Epigenetics in blood-brain barrier disruption.
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ABSTRACT:
SUBMITTER: Ihezie SA
PROVIDER: S-EPMC8025355 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and purposeCNS complications are often seen after heart surgery, and postsurgical disruption of the BBB may play an etiologic role. The objective of this study was to determine the prevalence of MR imaging-detected BBB disruption (HARM) and DWI lesions after cardiac surgery.Materials and methodsAll patients had an MRI after cardiac surgery. For half the patients (group 1), we administered gadolinium 24 hours after surgery and obtained high-resolution DWI and FLAIR images 24-48 hours later. We administered gadolinium to the other half (group 2) at the time of the postoperative scan, 2-4 days after surgery. Two stroke neurologists evaluated the images.ResultsOf the 19 patients we studied, none had clinical evidence of a stroke or delirium at the time of the gadolinium administration or the scan, but 9 patients (47%) had HARM (67% in group 1; 30% in group 2; P = .18) and 14 patients (74%) had DWI lesions (70% in group 1; 78% in group 2; P = 1.0). Not all patients with DWI lesions had HARM, and not all patients with HARM had DWI lesions (P = .56).ConclusionsAlmost half the patients undergoing cardiac surgery have evidence of HARM, and three-quarters have acute lesions on DWI after surgery. BBB disruption is more prevalent in the first 24 hours after surgery. These findings suggest that MR imaging can be used as an imaging biomarker to assess therapies that may protect the BBB in patients undergoing heart surgery.
| S-EPMC3509275 | biostudies-literature
Project description:BackgroundPrevious studies demonstrated that cardioembolism (CE) was prone to develop hemorrhagic transformation (HT), whereas hyper-permeability of blood-brain barrier (BBB) might be one reason for the development of HT. We, thus, aimed to investigate whether the BBB permeability (BBBP) was higher in CE stroke than other stroke subtypes in acute ischemic stroke (AIS) patients.MethodsThis study was a retrospective review of prospectively collected clinical and imaging database of AIS patients who underwent CT perfusion. Hypoperfusion was defined as Tmax >6?s. The average relative permeability-surface area product (rPS), reflecting the BBBP, was calculated within the hypoperfusion region (rPShypo). CE was diagnosed according to the international Trial of Org 10172 in Acute Stroke Treatment criteria. Receiver operating characteristics (ROC) curve analysis was used to determine predictive value of rPShypo for CE. Logistic regression was used to identify independent predictors for CE.ResultsA total of 187 patients were included in the final analysis [median age, 73 (61-80) years; 75 (40.1%) females; median baseline National Institutes of Health Stroke Scale score, 12 (7-16)]. Median rPShypo was 65.5 (35.8-110.1)%. Ninety-seven (51.9%) patients were diagnosed as CE. ROC analysis revealed that the optimal rPShypo threshold for CE was 86.71%. The value of rPShypo and the rate of rPShypo>86.71% were significantly higher in patients with CE than other stroke subtypes (p?<?0.05), after adjusting for the potential confounds.ConclusionThe extent of BBB disruption is more severe in CE stroke than other stroke subtypes during the hyperacute stage.
| S-EPMC5809413 | biostudies-literature
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.
| S-EPMC7869431 | biostudies-literature
Project description:Fucoxanthin is the most abundant marine carotenoid extracted from seaweed. Our previous study has shown that fucoxanthin inhibited oxidative stress after traumatic brain injury (TBI). However, the effects of fucoxanthin on TBI-induced blood-brain barrier (BBB) destruction have not been well understood. In the present study, we found that fucoxanthin improved neurological dysfunction, reduced brain edema, attenuated cortical lesion volume, and decreased dendrites loss after TBI in vivo. Moreover, fucoxanthin suppressed BBB leakage, preserved tight junction (TJ) and adherens junction (AJ) proteins, and inhibited MMP-9 expression. Furthermore, fucoxanthin alleviated apoptosis and ferroptosis, and activated mitophagy in endothelial cells (ECs) after TBI. However, the protection of fucoxanthin on BBB was attenuated when mitophagy was inhibited. Importantly, fucoxanthin also provided protective effects in bEnd.3 cells after TBI. Taken together, our results suggested that fucoxanthin played a key role in the protection of BBB after TBI through mitophagy.
