Abstract 712: Screening of Thrombolytic Agents in vivo Using a Novel Zebrafish Model of Ischemic Stroke Induced by Photochemical Thrombosis

Background: Timely thrombolytic therapy for acute ischemic stroke is important for improving neurological prognosis. Screening of thrombolytic agents on contemporary animal models of focal ischemic stroke is generally difficult as they require sophisticated surgical procedures such as induction of cerebral artery occlusion through mechanical ligation. Herein we seek to develop a novel zebrafish (Danio rerio) model of acute ischemic stroke for screening of thrombolytic drugs. Methods: All experiments were performed on a modified confocal optical microscope, which allows the induction of thrombosis at a selected blood vessel of larval zebrafish and the imaging of thrombotic and thrombolytic processes in real time. To initiate photochemical thrombosis, a 532-nm laser was focused at a blood vessel of a larva (4 dpf) that had been injected with a photosensitizer (rose bengal). To test the thrombolytic activity of tPA, we injected tPA to the blood vessel of a larval with a thrombus that partially occluded the blood flow. Results: Through photochemical means, we induced endothelial injury at selected blood vessel which subsequently triggered thrombosis. We show that an occlusion at the 1st branch of central artery drastically diminished the hemodynamics and cardiac function of larval zebrafish and impaired their capability to maintain balance during swimming whereas that at the basilar artery resulted in a high death rate. Immunofluorescent imaging shows that the photochemically induced thrombus comprised fibrins and platelets. After the injection of tPA to a larval with a partially occluded blood vessel, the fibrin mesh on the thrombus appeared sparse and limp which eventually led to the restoration of blood flow. Conclusions: Our zebrafish model of ischemic stroke is convenient to adapt and is highly reproducible. This model can potentially become an effective platform that benefits the screening of thrombolytic agents and the optimization of their dose.

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THE MISMATCH BETWEEN CEREBRAL BLOOD FLOW AND TMAX PREDICTS THE QUALITY OF COLLATERALS IN ACUTE ISCHEMIC STROKE

10.26226/morressier.58e389b1d462b80292385155 ◽

2017 ◽

Author(s):

Ivana Galinovic

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Ischemic Stroke ◽

Acute Ischemic Stroke

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A Larval Zebrafish Model for Assessing Hypoxic‐Induced In Vivo Cardiomyocyte Damage: Time Course for Induction and Cardiac Output Recovery

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.05935 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Warren Burggren ◽

Regina Abramova ◽

Naim Bautista ◽

Regina Fritsche Danielson ◽

Avi Gupta ◽

...

Keyword(s):

Cardiac Output ◽

Time Course ◽

Zebrafish Model ◽

Larval Zebrafish

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The impact of leptomeningeal collaterals in acute ischemic stroke

10.21203/rs.3.rs-36392/v1 ◽

2020 ◽

Author(s):

Nida Fatima ◽

Maher Saqqur ◽

Ashfaq Shuaib

Keyword(s):

Blood Flow ◽

Ischemic Stroke ◽

Clinical Outcome ◽

Acute Ischemic Stroke ◽

Meta Analysis ◽

Random Effect ◽

Random Effect Model ◽

Mesh Terms ◽

Favorable Clinical Outcome ◽

The Impact

Abstract Objectives: Leptomeningeal collaterals provide an alternate pathway to maintain cerebral blood flow in stroke to prevent ischemia, but their role in predicting outcome is still unclear. So, our study aims at assessing the significance of collateral blood flow (CBF) in acute stroke. Methods: Electronic databases were searched under different MeSH terms from Jan 2000 to Feb 2019. Studies were included if there was available data on good and poor CBF in acute ischemic stroke (AIS). The clinical outcomes included were modified rankin scale (mRS), recanalization, mortality, and symptomatic intracranial hemorrhage (sICH) at 90 days. Data was analyzed using random-effect model.Results: A total of 47 studies with 8,194 patients were included. Pooled meta-analysis revealed that there exist 2-fold higher likelihood of favorable clinical outcome (mRS≤2) at 90 days with good CBF compared with poor CBF (RR: 2.27; 95%CI: 1.94-2.65; p<0.00001) irrespective of the thrombolytic therapy [RR with IVT: 2.90; 95%CI: 2.14-3.94; p<0.00001, and RR with IAT/EVT: 1.99; 95% CI: 1.55-2.55; p<0.00001]. Moreover, there exists 1-fold higher probability of successful recanalization with good CBF (RR: 1.31; 95% CI: 1.15-1.49; p<0.00001). However, there was 54% and 64% lower risk of sICH and mortality respectively in patients with good CBF in AIS (p<0.00001).Conclusions: The relative risk of favorable clinical outcome is more in patients with good pretreatment CBF. This could be explained due to better chances of recanalization, combined with lesser risk of intracerebral hemorrhage in good CBF status.

