Journal: J Stroke

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Abstract

Neuroprotective Effects of GV1001 in Animal Stroke Model and Neural Cells Subject to Oxygen-Glucose Deprivation/Reperfusion Injury.

Kwon HS, Kim YE, Park HH, Son JW, ... Lee KY, Koh SH
Background:
and purpose
Previous studies have revealed the diverse neuroprotective effects of GV1001. In this study, we investigated the effects of GV1001 on focal cerebral ischemia-reperfusion injury (IRI) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in neural stem cells (NSCs) and cortical neurons.
Methods
Focal cerebral IRI was induced by transient middle cerebral artery occlusion (MCAO). Brain diffusion-weighted imaging (DWI) was performed 2 hours after occlusion, and a total of 37 rats were treated by reperfusion with GV1001 or saline 2 hours after occlusion. Fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging, immunohistochemistry, and neurobehavioral function analyses were performed. Additionally, OGD/R-injured NSCs and cortical neurons were treated with different GV1001 concentrations. Cell viability, proliferation, migration, and oxidative stress were determined by diverse molecular analyses.
Results
In the stroke model, GV1001 protected neural cells against IRI. The most effective dose of GV1001 was 60 μM/kg. The infarct volume on FLAIR 48 hours after MCAO compared to lesion volume on DWI showed a significantly smaller ratio in the GV1001-treated group. GV1001-treated rats exhibited better behavioral functions than the saline-treated rats. Treatment with GV1001 increased the viability, proliferation, and migration of the OGD/R-injured NSCs. Free radicals were significantly restored by treatment with GV1001. These neuroprotective effects of GV1001 have also been demonstrated in OGD/R-injured cortical neurons.
Conclusions
The results suggest that GV1001 has neuroprotective effects against IRI in NSCs, cortical neurons, and the rat brain. These effects are mediated through the induction of cellular proliferation, mitochondrial stabilization, and anti-apoptotic, anti-aging, and antioxidant effects.



J Stroke: 30 Aug 2021; 23:420-436
Kwon HS, Kim YE, Park HH, Son JW, ... Lee KY, Koh SH
J Stroke: 30 Aug 2021; 23:420-436 | PMID: 34649386
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Abstract

Effectiveness of Thrombectomy in Stroke According to Baseline Prognostic Factors: Inverse Probability of Treatment Weighting Analysis of a Population-Based Registry.

Rudilosso S, Ríos J, Rodríguez A, Gomis M, ... Chamorro Á, Catalan Stroke Code and Reperfusion (Cat-SCR) Consortium
Background:
and purpose
 In real-world practice, the benefit of mechanical thrombectomy (MT) is uncertain in stroke patients with very favorable or poor prognostic profiles at baseline. We studied the effectiveness of MT versus medical treatment stratifying by different baseline prognostic factors.
Methods
 Retrospective analysis of 2,588 patients with an ischemic stroke due to large vessel occlusion nested in the population-based registry of stroke code activations in Catalonia from January 2017 to June 2019. The effect of MT on good functional outcome (modified Rankin Score ≤2) and survival at 3 months was studied using inverse probability of treatment weighting (IPTW) analysis in three pre-defined baseline prognostic groups: poor (if pre-stroke disability, age >85 years, National Institutes of Health Stroke Scale [NIHSS] >25, time from onset >6 hours, Alberta Stroke Program Early CT Score <6, proximal vertebrobasilar occlusion, supratherapeutic international normalized ratio >3), good (if NIHSS <6 or distal occlusion, in the absence of poor prognostic factors), or reference (not meeting other groups\' criteria).
Results
 Patients receiving MT (n=1,996, 77%) were younger, had less pre-stroke disability, and received systemic thrombolysis less frequently. These differences were balanced after the IPTW stratified by prognosis. MT was associated with good functional outcome in the reference (odds ratio [OR], 2.9; 95% confidence interval [CI], 2.0 to 4.4), and especially in the poor baseline prognostic stratum (OR, 3.9; 95% CI, 2.6 to 5.9), but not in the good prognostic stratum. MT was associated with survival only in the poor prognostic stratum (OR, 2.6; 95% CI, 2.0 to 3.3).
Conclusions
 Despite their worse overall outcomes, the impact of thrombectomy over medical management was more substantial in patients with poorer baseline prognostic factors than patients with good prognostic factors.



J Stroke: 30 Aug 2021; 23:401-410
Rudilosso S, Ríos J, Rodríguez A, Gomis M, ... Chamorro Á, Catalan Stroke Code and Reperfusion (Cat-SCR) Consortium
J Stroke: 30 Aug 2021; 23:401-410 | PMID: 34649384
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Abstract

Stroke Etiology and Outcomes after Endovascular Thrombectomy: Results from the SITS Registry and a Meta-Analysis.