| S-EPMC10641514 | biostudies-literature
Project description:The acknowledgement of risks for traumatic brain injury in American football players has prompted studies for sideline concussion diagnosis and testing for neurological deficits. While concussions are recognized etiological factors for a spectrum of neurological sequelae, the consequences of sub-concussive events are unclear. We tested the hypothesis that blood-brain barrier disruption (BBBD) and the accompanying surge of the astrocytic protein S100B in blood may cause an immune response associated with production of auto-antibodies. We also wished to determine whether these events result in disrupted white matter on diffusion tensor imaging (DT) scans. Players from three college football teams were enrolled (total of 67 volunteers). None of the players experienced a concussion. Blood samples were collected before and after games (n = 57); the number of head hits in all players was monitored by movie review and post-game interviews. S100B serum levels and auto-antibodies against S100B were measured and correlated by direct and reverse immunoassays (n = 15 players; 5 games). A subset of players underwent DTI scans pre- and post-season and after a 6-month interval (n = 10). Cognitive and functional assessments were also performed. After a game, transient BBB damage measured by serum S100B was detected only in players experiencing the greatest number of sub-concussive head hits. Elevated levels of auto-antibodies against S100B were elevated only after repeated sub-concussive events characterized by BBBD. Serum levels of S100B auto-antibodies also predicted persistence of MRI-DTI abnormalities which in turn correlated with cognitive changes. Even in the absence of concussion, football players may experience repeated BBBD and serum surges of the potential auto-antigen S100B. The correlation of serum S100B, auto-antibodies and DTI changes support a link between repeated BBBD and future risk for cognitive changes.
| S-EPMC3590196 | biostudies-literature
Project description:Bacterial meningitis is a serious infection of the CNS that results when blood-borne bacteria are able to cross the blood-brain barrier (BBB). Group B Streptococcus (GBS) is the leading cause of neonatal meningitis; however, the molecular mechanisms that regulate bacterial BBB disruption and penetration are not well understood. Here, we found that infection of human brain microvascular endothelial cells (hBMECs) with GBS and other meningeal pathogens results in the induction of host transcriptional repressor Snail1, which impedes expression of tight junction genes. Moreover, GBS infection also induced Snail1 expression in murine and zebrafish models. Tight junction components ZO-1, claudin 5, and occludin were decreased at both the transcript and protein levels in hBMECs following GBS infection, and this repression was dependent on Snail1 induction. Bacteria-independent Snail1 expression was sufficient to facilitate tight junction disruption, promoting BBB permeability to allow bacterial passage. GBS induction of Snail1 expression was dependent on the ERK1/2/MAPK signaling cascade and bacterial cell wall components. Finally, overexpression of a dominant-negative Snail1 homolog in zebrafish elevated transcription of tight junction protein-encoding genes and increased zebrafish survival in response to GBS challenge. Taken together, our data support a Snail1-dependent mechanism of BBB disruption and penetration by meningeal pathogens.
| S-EPMC4497739 | biostudies-literature
Project description:ObjectiveThis study sought to confirm the relationship between the degree of blood-brain barrier (BBB) damage and the severity of intracranial hemorrhage (ICH) in a population of patients who received endovascular therapy.MethodsThe degree of BBB disruption on pretreatment MRI scans was analyzed, blinded to follow-up data, in the DEFUSE 2 cohort in which patients had endovascular therapy within 12 hours of stroke onset. BBB disruption was compared with ICH grade previously established by the DEFUSE 2 core lab. A prespecified threshold for predicting parenchymal hematoma (PH) was tested.ResultsOf the 108 patients in the DEFUSE 2 trial, 100 had adequate imaging and outcome data and were included in this study; 24 developed PH. Increasing amounts of BBB disruption on pretreatment MRIs was associated with increasing severity of ICH grade (p = 0.004). BBB disruption on the pretreatment scan was associated with PH (p = 0.020) with an odds ratio for developing PH of 1.69 for each 10% increase in BBB disruption (95% confidence interval 1.09-2.64), although a reliably predictive threshold was not identified.ConclusionsThe amount of BBB disruption on pretreatment MRI is associated with the severity of ICH after acute intervention. This relationship has now been identified in patients receiving IV, endovascular, and combined therapies. Further study is needed to determine its role in guiding treatment.
