Blood Brain Barrier Disruption in Diabetic Stroke Related to Unfavorable Outcome

2016 ◽  
Vol 42 (1-2) ◽  
pp. 49-56 ◽  
Author(s):  
Xinfeng Yu ◽  
Xiaojun Xu ◽  
Alan Jackson ◽  
Jianzhong Sun ◽  
Peiyu Huang ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Blood Brain Barrier ◽  
Unfavorable Outcome ◽  
Brain Barrier ◽  
Diabetic Patients ◽  
Stroke Outcome ◽  
Ischemic Lesion ◽  
Post Contrast ◽  
Blood Brain ◽  
Wide Range

Background: Diabetes mellitus (DM) is associated with a wide range of microvascular abnormalities in the brain. These include the dysfunction of the blood brain barrier (BBB). In this study, we test the hypotheses that disruption of the BBB in patients presenting with acute stroke is common in patients with DM and is related to outcome. Methods: Sixty-two consecutive patients with ischemic stroke in the middle cerebral artery territory were enrolled within 3-7 days after onset. In ischemic lesion, BBB disruption was detected by parenchymal enhancement (PE) on 5 min delayed post-contrast T1 weighted imaging. National Institute of Health Stroke Score (NIHSS) assessed neurologic impairment on admission. Clinical outcome at 3 months was classified as unfavorable if the modified Rankin scale was >1. The independent factors associated with clinical outcome were analyzed using multivariate logistic regression analysis and OR with its 95% CIs were estimated. Results: An unfavorable stroke outcome was found in 19 diabetic patients and 21 non-diabetic patients. Diabetic patients had a significantly higher frequency of PE than non-diabetic patients (58.6 vs. 27.3%, p = 0.013) and DM was independently associated with PE (OR 4.40; 95% CI 1.22-15.83; p = 0.023). PE was significantly more common in diabetic patients with unfavorable stroke outcome (73.7%) than in other 3 subgroups: diabetic patients with favorable stroke outcome (30.0%), non-diabetic patients with favorable stroke outcome (38.1%) and unfavorable stroke outcome (8.3%; p = 0.002). PE was independently associated with unfavorable outcome (UO) in diabetic stroke (DS; OR 7.04; 95% CI 1.20-41.52; p = 0.031). Admission NIHSS score was associated with UO in non-DS (NDS) (OR 1.71; 95% CI 1.10-2.66; p = 0.017). Conclusions: Compared with NDS, DS had increased BBB disruption defined by the presence of PE. A different form of the relationship between admission NIHSS and UO in NDS, BBB disruption was related with UO in diabetic patients after stroke.

scholarly journals Combined Perfusion and Permeability Imaging Reveals Different Pathophysiologic Tissue Responses After Successful Thrombectomy

2021 ◽  
Author(s):  
Arne Potreck ◽  
Matthias A. Mutke ◽  
Charlotte S. Weyland ◽  
Johannes A. R. Pfaff ◽  
Peter A. Ringleb ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Blood Brain Barrier ◽  
Hemorrhagic Transformation ◽  
Brain Barrier ◽  
Dynamic Susceptibility ◽  
Blood Brain Barrier Disruption ◽  
Flow Maps ◽  
Blood Brain ◽  
Patients At Risk ◽  
Brain Barrier Disruption

AbstractDespite successful recanalization of large-vessel occlusions in acute ischemic stroke, individual patients profit to a varying degree. Dynamic susceptibility-weighted perfusion and dynamic T1-weighted contrast-enhanced blood-brain barrier permeability imaging may help to determine secondary stroke injury and predict clinical outcome. We prospectively performed perfusion and permeability imaging in 38 patients within 24 h after successful mechanical thrombectomy of an occlusion of the middle cerebral artery M1 segment. Perfusion alterations were evaluated on cerebral blood flow maps, blood-brain barrier disruption (BBBD) visually and quantitatively on ktrans maps and hemorrhagic transformation on susceptibility-weighted images. Visual BBBD within the DWI lesion corresponded to a median ktrans elevation (IQR) of 0.77 (0.41–1.4) min−1 and was found in all 7 cases of hypoperfusion (100%), in 10 of 16 cases of hyperperfusion (63%), and in only three of 13 cases with unaffected perfusion (23%). BBBD was significantly associated with hemorrhagic transformation (p < 0.001). While BBBD alone was not a predictor of clinical outcome at 3 months (positive predictive value (PPV) = 0.8 [0.56–0.94]), hypoperfusion occurred more often in patients with unfavorable clinical outcome (PPV = 0.43 [0.10–0.82]) compared to hyperperfusion (PPV = 0.93 [0.68–1.0]) or unaffected perfusion (PPV = 1.0 [0.75–1.0]). We show that combined perfusion and permeability imaging reveals distinct infarct signatures after recanalization, indicating the severity of prior ischemic damage. It assists in predicting clinical outcome and may identify patients at risk of stroke progression.