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2D Parametric Parenchymal Blood Flow as a Predictor of the Hemorrhagic Events after Endovascular Treatment of Acute Ischemic Stroke: A Single-Center Retrospective Study

Interventional Neurology ◽

10.1159/000491762 ◽

2018 ◽

Vol 7 (6) ◽

pp. 522-532 ◽

Cited By ~ 4

Author(s):

Nada Elsaid ◽

Ahmed Saied ◽

Krishna Joshi ◽

Jessica Nelson ◽

John Baumgart ◽

...

Keyword(s):

Blood Flow ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Dual Energy Ct ◽

Anterior Circulation ◽

Brain Scans ◽

Increased Risk ◽

Significant Difference ◽

Hemorrhagic Events ◽

Ct Brain

Background and Purpose: Intracranial hemorrhage (ICH) is one of the major adverse events related to the endovascular management of acute ischemic stroke. It is important to evaluate the risk of ICH as it may result in clinical deterioration of the patients. Development of tools which can predict the risk of ICH after thrombectomy can reduce the procedure-related morbidity and mortality. 2D parenchymal blood flow could potentially act as an indicator for ICH. Methods: 2D parenchymal blood flow was used to evaluate pre- and postthrombectomy digital subtraction angiography series of patients with acute ischemic stroke in the anterior circulation. A recently developed software allows the separation of the vascular filling and parenchymal blush signals using band-pass and band-reject filtering to allow for greater visibility of the parenchyma offering a better visual indicator of the effect of treatment. The “wash-in rate” was selected as the parameter of interest to predict ICH. Results: According to the presence or absence of signs of intracranial parenchymal hemorrhage in the follow-up dual-energy CT brain scans, the patients were classified into a hemorrhagic and nonhemorrhagic group (15 patients each). The only significant difference between the groups is the calculated wash-in rate after thrombectomy (p = 0.024). The cutoff value of the wash-in rate after thrombectomy was suggested to be 11,925.0, with 60% sensitivity to predict the hemorrhage and 93.3% specificity. Conclusions: Elevated parametric parenchymal blood flow wash-in rates after thrombectomy may be associated with increased risk of hemorrhagic events.

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Early microvascular cerebral blood flow response to head-of-bed elevation is related to outcome in acute ischemic stroke

Journal of Neurology ◽

10.1007/s00415-019-09226-y ◽

2019 ◽

Vol 266 (4) ◽

pp. 990-997 ◽

Cited By ~ 4

Author(s):

Clara Gregori-Pla ◽

Igor Blanco ◽

Pol Camps-Renom ◽

Peyman Zirak ◽

Isabel Serra ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Blood Flow Response ◽

Bed Elevation ◽

Flow Response ◽

Head Of Bed Elevation

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Acute Ischemic Stroke

10.1093/med/9780199937837.003.0101 ◽

2017 ◽

Author(s):

Harold P. Adams

Keyword(s):

Public Health ◽

Blood Flow ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Health Problem ◽

Neurological Disease ◽

Public Health Problem ◽

Neurological Outcomes ◽

Success Of Treatment ◽

Early Restoration

Ischemic stroke is a leading public health problem and the most common acute neurological disease. Advances in the understanding of the pathophysiology of stroke, in particular the importance of early restoration of adequate perfusion, have resulted in improvements in the management of patients with acute ischemic stroke. The interval from onset of stroke until the administration of interventions to restore blood flow is a crucial factor in success of treatment. Still, patients with stroke now are being treated successfully with neurological outcomes improving. These advances are reducing the likelihood of death or disability from this potentially devastating neurological disease.

