Abstract 2618: Blood Brain Barrier Permeability Increases in Intracerebral Hemorrhage do not Predict Perihematoma Edema Growth

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Sana Vahidy ◽  
Rebecca McCourt ◽  
E B Gould ◽  
Deepak Gupta ◽  
Umair Mushtaq ◽  
...  

Background: The etiology of edema in intracerebral hemorrhage (ICH) is controversial. Most studies are consistent with a vasogenic rather than cytotoxic pathophysiology. It is unknown, however, if the blood brain barrier (BBB) is compromised in ICH and to what extent this is related to either hematoma expansion or edema development. BBB permeability was measured with CT perfusion (CTP) in ICH patients. We hypothesized that perihematoma edema volume and growth would be associated with elevated permeability. We also tested the hypothesis that elevated PS would be associated with hematoma growth. Methods: Patients with ICH were assessed with CTP within 24 hours of symptom onset. Maps of BBB permeability-surface area product (PS), a measure of extravascular contrast leakage rate, were calculated from CTP source images. Mean PS was measured in regions of interest (ROI) defining the hematoma, a 1cm radial peri-hematoma region, and ipsilateral and contralateral hemispheres. The total perihematoma edema volume was also measured objectively, based on Hounsfield unit thresholds of ≤24 at the time of the CTP and 24 h later. Results: PS maps were generated in 50 patients (13 female). The median (IQR) time from symptom onset to CTP was 8.2 (12.4) h. Median hematoma volume at baseline was 16.4 (28.2) mL. Mean PS was higher in the hematoma (3.24±1.34 ml/100g/min), relative to contralateral regions (1.82±0.84 ml/100g/min, P<0.0001). PS was also elevated in the perihematoma region (2.50±1.13 ml/100g/min vs. 1.78±0.81 ml/100g/min, P<0.0001). Ipsilateral hemispheric PS was higher (2.08±1.00 ml/100g/min) than in the contralateral hemisphere (1.82±0.82 ml/100g/min, P=0.002). Acute hematoma volume did not predict PS elevations in the hematoma itself (R=0.004 [-0.01, 0.02], P=0.07) or perihematoma region (R=0.002 [-0.01, 0.01], P=0.74). Linear regression indicated that acute edema volume was not predicted by perihematoma PS (R=-0.68 [-2.15, 0.79], P=0.36). Follow-up CT scans at a median of 22.5 (IQR=2.4) h after the baseline CTP were obtained in 43 patients. Median perihematoma edema volume increased from 1.9 (2.6) mL to 3.2 (5.0) mL (P=<0.0001). This edema volume growth was not predicted by the acute perihematoma PS (R=0.03 [-1.62, 1.68], P=0.98). Significant hematoma expansion (>6 ml) was seen in 5 patients. There was a non-significant trend to higher median hematoma PS values in these 5 patients (3.7 (1.9) vs. 2.7 (1.7) in those with stable hematoma volumes, P=0.09). Conclusions: Small elevations in BBB permeability in and around the hematoma are common in ICH and do not appear to be related to hematoma volume. Neither acute perihematoma edema volume or edema growth is explained by BBB compromise. A relationship between elevated intra-hematoma permeability and significant hematoma expansion cannot be excluded and should be explored in a larger ICH population.

Neurology ◽  
2016 ◽  
Vol 88 (5) ◽  
pp. 433-440 ◽  
Author(s):  
Kersten Villringer ◽  
Borja E. Sanz Cuesta ◽  
Ann-Christin Ostwaldt ◽  
Ulrike Grittner ◽  
Peter Brunecker ◽  
...  

Objective:To quantitatively evaluate blood–brain barrier changes in ischemic stroke patients using dynamic contrast-enhanced (DCE) MRI.Methods:We examined 54 stroke patients (clinicaltrials.govNCT00715533, NCT02077582) in a 3T MRI scanner within 48 hours after symptom onset. Twenty-eight patients had a follow-up examination on day 5–7. DCE T1 mapping and Patlak analysis were employed to assess BBB permeability changes.Results:Median stroke Ktrans values (0.7 × 10−3 min−1 [interquartile range (IQR) 0.4–1.8] × 10−3 min−1) were more than 3-fold higher compared to median mirror Ktrans values (0.2 × 10−3 min−1, IQR 0.1–0.7 × 10−3 min−1, p < 0.001) and further increased at follow-up (n = 28, 2.3 × 10−3 min−1, IQR 0.8–4.6 × 10−3 min−1, p < 0.001). By contrast, mirror Ktrans values decreased over time with a clear interaction of timepoint and stroke/mirror side (p < 0.001). Median stroke Ktrans values were 2.5 times lower than in hemorrhagic transformed regions (0.7 vs 1.8 × 10−3 min−1; p = 0.055). There was no association between stroke Ktrans values and the delay from symptom onset to baseline examination, age, and presence of hyperintense acute reperfusion marker.Conclusion:BBB in acute stroke patients can be successfully assessed quantitatively. The decrease of BBB permeability in unaffected regions at follow-up may be an indicator of global BBB leakage even in vessel territories remote from the index infarct.