scholarly journals Severe Hypoglycemia Contributing to Cognitive Dysfunction in Diabetic Mice is Associated with Pericyte and Blood–Brain Barrier Dysfunction

2021 ◽  
Author(s):  
Lu Lin ◽  
Lishan Huang ◽  
Lijing Wang ◽  
Yubin Wu ◽  
Zhou Chen ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cognitive Dysfunction ◽  
Blood Brain Barrier ◽  
Severe Hypoglycemia ◽  
Brain Barrier ◽  
Blue Staining ◽  
Diabetic Patients ◽  
Inflammatory Factor ◽  
Diabetic Mice ◽  
Blood Brain

Abstract Background: Severe hypoglycemia can cause cognitive impairment in diabetic patients, but the underlying molecular mechanism remains unclear.Objective: To assess the effect of severe hypoglycemia on cognitive function in diabetic mice to clarify the relationship between the mechanism and dysfunction of pericytes and the blood–brain barrier (BBB).Method: We established type 1 diabetes mellitus in 80 male C57BL/6J mice by intraperitoneal injection of streptozotocin (180 mg/kg). Further abdominal injection of short-acting insulin induced severe hypoglycemia. The mice were divided into normal, diabetes, and diabetic + severe hypoglycemia groups, and their blood glucose and general weight index were examined. Pericyte and BBB morphology and function were detected by histological and western blot analyses, BBB permeability was detected by Evans blue staining, and cognitive function was detected with the Morris water maze.Results: Severe hypoglycemia aggravated the histological damage, BBB damage, brain edema, and pericyte loss in the diabetic mice. It also reduced the expression of the BBB tight junction proteins occludin and claudin-5, the expression of the pericyte-specific markers PDGFR-β (platelet-derived growth factor receptor-β) and α-SMA, and increased the expression of the inflammatory factor MMP9. At the same time, diabetic mice with severe hypoglycemia had significantly reduced cognitive function.Conclusion: Severe hypoglycemia leads to cognitive dysfunction in diabetic mice, and its possible mechanism is related to pericyte dysfunction and BBB destruction.

scholarly journals The Relationship Between Penumbral Tissue and Blood-Brain Barrier Disruption in Acute Stroke Patients Presenting in an Extended Time Window

2020 ◽  
Vol 11 ◽  
Author(s):  
Parisa Heidari ◽  
Sarah Blayney ◽  
Jarrhett Butler ◽  
Emi Hitomi ◽  
Marie Luby ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Time Window ◽  
Brain Barrier ◽  
Extended Time ◽  
Stroke Patients ◽  
Ischemic Lesion ◽  
Blood Brain ◽  
The Mean ◽  
Target Profile ◽  
The Relationship

Background: Penumbral brain tissue identified with multimodal imaging can be salvaged with reperfusion in an extended time window. The risk of severe hemorrhagic complications after reperfusion therapy increases with worsening disruption of the blood-brain barrier (BBB). The relationship between penumbral tissue and BBB disruption has not been previously studied.Methods: Stroke patients presenting in an extended time window without a large vessel occlusion who underwent diffusion-perfusion MRI within 24 h of last-seen-normal were included. The volume of penumbral tissue was calculated using mismatch on MRI. Mean permeability derangement (MPD) of the BBB was measured within the ischemic lesion. A target profile (TP) for treatment was defined based on the EXTEND trial.Results: 222 patients were included with a median age of 73 and 55% women. The median NIHSS was 6, the mean core volume was 14 ml, the mean ischemic volume was 47 mL and the mean mismatch volume was 33 mL. Higher MPD was significantly associated with less mismatch volume (p = 0.001). A target profile was associated with lower MPD (OR 0.97; CI 0.96:0.99; p &lt; 0.001). Of the 105 patients who had a TP, 31 (30%) had a MPD &gt; 20% suggesting an increased risk of hemorrhage. Thus, 33% (74/222) of patients had a favorable profile for benefit and safety.Conclusions: Patients presenting in an extended time window with a favorable penumbral profile for treatment have less severe BBB disruption. Up to a third of patients who currently go untreated could be considered for enrollment in a clinical trial of thrombolysis in an extended time window.