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AP-1 (Activated Protein-1) Transcription Factor JunD Regulates Ischemia/Reperfusion Brain Damage via IL-1β (Interleukin-1β)

Stroke ◽

10.1161/strokeaha.118.023739 ◽

2019 ◽

Vol 50 (2) ◽

pp. 469-477 ◽

Cited By ~ 10

Author(s):

Candela Diaz-Cañestro ◽

Martin F. Reiner ◽

Nicole R. Bonetti ◽

Luca Liberale ◽

Mario Merlini ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Acute Ischemic Stroke ◽

Peripheral Blood ◽

Ischemia Reperfusion ◽

Interleukin 1Β ◽

Blood Monocytes ◽

Peripheral Blood Monocytes

Background and Purpose— Inflammation is a major pathogenic component of ischemia/reperfusion brain injury, and as such, interventions aimed at inhibiting inflammatory mediators promise to be effective strategies in stroke therapy. JunD—a member of the AP-1 (activated protein-1) family of transcription factors—was recently shown to regulate inflammation by targeting IL (interleukin)-1β synthesis and macrophage activation. The purpose of the present study was to assess the role of JunD in ischemia/reperfusion-induced brain injury. Methods— WT (wild type) mice randomly treated with either JunD or scramble (control) siRNA were subjected to 45 minutes of transient middle cerebral artery occlusion followed by 24 hours of reperfusion. Stroke size, neurological deficit, plasma/brain cytokines, and oxidative stress determined by 4-hydroxynonenal immunofluorescence staining were evaluated 24 hours after reperfusion. Additionally, the role of IL-1β was investigated by treating JunD siRNA mice with an anti–IL-1β monoclonal antibody on reperfusion. Finally, JunD expression was assessed in peripheral blood monocytes isolated from patients with acute ischemic stroke. Results— In vivo JunD knockdown resulted in increased stroke size, reduced neurological function, and increased systemic inflammation, as confirmed by higher neutrophil count and lymphopenia. Brain tissue IL-1β levels were augmented in JunD siRNA mice as compared with scramble siRNA, whereas no difference was detected in IL-6, TNF-α (tumor necrosis factor-α), and 4-hydroxynonenal levels. The deleterious effects of silencing of JunD were rescued by treating mice with an anti–IL-1β antibody. In addition, JunD expression was decreased in peripheral blood monocytes of patients with acute ischemic stroke at 6 and 24 hours after onset of stroke symptoms compared with sex- and age-matched healthy controls. Conclusions— JunD blunts ischemia/reperfusion-induced brain injury via suppression of IL-1β.

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Computed Tomography Perfusion–Based Machine Learning Model Better Predicts Follow-Up Infarction in Patients With Acute Ischemic Stroke

Stroke ◽

10.1161/strokeaha.120.030092 ◽

2021 ◽

Vol 52 (1) ◽

pp. 223-231

Author(s):

Hulin Kuang ◽

Wu Qiu ◽

Anna M. Boers ◽

Scott Brown ◽

Keith Muir ◽

...

Keyword(s):

Computed Tomography ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Infarct Volume ◽

Interquartile Range ◽

Time Dependent ◽

Computed Tomography Perfusion

Background and Purpose: Prediction of infarct extent among patients with acute ischemic stroke using computed tomography perfusion is defined by predefined discrete computed tomography perfusion thresholds. Our objective is to develop a threshold-free computed tomography perfusion–based machine learning (ML) model to predict follow-up infarct in patients with acute ischemic stroke. Methods: Sixty-eight patients from the PRoveIT study (Measuring Collaterals With Multi-Phase CT Angiography in Patients With Ischemic Stroke) were used to derive a ML model using random forest to predict follow-up infarction voxel by voxel, and 137 patients from the HERMES study (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) were used to test the derived ML model. Average map, T max , cerebral blood flow, cerebral blood volume, and time variables including stroke onset-to-imaging and imaging-to-reperfusion time, were used as features to train the ML model. Spatial and volumetric agreement between the ML model predicted follow-up infarct and actual follow-up infarct were assessed. Relative cerebral blood flow <0.3 threshold using RAPID software and time-dependent T max thresholds were compared with the ML model. Results: In the test cohort (137 patients), median follow-up infarct volume predicted by the ML model was 30.9 mL (interquartile range, 16.4–54.3 mL), compared with a median 29.6 mL (interquartile range, 11.1–70.9 mL) of actual follow-up infarct volume. The Pearson correlation coefficient between 2 measurements was 0.80 (95% CI, 0.74–0.86, P <0.001) while the volumetric difference was −3.2 mL (interquartile range, −16.7 to 6.1 mL). Volumetric difference with the ML model was smaller versus the relative cerebral blood flow <0.3 threshold and the time-dependent T max threshold ( P <0.001). Conclusions: A ML using computed tomography perfusion data and time estimates follow-up infarction in patients with acute ischemic stroke better than current methods.

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