ercole Ari A Ghatan Per Hamid PH von Horn Henrik H Risling Mårten M Svensson Mikael M Agoston Denes V DV Bellander Bo-Michael BM Thelin Eric Peter EP

Journal of neurotrauma 20200306 12

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 CS ...[more]

PMID: 32013731

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Project description:Disruption of the blood-brain barrier (BBB) results in cerebral edema formation, which is a major cause for high mortality after traumatic brain injury (TBI). As anesthetic care is mandatory in patients suffering from severe TBI it may be important to elucidate the effect of different anesthetics on cerebral edema formation. Tight junction proteins (TJ) such as zonula occludens-1 (ZO-1) and claudin-5 (cl5) play a central role for BBB stability. First, the influence of the volatile anesthetics sevoflurane and isoflurane on in-vitro BBB integrity was investigated by quantification of the electrical resistance (TEER) in murine brain endothelial monolayers and neurovascular co-cultures of the BBB. Secondly brain edema and TJ expression of ZO-1 and cl5 were measured in-vivo after exposure towards volatile anesthetics in native mice and after controlled cortical impact (CCI). In in-vitro endothelial monocultures, both anesthetics significantly reduced TEER within 24 hours after exposure. In BBB co-cultures mimicking the neurovascular unit (NVU) volatile anesthetics had no impact on TEER. In healthy mice, anesthesia did not influence brain water content and TJ expression, while 24 hours after CCI brain water content increased significantly stronger with isoflurane compared to sevoflurane. In line with the brain edema data, ZO-1 expression was significantly higher in sevoflurane compared to isoflurane exposed CCI animals. Immunohistochemical analyses revealed disruption of ZO-1 at the cerebrovascular level, while cl5 was less affected in the pericontusional area. The study demonstrates that anesthetics influence brain edema formation after experimental TBI. This effect may be attributed to modulation of BBB permeability by differential TJ protein expression. Therefore, selection of anesthetics may influence the barrier function and introduce a strong bias in experimental research on pathophysiology of BBB dysfunction. Future research is required to investigate adverse or beneficial effects of volatile anesthetics on patients at risk for cerebral edema.

Project description:IntroductionTraumatic brain injury (TBI) is considered one of the most pervasive causes of disability in people under the age of 45. TBI often results in disorders of consciousness, and clinical assessment of the state of consciousness in these patients is challenging due to the lack of behavioural responsiveness. Functional neuroimaging offers a means to assess these patients without the need for behavioural signs, indicating that brain connectivity plays a major role in consciousness emergence and maintenance. However, little is known regarding how changes in connectivity during recovery from TBI accompany changes in the level of consciousness. Here, we aim to combine cutting-edge neuroimaging techniques to follow changes in brain connectivity in patients recovering from severe TBI.Methods and analysisA multimodal, longitudinal assessment of 30 patients in the subacute stage after severe TBI will be made comprising an MRI session combined with electroencephalography (EEG), a positron emission tomography session and a transcranial magnetic stimulation (TMS) combined with EEG (TMS/EEG) session. A group of 20 healthy participants will be included for comparison. Four sessions for patients and two sessions for healthy participants will be planned. Data analysis techniques will focus on whole-brain, both data-driven and hypothesis-driven, connectivity measures that will be specific to the imaging modality.Ethics and disseminationThe project has received ethical approval by the local ethics committee of the Capital Region of Denmark and by the Danish Data Protection. Results will be published as original research articles in peer-reviewed journals and disseminated in international conferences. None of the measurements will have any direct clinical impact on the patients included in the study but may benefit future patients through a better understanding of the mechanisms underlying the recovery process after TBI. TRIAL REGISTRATION NUMBER NCT02424656; PRE-RESULTS.

Project description:ImportanceModerate to severe traumatic brain injury (msTBI) is a major cause of death and disability in the US and worldwide. Few studies have enabled prospective, longitudinal outcome data collection from the acute to chronic phases of recovery after msTBI.ObjectiveTo prospectively assess outcomes in major areas of life function at 2 weeks and 3, 6, and 12 months after msTBI.Design, setting, and participantsThis cohort study, as part of the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, was conducted at 18 level 1 trauma centers in the US from February 2014 to August 2018 and prospectively assessed longitudinal outcomes, with follow-up to 12 months postinjury. Participants were patients with msTBI (Glasgow Coma Scale scores 3-12) extracted from a larger group of patients with mild, moderate, or severe TBI who were enrolled in TRACK-TBI. Data analysis took place from October 2019 to April 2021.ExposuresModerate or severe TBI.Main outcomes and measuresThe Glasgow Outcome Scale-Extended (GOSE) and Disability Rating Scale (DRS) were used to assess global functional status 2 weeks and 3, 6, and 12 months postinjury. Scores on the GOSE were dichotomized to determine favorable (scores 4-8) vs unfavorable (scores 1-3) outcomes. Neurocognitive testing and patient reported outcomes at 12 months postinjury were analyzed.ResultsA total of 484 eligible patients were included from the 2679 individuals in the TRACK-TBI study. Participants with severe TBI (n = 362; 283 men [78.2%]; median [interquartile range] age, 35.5 [25-53] years) and moderate TBI (n = 122; 98 men [80.3%]; median [interquartile range] age, 38 [25-53] years) were comparable on demographic and premorbid variables. At 2 weeks postinjury, 36 of 290 participants with severe TBI (12.4%) and 38 of 93 participants with moderate TBI (41%) had favorable outcomes (GOSE scores 4-8); 301 of 322 in the severe TBI group (93.5%) and 81 of 103 in the moderate TBI group (78.6%) had moderate disability or worse on the DRS (total score ≥4). By 12 months postinjury, 142 of 271 with severe TBI (52.4%) and 54 of 72 with moderate TBI (75%) achieved favorable outcomes. Nearly 1 in 5 participants with severe TBI (52 of 270 [19.3%]) and 1 in 3 with moderate TBI (23 of 71 [32%]) reported no disability (DRS score 0) at 12 months. Among participants in a vegetative state at 2 weeks, 62 of 79 (78%) regained consciousness and 14 of 56 with available data (25%) regained orientation by 12 months.Conclusions and relevanceIn this study, patients with msTBI frequently demonstrated major functional gains, including recovery of independence, between 2 weeks and 12 months postinjury. Severe impairment in the short term did not portend poor outcomes in a substantial minority of patients with msTBI. When discussing prognosis during the first 2 weeks after injury, clinicians should be particularly cautious about making early, definitive prognostic statements suggesting poor outcomes and withdrawal of life-sustaining treatment in patients with msTBI.

Dataset Information

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

Publications

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

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