Abstract 1122‐000167: Hyperintense Acute Reperfusion Marker and Hemorrhagic Conversion in Stroke Patients Undergoing Mechanical Reperfusion

2021 ◽  
Vol 1 (S1) ◽  
Author(s):  
Pouria Moshayedi ◽  
Hamidreza Saber ◽  
David S Liebeskind ◽  
Jeffrey Gornbein ◽  
Bryan Yoo ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
White Matter ◽  
Clinical Outcome ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Periventricular White Matter ◽  
Vessel Occlusion ◽  
Blood Brain ◽  
Ischemic Core ◽  
Core Volume

Introduction : Endovascular thrombectomy (EVT) is a highly effective treatment to improve clinical outcome in patients with acute ischemic stroke due to large vessel occlusion (AIS‐LVO). However, blood‐brain barrier (BBB) disruption causing hemorrhagic transformation and reperfusion injury can potentially negate the beneficial effect of reperfusion. Studying determinants, frequency, and outcomes of the hyperintense acute reperfusion marker (HARM) sign, a biomarker of BBB disruption, would help to identify individual patients at increased risk, as well as developing therapies to prevent BBB breakdown. Methods : In consecutive AIS‐LVO patients with AIS‐LVO who underwent EVT followed by MRI within the next 24 hours, we evaluated frequency, determinants, and outcomes of HARM sign. Results : Among 81 patients meeting study criteria, age was 71.0 (SD 19.7), 58% female, mean NIHSS was 14.5 (SD 6.8), and time from last known well to treatment was 355 min (IQR 206.5 ‐ 664). HARM sign was observed in 64% (52/81) of patients. On multivariate logistic analysis, presence of HARM sign was independently associated with greater periventricular white matter hyperintensity, higher pre‐EVT ischemic core volume, more proximal target vessel occlusion, and achievement of successful reperfusion or better. Hemorrhagic conversion was seen in 31.8% of patients with HARM sign and 26.7% of patients without HARM sign. Multivariate analysis identified higher blood glucose, lower ASPECT, score and greater post‐EVT ischemic core volume as independent predictors of hemorrhagic conversion. HARM sign was identified to correlate with poor clinical outcome in bivariate analysis, but multivariate analysis only identified less neurological deficits, lower baseline systolic BP, lower degree of periventricular white matter hyperintensities, shorter time to device deployment and reduced post EVT ischemic core volume as independent predictors of good clinical outcome (mRS 0–2) upon discharge. Conclusions : The HARM sign indicating disruption of the blood‐brain barrier following EVT is common, present in about 6 of every 10 treated patients. Independent risk factors for HARM sign are chronic ischemic microangiopathy, greater acute ischemic core, and successful reperfusion. HARM sign presence is associated with worse functional outcome.

Quantitative contrast-enhanced magnetic resonance imaging to evaluate blood-brain barrier integrity in multiple sclerosis: a preliminary study

2001 ◽  
Vol 7 (2) ◽  
pp. 75-82 ◽  
Author(s):  
N C Silver ◽  
P S Tofts ◽  
M R Symms ◽  
G J Barker ◽  
A J Thompson ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Multiple Sclerosis ◽  
White Matter ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Resonance Imaging ◽  
Post Contrast ◽  
Time Points ◽  
Normal Appearing White Matter ◽  
Blood Brain

Gadolinium enhanced magnetic resonance imaging detects focal blood-brain barrier breakdown in new inflammatory multiple sclerosis lesions, but such lesions do not correlate with disease progression. To explore whether the latter might relate to subtle but widespread blood-brain barrier (BBB) breakdown with low grade inflammation mediating tissue damage, quantitative techniques were used to detect subtle gadolinium enhancement within otherwise normal-appearing white matter and within lesions not showing visible enhancement. T1-weighted imaging was performed prior to and at 5, 20 and 40 min following injection of 0.3 mmol/kg gadopentate dimeglumine in 33 patients with multiple sclerosis and five healthy control subjects. In healthy controls, a significant increase in white matter signal 5 min following contrast injection was observed (1.8%, P < 0.0005); the signal returned to baseline values by 20 min. In multiple sclerosis patients, a non-significant trend was noted for signal to remain elevated in normal-appearing white matter at the 20 and 40 min post-contrast time points; this was most apparent in primary progressive multiple sclerosis. Significant increases in signal intensity were noted at all time points post contrast in apparent non-enhancing lesions. The transient post contrast signal increase in controls is likely due to intravascular gadopentate dimeglumine. The persistent increases in signal intensity in non-enhancing lesions suggest more widespread abnormalities in BBB than is visually apparent, but substantiation of BBB leakage in normal appearing white matter will require further study using more sensitive methods.