2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Wei Zhao ◽  
Lianhua Zhao ◽  
Zaiyu Guo ◽  
Yanwei Hou ◽  
Jiafeng Jiang ◽  
...  

Valproate sodium (VPA) is a traditional antiepileptic drug with a neuroprotective role in cerebrovascular disease. After intracerebral hemorrhage (ICH), mechanical compression by hematoma, neuroinflammation, oxidative stress, and cytotoxicity of hematoma lysates caused the destruction of the blood brain barrier (BBB). Targeting BBB is a major therapeutic method for patients with ICH. The purpose of the present study was to explore the role of VPA in preserving BBB integrity in the ICH model and investigate the underlying molecular mechanisms. One hundred and thirty-six adult male CD1 mice were randomly divided into five groups in the study. Mice subjected to ICH were administered intraperitoneally with VPA at 3, 24, and 48 h post-ICH, respectively. Neurobehavioral assessments, BBB permeability, Evans blue fluorescence, hematoma volume, and protein expression were evaluated. The administration of VPA reduced BBB permeability and improved the neurobehavior significantly post-ICH. VPA administration significantly decreased the expression of phosphorylated nuclear factor-kappa B (p-NFκB), matrix metalloproteinases 9 (MMP9), tumor necrosis factorα (TNFα), and interleukin-6 (IL-6), while it enhanced the expression of claudin 5 and occludin in the brain. In conclusion, VPA administration maintained the integrity of BBB after experimental ICH, thus reducing brain edema and improving the neurological outcomes. Therefore, VPA administration might be a new therapeutic method to protect BBB integrity for patients with ICH.


2021 ◽  
Author(s):  
Kersten Villringer ◽  
Uchralt Temuulen ◽  
Ralf Mekle ◽  
Jochen B. Fiebach ◽  
Christin H. Nolte ◽  
...  

Abstract Neurological diseases such as ischemic stroke and dementia are associated with compromised blood-brain barrier (BBB) permeability. Knowledge about the time course of BBB leakage may have impact on therapeutic interventions and diagnostic measures such as testing for blood biomarkers. However, reports on the timeline and pattern of this leakage are contradictory. Therefore, we aimed to assess the time course of BBB permeability in ischemic stroke patients during the first 24 hours after symptom onset using dynamic contrast enhanced (DCE) MRI at 3 Tesla. We categorized time from stroke symptom onset to imaging into the following groups 1) 0-6 hours (n=10), 2) 6-16 hours (n=14) and 3) 16-24 hours (n=29). BBB permeability differed significantly between stroke lesions and the contralesional tissue for groups 2 and 3 (p=0.006, p<0.001, Wilcoxon-signed rank test). Using univariate or multivariate linear regression analyses we found no association between BBB leakage and age, sex, hyperintense reperfusion marker (another marker of BBB permeability) hemorrhagic transformation, white matter lesion load, symptom severity, functional disability and cerebrovascular risk factors. The results of our study therefore suggest continuous BBB leakage in the first 24 hours after stroke.


2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wei He ◽  
Qin Lu ◽  
Prativa Sherchan ◽  
Lei Huang ◽  
Xin Hu ◽  
...  

Abstract Background Destruction of blood–brain barrier (BBB) ​​is one of the main mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Frizzled-7 is a key protein expressed on the surface of endothelial cells that controls vascular permeability through the Wnt-canonical pathway involving WNT1-inducible signaling pathway protein 1 (WISPI). This study aimed to investigate the role of Frizzled-7 signaling in BBB preservation after ICH in mice. Methods Adult CD1 mice were subjected to sham surgery or collagenase-induced ICH. Frizzled-7 activation or knockdown was performed by administration of Clustered Regularly Interspaced Palindromic Repeats (CRISPR) by intracerebroventricular injection at 48 h before ICH induction. WISP1 activation or WISP1 knockdown was performed to evaluate the underlying signaling pathway. Post-ICH assessments included neurobehavior, brain edema, BBB permeability, hemoglobin level, western blot and immunofluorescence. Results The brain expressions of Frizzled-7 and WISP1 significantly increased post-ICH. Frizzled-7 was expressed in endothelial cells, astrocytes, and neurons after ICH. Activation of Frizzled-7 significantly improved neurological function, reduced brain water content and attenuated BBB permeability to large molecular weight substances after ICH. Whereas, knockdown of Frizzled-7 worsened neurological function and brain edema after ICH. Activation of Frizzled-7 significantly increased the expressions of Dvl, β-Catenin, WISP1, VE-Cadherin, Claudin-5, ZO-1 and reduced the expression of phospho-β-Catenin. WISP1 knockdown abolished the effects of Frizzled-7 activation on the expressions of VE-Cadherin, Claudin-5 and ZO-1 at 24 h after ICH. Conclusions Frizzled-7 activation potentially attenuated BBB permeability and improved neurological deficits after ICH through Dvl​​/β-Catenin/WISP1 pathway. Frizzled-7 may be a potential target for the development of ICH therapeutic drugs.


