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Identification of Reversible Disruption of the Human Blood-Brain Barrier Following Acute Ischemia.

ABSTRACT: BACKGROUND AND PURPOSE:Animal models of acute cerebral ischemia have demonstrated that diffuse blood-brain barrier (BBB) disruption can be reversible after early reperfusion. However, irreversible, focal BBB disruption in humans is associated with hemorrhagic transformation in patients receiving intravenous thrombolytic therapy. The goal of this study was to use a magnetic resonance imaging biomarker of BBB permeability to differentiate these 2 forms of BBB disruption. METHODS:Acute stroke patients imaged with magnetic resonance imaging before, 2 hours after, and 24 hours after treatment with intravenous tissue-type plasminogen activator were included. The average BBB permeability of the acute ischemic region before and 2 hours after treatment was calculated using a T2* perfusion-weighted source images. Change in average permeability was compared with percent reperfusion using linear regression. Focal regions of maximal BBB permeability from the pretreatment magnetic resonance imaging were compared with the occurrence of parenchymal hematoma (PH) formation on the 24-hour magnetic resonance imaging scan using logistic regression. RESULTS:Signals indicating reversible BBB permeability were detected in 18/36 patients. Change in average BBB permeability correlated inversely with percent reperfusion (P=0.006), indicating that early reperfusion is associated with decreased BBB permeability, whereas sustained ischemia is associated with increased BBB disruption. Focal regions of maximal BBB permeability were significantly associated with subsequent formation of PH (P=0.013). CONCLUSIONS:This study demonstrates that diffuse, mild BBB disruption in the acutely ischemic human brain is reversible with reperfusion. This study also confirms prior findings that focal severe BBB disruption confers an increased risk of hemorrhagic transformation in patients treated with intravenous tissue-type plasminogen activator.

SUBMITTER: Simpkins AN

PROVIDER: S-EPMC5111547 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Identification of Reversible Disruption of the Human Blood-Brain Barrier Following Acute Ischemia.

Simpkins Alexis N AN Dias Christian C Leigh Richard R

Stroke 20160726 9

<h4>Background and purpose</h4>Animal models of acute cerebral ischemia have demonstrated that diffuse blood-brain barrier (BBB) disruption can be reversible after early reperfusion. However, irreversible, focal BBB disruption in humans is associated with hemorrhagic transformation in patients receiving intravenous thrombolytic therapy. The goal of this study was to use a magnetic resonance imaging biomarker of BBB permeability to differentiate these 2 forms of BBB disruption.<h4>Methods</h4>Acu ...[more]

PMID: 27462115

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Project description:The meninges serve as a functional barrier surrounding the brain, critical to the immune response, and can be compromised following head trauma. Meningeal enhancement can be detected on contrast-enhanced MRI in patients presenting with acute traumatic brain injury, even when head CT is negative. Following head trauma, gadolinium-based contrast appears to extravasate from the vasculature, enhancing the dura within minutes, and later permeates the subarachnoid space. The aims of this study were to characterize the initial kinetics of the uptake of contrast agent after injury and the delayed redistribution of contrast enhancement in the subarachnoid space in hyperacute patients. Neuroimaging was obtained prospectively in two large ongoing observational studies of patients aged 18 years or older presenting to the emergency department with suspected acute head injury. Dynamic contrast-enhanced MRI studies in a cohort of consecutively enrolling patients with mild traumatic brain injury (n = 36) determined that the kinetic half-life of dural-related meningeal enhancement was 1.3 ± 0.6 min (95% enhancement within 6 min). The extravasation of contrast into the subarachnoid space was investigated in a cohort of CT negative mild traumatic brain injury patients initially imaged within 6 h of injury (hyperacute) who subsequently underwent a delayed MRI, with no additional contrast administration, several hours after the initial MRI. Of the 32 patients with delayed post-contrast imaging, 18 (56%) had conspicuous expansion of the contrast enhancement into the subarachnoid space, predominantly along the falx and superior sagittal sinus. Patients negative for traumatic meningeal enhancement on initial hyperacute MRI continued to have no evidence of meningeal enhancement on the delayed MRI. These studies demonstrate that (i) the initial enhancement of the traumatically injured meninges occurs within minutes of contrast injection, suggesting highly permeable meningeal vasculature, and that (ii) contrast in the meninges redistributes within the subarachnoid space over the period of hours, suggesting a compromise in the blood-brain and/or blood-cerebrospinal barriers. Data from the parent study indicate that up to one in two patients with mild traumatic brain injury have traumatic brain injury on acute (<48 h) MRI, with a higher prevalence seen in patients with moderate or severe traumatic brain injury. The current study's findings of traumatic meningeal enhancement and the subsequent delayed extravasation of contrast into the subarachnoid spaces indicate that a substantial percentage of patients with even mild traumatic brain injury may have a transient disruption in barriers separating the vasculature from the brain.

Project description:BackgroundDespite the great potential of FUS-BBB disruption (FUS-BBBD), it is still controversial whether FUS-BBBD acts as an inducing factor of neuro-inflammation or not, and the biological responses after FUS-BBBD triggers the inflammatory process are poorly understood. The aim of this study is to investigate the safety window for FUS levels based on a comprehensive safety assessment.MethodsThe mice were treated with two different ultrasound parameters (0.25 MPa and 0.42 MPa) in the thalamus region of brain. The efficacy of BBB opening was verified by dynamic contrast-enhanced MRI (DCE-MRI) and the cavitation monitoring. The transcriptome analysis was performed to investigate the molecular response for the two BBBD conditions after FUS-mediated BBB opening in time-dependent manners. Histological analysis was used for evaluation of the tissue damage, neuronal degeneration, and activation of glial cells induced by FUS-BBBD.ResultsThe BBBD, as quantified by the Ktrans, was approximately threefold higher in 0.42 MPa-treated group than 0.25 MPa-treated group. While the minimal tissue/cellular damage was found in 0.25 MPa-treated group, visible damages containing microhemorrhages and degenerating neurons were detected in 0.42 MPa-treated group in accordance with the extent of BBBD. In transcriptome analysis, 0.42 MPa-treated group exhibited highly dynamic changes in the expression levels of an inflammatory response or NF-κB pathway-relative genes in a time-dependent manner whereas, 0.25 MPa was not altered. Interestingly, although it is clear that 0.42 MPa induces neuroinflammation through glial activation, neuroprotective properties were evident by the expression of A2-type astrocytes.ConclusionsOur findings propose that a well-defined BBBD parameter of 0.25 MPa could ensure the safety without cellular/tissue damage or sterile inflammatory response in the brain. Furthermore, the fact that the excessive sonication parameters at 0.42 MPa could induce a sterile inflammation response via glial activation suggested the possibility that could lead to tissue repair toward the homeostasis of the brain microenvironment through A2-type reactive astrocytes.

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Identification of Reversible Disruption of the Human Blood-Brain Barrier Following Acute Ischemia.

Publications

Identification of Reversible Disruption of the Human Blood-Brain Barrier Following Acute Ischemia.

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