Oatp58Dc contributes to blood-brain barrier function by excluding organic anions from the Drosophila brain

2013 ◽  
Vol 305 (5) ◽  
pp. C558-C567 ◽  
Author(s):  
Sara Seabrooke ◽  
Michael J. O'Donnell
Keyword(s):  
Blood Brain Barrier ◽  
Organic Anion ◽  
Complex Structure ◽  
Critical Role ◽  
Organic Anions ◽  
Molecular Techniques ◽  
Brain Barrier ◽  
Blood Brain ◽  
Wide Range ◽  
The Brain

The blood-brain barrier (BBB) physiologically isolates the brain from the blood and, thus, plays a vital role in brain homeostasis. Ion transporters play a critical role in this process by effectively regulating access of chemicals to the brain. Organic anion-transporting polypeptides (Oatps) transport a wide range of amphipathic substrates and are involved in efflux of chemicals across the vertebrate BBB. The anatomic complexity of the vascularized vertebrate BBB, however, creates challenges for experimental analysis of these processes. The less complex structure of the Drosophila BBB facilitates measurement of solute transport. Here we investigate a physiological function for Oatp58Dc in transporting small organic anions across the BBB. We used genetic manipulation, immunocytochemistry, and molecular techniques to supplement a whole animal approach to study the BBB. For this whole animal approach, the traceable small organic anion fluorescein was injected into the hemolymph. This research shows that Oatp58Dc is involved in maintaining a chemical barrier against fluorescein permeation into the brain. Oatp58Dc expression was found in the perineurial and subperineurial glia, as well as in postmitotic neurons. We specifically targeted knockdown of Oatp58Dc expression in the perineurial and subperineurial glia to reveal that Oatp58Dc expression in the perineurial glia is necessary to maintain the barrier against fluorescein influx into the brain. Our results show that Oatp58Dc contributes to maintenance of a functional barrier against fluorescein influx past the BBB into the brain.

scholarly journals Infection of brain pericytes underlying neuropathology of COVID-19 patients

2021 ◽  
Author(s):  
Matteo Bocci ◽  
Clara Oudenaarden ◽  
Xavier Saenz-Sardà ◽  
Joel Simrén ◽  
Arvid Edén ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Vascular Inflammation ◽  
Vascular Wall ◽  
Brain Barrier ◽  
Blood Brain ◽  
Viral Particles ◽  
Brain Pericytes ◽  
Wide Range ◽  
Human Brains ◽  
Pericyte Marker

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69,5 years; and n = 7 control, median age = 68 years), and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in peri-vascular cells. Viral particles were identified in the vascular wall and paralleled by peri-vascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from an additional 16 individuals (n = 8 COVID-19, median age = 67 years; and n = 8 control, median age = 69,5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to peri-vascular inflammation and a locally compromised blood-brain barrier.

scholarly journals Three-dimensional microenvironment regulates gene expression, function, and tight junction dynamics of iPSC-derived blood-brain barrier microvessels

2021 ◽  
Author(s):  
Raleigh M. Linville ◽  
Matthew B. Sklar ◽  
Gabrielle N. Grifno ◽  
Renee F. Nerenberg ◽  
Justin Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Three Dimensional ◽  
Brain Barrier ◽  
Time Dynamics ◽  
Blood Brain ◽  
Wide Range ◽  
3D Microenvironment

The blood-brain barrier (BBB) plays a pivotal role in brain health and disease. In the BBB, brain microvascular endothelial cells (BMECs) are connected by tight junctions which regulate paracellular transport, and express specialized transporter systems which regulate transcellular transport. However, existing in vitro models of the BBB display variable physiological accuracy across a wide range of characteristics including gene/protein expression and barrier function. Here, we use an isogenic family of fluorescently-labeled iPSC-derived BMEC-like cells (iBMECs) and brain pericyte-like cells (iPCs) within two-dimensional confluent monolayers (2D) and three-dimensional (3D) tissue-engineered microvessels to explore how 3D microenvironment regulates gene expression and function of the in vitro BBB. We show that 3D microenvironment (shear stress, cell-ECM interactions, and cylindrical geometry) increases BBB phenotype and endothelial identity, and alters angiogenic and cytokine responses in synergy with pericyte co-culture. Tissue-engineered microvessels incorporating junction-labeled iBMECs enable study of the real-time dynamics of tight junctions during homeostasis and in response to physical and chemical perturbations.

