Quantitative dynamic contrast-enhanced MR imaging shows widespread blood-brain barrier disruption in mild traumatic brain injury patients with post-concussion syndrome

Yoo, Roh Eul; Choi, Seung Hong; Oh, Byung Mo; Shin, Sang Do; Lee, Eun Jung; Shin, Dong Jae; Jo, Sang Won; Kang, Koung Mi; Yun, Tae Jin; Kim, Ji-Hoon; Sohn, Chul Ho

doi:10.1007/s00330-018-5656-z

Cited by 27 publications

(30 citation statements)

References 36 publications

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“…BBB disruption has received increased attention as one of the major pathophysiologies underlying TBI, based on the results of previous studies that assessed BBB disruption in animal models using Evans blue staining (21) or immunohistochemistry for serum proteins (29). In parallel with the growing evidence from histopathological data, DCE MR imaging has been highlighted as a promising imaging counterpart for the noninvasive evaluation of BBB injury in TBI animal models (21,30) and humans (20,23). To our knowledge, this study is one of the few clinical studies applying DCE MR imaging on mTBI patients.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the pre-contrast 3D T1-weighted images, automatic cortical reconstruction and volumetric whole-brain segmentation were performed using open-source software (FreeSurfer, version 6.0, Laboratory for Computational Neuroimaging). Using a dedicated commercial software package (NordicICE, version 4.1.2, NordicNeuroLab), K trans and vp maps were derived based on two pharmacokinetic models (the Patlak model and extended Tofts and Kermode model) by two reviewers (with 3 and 9 years of experience in neuroradiology, respectively), blinded to the results of neuropsychological tests, according to previously described methods (13,23). Specifically, DCE MR imaging parameters were obtained using the arterial input function (AIF), which was semiautomatically derived from the main intracranial arteries, including the middle cerebral arteries at the level of the circle of Willis.…”

Section: Automatic Brain Segmentation and Dce Mr Imaging Analysismentioning

confidence: 99%

“…A previous study on football players with histories of concussion revealed BBB dysfunction in various cortical regions (20). Furthermore, a more recent study on mTBI patients with PCS demonstrated that DCE MR imaging parameters, based on a two-compartment pharmacokinetic model proposed by Tofts and Kermode (12,21,22), significantly differed between mTBI patients and controls in certain manually defined regions-of-interest (ROIs) (23), implying that BBB disruption may have an important role in the pathophysiology of PCS in mTBI patients. However, given that manual ROI placement can be subjective, and subtle BBB disruption may be better reflected by the Patlak model (12,21,22), the potential clinical utility of DCE MR imaging in mTBI patients with PCS, as demonstrated by the previous study (23), remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Automatic Brain Segmentation and Dce Mr Imaging Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…brain barrier (BBB) disruption following injury has recently been demonstrated in various experimental TBI models [38][39][40] . To investigate the occurrence of BBB disruption in our micro pig model of cFPI, we assessed the Box plots of the change in serum GFAP level from pre-injury to 3 hr post-injury ("3 hr-pre-injury") or change in serum GFAP level from pre-injury to 6 hr post-injury ("6 h-pre-injury") in sham-injured (n = 3) or cFPI (n = 14) micropigs.…”

Section: Blood Brain Barrier Permeability In the Thalamus Is Altered mentioning

confidence: 99%

Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI

Lafrenaye

Mondello

Wang

et al. 2020

Sci Rep

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Serum biomarkers are promising tools for evaluating patients following traumatic brain injury (tBi). However, their relationship with diffuse histopathology remains unclear. Additionally, translatability is a focus of neurotrauma research, however, studies using translational animal models are limited. Here, we evaluated associations between circulating biomarkers and acute thalamic histopathology in a translational micro pig model of mTBI. Serum samples were collected pre-injury, and 1 min-6 h following mTBI. Markers of neuronal injury (Ubiquitin Carboxy-terminal Hydrolase L1 [UCH-L1]), microglial/macrophage activation (Ionized calcium binding adaptor molecule-1 [Iba-1]) and interleukin-6 [IL-6]) and astrogliosis/astrocyte damage (glial fibrillary acidic protein [GFAP]) were measured. Axonal injury and histological features of neurons and glia were also investigated using immunofluorescent labeling and correlated to serum levels of the associated biomarkers. Consistent with prior experimental and human studies, GFAP, was highest at 6 h post-injury, while no substantial changes were observed in UCH-L1, Iba-1 or IL-6 over 6 h. This study also found promising associations between thalamic glial histological signatures and ensuing release of Iba-1 and GFAP into the circulation. Our findings suggest that in diffuse injury, monitoring serum Iba-1 and GFAP levels can provide clinically relevant insight into the underlying acute pathophysiology and biomarker release kinetics following mTBI, providing previously underappreciated diagnostic capability. Traumatic brain injury (TBI) is an increasing challenge and a global health priority 1 , with more than 50 million TBIs occurring worldwide each year with an associated cost of approximately $400 billion 2. The vast majority (~ 95%) of patients suffer a mild TBI (mTBI) with Glasgow Come Scale (GCS) scores of 13-15 3,4 which, contrary to common perception, cause structural sequelae with variable degrees of injury to neurons, glia, and vascular structures, leading to a spectrum of potential clinical outcomes. As translatability is a primary focus of neurotrauma research, there has been a call for use of higher-order gyrencephalic animal models prior to transitioning to the clinic 5-9 , however, knowledge regarding the TBI-induced pathophysiology in higher order animal models is still limited. Operation Brain Trauma Therapy (OBTT) is a drug-and biomarker-screening

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“…For example, different degrees of traumatic brain injury cause BBB dysfunction. Thus, there is evidence of BBB dysfunction in adolescent rugby players to professional mixed martial arts fighters [143] and Yoo et al [144] found that BBB dysfunction after mild traumatic brain injury was associated with post-concussion syndrome (events such as headaches and dizziness lasting for weeks). In more severe traumatic brain injury, there is evidence that cerebral microvascular injury is a therapeutic target by contributing to neurodegeneration [145].…”

Section: The Contribution Of Brain Vascular Dysfunction To Different mentioning

confidence: 99%

This was the year that was: brain barriers and brain fluid research in 2019

Keep

Jones²,

Drewes

2020

Fluids Barriers CNS

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This editorial highlights advances in brain barrier and brain fluid research published in 2019, as well as addressing current controversies and pressing needs. Topics include recent advances related to: the cerebral endothelium and the neurovascular unit; the choroid plexus, arachnoid membrane; cerebrospinal fluid and the glymphatic hypothesis; the impact of disease states on brain barriers and brain fluids; drug delivery to the brain; and translation of preclinical data to the clinic. This editorial also mourns the loss of two important figures in the field, Malcolm B. Segal and Edward G. Stopa.

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Quantitative dynamic contrast-enhanced MR imaging shows widespread blood-brain barrier disruption in mild traumatic brain injury patients with post-concussion syndrome

Cited by 27 publications

References 36 publications

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

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

Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI

This was the year that was: brain barriers and brain fluid research in 2019

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