| S-EPMC4955280 | biostudies-literature
Project description:This article reviews current knowledge of the mechanisms underlying the initial hemorrhage and secondary blood-brain barrier (BBB) dysfunction in primary spontaneous intracerebral hemorrhage (ICH) in adults. Multiple etiologies are associated with ICH, for example, hypertension, Alzheimer's disease, vascular malformations and coagulopathies (genetic or drug-induced). After the initial bleed, there can be continued bleeding over the first 24 hours, so-called hematoma expansion, which is associated with adverse outcomes. A number of clinical trials are focused on trying to limit such expansion. Significant progress has been made on the causes of BBB dysfunction after ICH at the molecular and cell signaling level. Blood components (e.g. thrombin, hemoglobin, iron) and the inflammatory response to those components play a large role in ICH-induced BBB dysfunction. There are current clinical trials of minimally invasive hematoma removal and iron chelation which may limit such dysfunction. Understanding the mechanisms underlying the initial hemorrhage and secondary BBB dysfunction in ICH is vital for developing methods to prevent and treat this devastating form of stroke.
| S-EPMC4130123 | biostudies-literature
Project description:Treatment of many pathologies of the brain could be improved markedly by the development of noninvasive therapeutic approaches that elicit robust, endothelial cell-selective gene expression in specific brain regions that are targeted under MR image guidance. While focused ultrasound (FUS) in conjunction with gas-filled microbubbles (MBs) has emerged as a noninvasive modality for MR image-guided gene delivery to the brain, it has been used exclusively to transiently disrupt the blood-brain barrier (BBB), which may induce a sterile inflammation response. Here, we introduce an MR image-guided FUS method that elicits endothelial-selective transfection of the cerebral vasculature (i.e., "sonoselective" transfection), without opening the BBB. We first determined that activating circulating, cationic plasmid-bearing MBs with pulsed low-pressure (0.1 MPa) 1.1-MHz FUS facilitates sonoselective gene delivery to the endothelium without MRI-detectable disruption of the BBB. The degree of endothelial selectivity varied inversely with the FUS pressure, with higher pressures (i.e., 0.3-MPa and 0.4-MPa FUS) consistently inducing BBB opening and extravascular transfection. Bulk RNA sequencing analyses revealed that the sonoselective low-pressure regimen does not up-regulate inflammatory or immune responses. Single-cell RNA sequencing indicated that the transcriptome of sonoselectively transfected brain endothelium was unaffected by the treatment. The approach developed here permits targeted gene delivery to blood vessels and could be used to promote angiogenesis, release endothelial cell-secreted factors to stimulate nerve regrowth, or recruit neural stem cells.
| S-EPMC7084076 | biostudies-literature
Project description:Although concussion is now recognized as a major health issue, its non-lethal nature has limited characterization of the underlying pathophysiology. In particular, potential neuropathological changes have typically been inferred from non-invasive techniques or post-mortem examinations of severe traumatic brain injury (TBI). Here, we used a swine model of head rotational acceleration based on human concussion to examine blood-brain barrier (BBB) integrity after injury in association with diffuse axonal injury and glial responses. We then determined the potential clinical relevance of the swine concussion findings through comparisons with pathological changes in human severe TBI, where post-mortem examinations are possible. At 6-72 h post-injury in swine, we observed multifocal disruption of the BBB, demonstrated by extravasation of serum proteins, fibrinogen and immunoglobulin-G, in the absence of hemorrhage or other focal pathology. BBB disruption was observed in a stereotyped distribution consistent with biomechanical insult. Specifically, extravasated serum proteins were frequently observed at interfaces between regions of tissue with differing material properties, including the gray-white boundary, periventricular and subpial regions. In addition, there was substantial overlap of BBB disruption with regions of axonal pathology in the white matter. Acute perivascular cellular uptake of blood-borne proteins was observed to be prominent in astrocytes (GFAP-positive) and neurons (MAP-2-positive), but not microglia (IBA1-positive). Parallel examination of human severe TBI revealed similar patterns of serum extravasation and glial uptake of serum proteins, but to a much greater extent than in the swine model, attributed to the higher injury severity. These data suggest that BBB disruption represents a new and important pathological feature of concussion.
| S-EPMC6532777 | biostudies-literature