Abstract T P363: Blood-Brain Barrier Damage in Vascular Risk Factor Associated White Matter Disease

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Richard Leigh ◽  
Peter B Barker ◽  
Argye E Hillis
Keyword(s):  
Risk Factor ◽  
White Matter ◽  
Blood Brain Barrier ◽  
Vascular Risk Factor ◽  
Brain Barrier ◽  
White Matter Disease ◽  
Vascular Risk ◽  
Post Contrast ◽  
Blood Brain ◽  
Blood Brain Barrier Damage

Background: Vascular risk factor associated white matter disease (WMD), or leukoaraiosis, has been shown to demonstrate blood brain barrier damage (BBB) in patients with vascular dementia even when not detectable with standard clinical T1 post-contrast imaging. Purpose: We sought to study the prevalence of white matter BBB damage in a population of patients admitted to an inpatient stroke service. Methods: MRI scans of patients admitted for TIA or stroke were reviewed for evidence of confluent WMD in the centrum semiovale (CSO). To be included in the study patients must also have undergone a successful DSC image acquisition, also known as perfusion weighted image (PWI). The source images of the PWI were analyzed to generate blood-brain permeability images (BBPI) as described in a previous publication (Leigh et al, PLOS One 2012). The CSO in the first image above the lateral ventricles was used in each patient to generate BBPI measures. The pre-injection images of the PWI are T2* weighted and were therefore used to outline the area of confluent T2 signal change bilaterally. No acute strokes were present in any CSO analyzed as confirmed on DWI. The mean percent leakage (MPL) of contrast was calculated for each patient. A threshold of 2% of cerebral blood volume (CBV) was used to differentiate BBB damage from noise. Results: 20 patients were included in the study, 8 were female, with a mean age of 65 years. The diagnosis was stroke in 15 patients and TIA in 5 patients. The location of the strokes were 5 pons, 3 basil ganglia, 3 periventricular, 1 thalamus, 1 cerebellar, 1 PCA, and 1 embolic shower. Of the 20 patients, 11 stroke patients and 3 TIA patients demonstrated BBB damage. The MPL ranged from 2.1% to 23.7% with an average value of 6.9% (of CBV). The MPL was even higher for the TIA group (12.2%) than for the for the stroke group (5.4%), although this difference failed to reach significance (p=0.056) . Conclusions: In patients admitted for stroke evaluation, BBB damage in confluent WMD is common. The relevance of this finding remains unclear. However there appears to be a trend towards increased BBB damage in patients who present with events that do not localize to an acute stroke; further research should be directed at establishing the clinical implications of BBB damage in this population.

scholarly journals Impaired Cerebral Perfusion in Multiple Sclerosis: Relevance of Endothelial Factors

2018 ◽  
Vol 13 ◽  
pp. 117727191877480 ◽  
Author(s):  
Lucia Monti ◽  
Lucia Morbidelli ◽  
Alessandro Rossi
Keyword(s):  
Multiple Sclerosis ◽  
Blood Brain Barrier ◽  
Imaging Techniques ◽  
Brain Perfusion ◽  
Brain Barrier ◽  
Vasoactive Substances ◽  
Blood Brain ◽  
Wide Range ◽  
Magnetic Resonance Imaging Techniques

Magnetic resonance imaging techniques measuring in vivo brain perfusion and integrity of the blood-brain barrier have developed rapidly in the past decade, resulting in a wide range of available methods. This review first discusses their principles, possible pitfalls, and potential for quantification and outlines clinical application in neurological disorders. Then, we focus on the endothelial cells of the blood-brain barrier, pointing out their contribution in regulating vascular tone by production of vasoactive substances. Finally, the role of these substances in brain hypoperfusion in multiple sclerosis is discussed.

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