2019 ◽  
Vol 20 (3) ◽  
pp. 571 ◽  
Author(s):  
Shotaro Michinaga ◽  
Yutaka Koyama

The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage. Emerging evidence suggests key roles of astrocyte-derived factors in BBB disruption and recovery after brain damage. The astrocyte-derived vascular permeability factors include vascular endothelial growth factors, matrix metalloproteinases, nitric oxide, glutamate and endothelin-1, which enhance BBB permeability leading to BBB disruption. By contrast, the astrocyte-derived protective factors include angiopoietin-1, sonic hedgehog, glial-derived neurotrophic factor, retinoic acid and insulin-like growth factor-1 and apolipoprotein E which attenuate BBB permeability resulting in recovery of BBB function. In this review, the roles of these astrocyte-derived factors in BBB function are summarized, and their significance as therapeutic targets for BBB protection and recovery after brain damage are discussed.


2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qianshuo Liu ◽  
Xiaobai Liu ◽  
Defeng Zhao ◽  
Xuelei Ruan ◽  
Rui Su ◽  
...  

AbstractThe blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.


1999 ◽  
Vol 19 (9) ◽  
pp. 1020-1028 ◽  
Author(s):  
Yvan Gasche ◽  
Miki Fujimura ◽  
Yuiko Morita-Fujimura ◽  
Jean-Christophe Copin ◽  
Makoto Kawase ◽  
...  

During cerebral ischemia blood–brain barrier (BBB) disruption is a critical event leading to vasogenic edema and secondary brain injury. Gelatinases A and B are matrix metalloproteinases (MMP) able to open the BBB. The current study analyzes by zymography the early gelatinases expression and activation during permanent ischemia in mice (n = 15). ProMMP-9 expression was significantly ( P < 0.001) increased in ischemic regions compared with corresponding contralateral regions after 2 hours of ischemia (mean 694.7 arbitrary units [AU], SD ± 238.4 versus mean 107.6 AU, SD ± 15.6) and remained elevated until 24 hours (mean 745,7 AU, SD ± 157.4). Moreover, activated MMP-9 was observed 4 hours after the initiation of ischemia. At the same time as the appearance of activated MMP-9, we detected by the Evan's blue extravasation method a clear increase of BBB permeability, Tissue inhibitor of metalloproteinase-1 was not modified during permanent ischemia at any time. The ProMMP-2 was significantly ( P < 0.05) increased only after 24 hours of permanent ischemia (mean 213.2 AU, SD ± 60.6 versus mean 94.6 AU, SD ± 13.3), and no activated form was observed. The appearance of activated MMP-9 after 4 hours of ischemia in correlation with BBB permeability alterations suggests that MMP-9 may play an active role in early vasogenic edema development after stroke.


2017 ◽  
Vol 38 (11) ◽  
pp. 1979-1992 ◽  
Author(s):  
Jiajia Zhu ◽  
Xing Li ◽  
Jia Yin ◽  
Yafang Hu ◽  
Yong Gu ◽  
...  

The role of glycocalyx in blood–brain barrier (BBB) integrity and brain damage is poorly understood. Our study aimed to investigate the impacts of endothelial glycocalyx on BBB function in a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Male Sprague-Dawley rats subjected to 8-min asphyxia CA/CPR. Compared to controls, glycocalyx was mildly injured by CA, severely disrupted by hyaluronidase (HAase) with CA, and mitigated by hydrocortisone (HC) with CA. More importantly, the disruption of glycocalyx caused by HAase treatment was associated with higher BBB permeability and aggravated brain edema at 24 h after return of spontaneous circulation, as well as lower survival rate and poorer neurologic outcome at seventh day. Reversely, less degradation of glycocalyx by HC treatment was accompanied by higher seven-day survival rate and better neurologic outcome. Mechanistically, HAase treatment further increased CA/CPR-induced activation of glia cells and expression of inflammatory factors, whereas HC decreased them in the brain cortex and hippocampus. Glycocalyx degradation results in BBB leakage, brain edema, and deteriorates neurologic outcome after asphyxia CA/CPR in rats. Preservation of glycocalyx by HC could improve neurologic outcome and reduce BBB permeability, apparently through reduced gene transcription-protein synthesis and inflammation.


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