Blood–brain barrier dysfunction following traumatic brain injury: correlation of K<sup>trans</sup>(DCE-MRI) and SUVR (99mTc-DTPA SPECT) but not serum S100B

Winter, Chris; Bell, Christopher J.; Whyte, T.R.; Cardinal, John; Macfarlane, David; Rose, Stephen

doi:10.1179/1743132815y.0000000018

Cited by 22 publications

(22 citation statements)

References 43 publications

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“…Further, even though Q A is the current golden-standard method for BBB integrity, the TBI field would benefit from a new BBB integrity biomarker. Radiological tools, notably dynamic enhanced contrast magnetic resonance imaging, have been utilized in other neurological disorders to assess BBB disruption [9], but has as of yet been but sparsely utilized in the TBI setting [76,77]. Meanwhile, we show that BBB disruption measured utilizing Q A is a novel important outcome predictor following severe TBI.…”

Section: Tbi Studies Benefit From Csf But Warrant a New Bbb Disruptimentioning

confidence: 81%

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

Lindblad

Just

et al. 2021

Crit Care

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Background Severe traumatic brain injury (TBI) is associated with blood–brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-term functional outcome in TBI patients and healthy controls. Methods We conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Score, was collected after 6–12 months. We utilized a suspension bead antibody array analyzed on a FlexMap 3D Luminex platform to characterize 177 unique proteins in matched CSF and serum samples. In addition, we assessed BBB disruption using the CSF-serum albumin quotient (QA), and performed Apolipoprotein E-genotyping as the latter has been linked to BBB function in the absence of trauma. We employed pathway-, cluster-, and proportional odds regression analyses. Key findings were validated in blood samples from an independent TBI cohort. Results TBI patients had an upregulation of structural CNS and neuroinflammatory pathways in both CSF and serum. In total, 114 proteins correlated with QA, among which the top-correlated proteins were complement proteins. A cluster analysis revealed protein levels to be strongly associated with BBB integrity, but not carriage of the Apolipoprotein E4-variant. Among cluster-derived proteins, innate immune pathways were upregulated. Forty unique proteins emanated as novel independent predictors of clinical outcome, that individually explained ~ 10% additional model variance. Among proteins significantly different between TBI patients with intact or disrupted BBB, complement C9 in CSF (p = 0.014, ΔR2 = 7.4%) and complement factor B in serum (p = 0.003, ΔR2 = 9.2%) were independent outcome predictors also following step-down modelling. Conclusions This represents the largest concomitant CSF and serum proteomic profiling study so far reported in TBI, providing substantial support to the notion that neuroinflammatory markers, including complement activation, predicts BBB disruption and long-term outcome. Individual proteins identified here could potentially serve to refine current biomarker modelling or represent novel treatment targets in severe TBI.

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Section: Tbi Studies Benefit From Csf But Warrant a New Bbb Disruptimentioning

confidence: 81%

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

Lindblad

Just

et al. 2021

Crit Care

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“…To our knowledge, this study is one of the few clinical studies applying DCE MR imaging on mTBI patients. Unlike previous studies (20,31), we applied automatic segmentation and A. Mean K trans value in bilateral cerebral cortex was significantly higher in mTBI patients (median, 0.0104 x 10 -1 min -1 ) than in controls (median, 0.0084 x 10 -1 min -1 ).…”

Section: Discussionmentioning

confidence: 99%

Blood-Brain Barrier Disruption in Mild Traumatic Brain Injury Patients with Post-Concussion Syndrome: Evaluation with Region-Based Quantification of Dynamic Contrast-Enhanced MR Imaging Parameters Using Automatic Whole-Brain Segmentation

et al. 2021

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This study aimed to investigate the blood-brain barrier (BBB) disruption in mild traumatic brain injury (mTBI) patients with post-concussion syndrome (PCS) using dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging and automatic whole brain segmentation. Materials and Methods: Forty-two consecutive mTBI patients with PCS who had undergone post-traumatic MR imaging, including DCE MR imaging, between October 2016 and April 2018, and 29 controls with DCE MR imaging were included in this retrospective study. After performing three-dimensional T1-based brain segmentation with FreeSurfer software (Laboratory for Computational Neuroimaging), the mean K trans and vp from DCE MR imaging (derived using the Patlak model and extended Tofts and Kermode model) were analyzed in the bilateral cerebral/cerebellar cortex, bilateral cerebral/cerebellar white matter (WM), and brainstem. K trans values of the mTBI patients and controls were calculated using both models to identify the model that better reflected the increased permeability owing to mTBI (tendency toward higher K trans values in mTBI patients than in controls). The Mann-Whitney U test and Spearman rank correlation test were performed to compare the mean K trans and vp between the two groups and correlate K trans and vp with neuropsychological tests for mTBI patients. Results: Increased permeability owing to mTBI was observed in the Patlak model but not in the extended Tofts and Kermode model. In the Patlak model, the mean K trans in the bilateral cerebral cortex was significantly higher in mTBI patients than in controls (p = 0.042). The mean vp values in the bilateral cerebellar WM and brainstem were significantly lower in mTBI patients than in controls (p = 0.009 and p = 0.011, respectively). The mean K trans of the bilateral cerebral cortex was significantly higher in patients with atypical performance in the auditory continuous performance test (commission errors) than in average or good performers (p = 0.041). Conclusion: BBB disruption, as reflected by the increased K trans and decreased vp values from the Patlak model, was observed throughout the bilateral cerebral cortex, bilateral cerebellar WM, and brainstem in mTBI patients with PCS.

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“…We assessed how a trauma-induced BBBD affects brain biomarker concentrations in blood. Even though some radiological techniques have been proposed to quantify BBBD, 58,59 Q A remains the gold standard assessment, [19][20][21][22][23][24][25] because the 67 kDa protein albumin lacks intracranial synthesis, 19 is not catabolized in the CNS, 60 and has a 200 times lower concentration in CSF compared with serum. 19 We found that whereas Q A on a group basis had a decreasing trend over the 1st week, patients who had normal Q A values at study onset maintained normal values throughout the study period and vice versa.…”

Section: The Disrupted Bbb In Tbimentioning

confidence: 99%

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

Lindblad

Nelson

Zeiler

et al. 2020

Journal of Neurotrauma

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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.

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Blood–brain barrier dysfunction following traumatic brain injury: correlation of K^trans(DCE-MRI) and SUVR (99mTc-DTPA SPECT) but not serum S100B

Cited by 22 publications

References 43 publications

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

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

Blood-Brain Barrier Disruption in Mild Traumatic Brain Injury Patients with Post-Concussion Syndrome: Evaluation with Region-Based Quantification of Dynamic Contrast-Enhanced MR Imaging Parameters Using Automatic Whole-Brain Segmentation

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

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Blood–brain barrier dysfunction following traumatic brain injury: correlation of Ktrans(DCE-MRI) and SUVR (99mTc-DTPA SPECT) but not serum S100B

Cited by 22 publications

References 43 publications

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

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

Blood-Brain Barrier Disruption in Mild Traumatic Brain Injury Patients with Post-Concussion Syndrome: Evaluation with Region-Based Quantification of Dynamic Contrast-Enhanced MR Imaging Parameters Using Automatic Whole-Brain Segmentation

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

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Blood–brain barrier dysfunction following traumatic brain injury: correlation of K^trans(DCE-MRI) and SUVR (99mTc-DTPA SPECT) but not serum S100B