Matusevicius M, Cooray C, Rand VM, Nunes AP, ... Holmin S, Ahmed N
Background:
and purpose
The influence of stroke etiology on outcomes after endovascular thrombectomy (EVT) is not well understood. We aimed to investigate whether stroke etiology subgrouped as large artery atherosclerosis (LAA) and cardiac embolism (CE) influences outcomes in large artery occlusion (LAO) treated by EVT.
Methods
We included EVT treated LAO stroke patients registered in the Safe Implementation of Treatment in Stroke (SITS) thrombectomy register between January 1, 2014 and September 3, 2019. Primary outcome was successful reperfusion (modified Treatment in Cerebral Infarction 2b-3). Secondary outcomes were symptomatic intracranial hemorrhage (SICH), 3-month functional independence (modified Ranking Scale 0-2) and death. Multivariable logistic regression models were used for comparisons. In addition, a meta-analysis of aggregate data from the current literature was conducted (PROSPERO, ID 167447).
Results
Of 7,543 patients, 1,903 (25.2%) had LAA, 3,214 (42.6%) CE, and 2,426 (32.2%) unknown, other, or multiple etiologies. LAA patients were younger (66 vs. 74, P<0.001) and had lower National Institutes of Health Stroke Scale score at baseline (15 vs. 16, P<0.001) than CE patients. Multivariable analyses showed that LAA patients had lower odds of successful reperfusion (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.57 to 0.86) and functional independence (OR, 0.74; 95% CI, 0.63 to 0.85), higher risk of death (OR, 1.44; 95% CI, 1.21 to 1.71), but no difference in SICH (OR, 1.09; 95% CI, 0.71 to 1.66) compared to CE patients. The systematic review found 25 studies matching the criteria. The meta-analysis did not find any difference between etiologies.
Conclusions
From the SITS thrombectomy register, we observed a lower chance of reperfusion and worse outcomes after thrombectomy in patients with LAA compared to CE etiology, despite more favorable baseline characteristics. In contrast, the meta-analysis did not find any difference between etiologies with aggregate data.



J Stroke: 30 Aug 2021; 23:388-400
Matusevicius M, Cooray C, Rand VM, Nunes AP, ... Holmin S, Ahmed N
J Stroke: 30 Aug 2021; 23:388-400 | PMID: 34649383
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Abstract

Impact of Multiphase Computed Tomography Angiography for Endovascular Treatment Decision-Making on Outcomes in Patients with Acute Ischemic Stroke.

Ospel JM, Volny O, Qiu W, Najm M, ... Goyal M, Menon BK
Background:
and purpose
Various imaging paradigms are used for endovascular treatment (EVT) decision-making and outcome estimation in acute ischemic stroke (AIS). We aim to compare how these imaging paradigms perform for EVT patient selection and outcome estimation.
Methods
Prospective multi-center cohort study of patients with AIS symptoms with multi-phase computed tomography angiography (mCTA) and computed tomography perfusion (CTP) baseline imaging. mCTA-based EVT-eligibility was defined as presence of large vessel occlusion (LVO) and moderate-to-good collaterals on mCTA. CTP-based eligibility was defined as presence of LVO, ischemic core (defined on relative cerebral blood flow, absolute cerebral blood flow, and cerebral blood volume maps) <70 mL, mismatch-ratio >1.8, absolute mismatch >15 mL. EVT-eligibility and adjusted rates of good outcome (modified Rankin Scale 0-2) based on these imaging paradigms were compared.
Results
Of 289/464 patients with LVO, 263 (91%) were EVT-eligible by mCTA-criteria versus 63 (22%), 19 (7%) and 103 (36%) by rCBF, aCBF, and CBV-CTP-criteria. CTP and mCTA-criteria were discordant in 40% to 53%. Estimated outcomes were best in patients who met both mCTA and CTP eligibility-criteria and were treated with EVT (62% to 87% good outcome). Patients eligible for EVT by mCTA-criteria and not by CTP-criteria receiving EVT achieved good outcome rates of 53% to 57%. Few patients met CTP-criteria and not mCTA-criteria for EVT.
Conclusions
Simpler imaging selection criteria that rely on little else than detection of the occluded blood vessel may be more sensitive and less specific, thus resulting in more patients being offered EVT and arguably benefiting from it.



J Stroke: 30 Aug 2021; 23:377-387
Ospel JM, Volny O, Qiu W, Najm M, ... Goyal M, Menon BK
J Stroke: 30 Aug 2021; 23:377-387 | PMID: 34649382
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Abstract

Soluble CD40 Levels in Plasma Are Associated with Cardiovascular Disease and in Carotid Plaques with a Vulnerable Phenotype.

Shami A, Edsfeldt A, Bengtsson E, Nilsson J, ... Lutgens E, Gonçalves I
Background:
and purpose
CD40 and CD40 ligand (CD40L) are costimulatory molecules of the tumor necrosis factor receptor superfamily and well known for their involvement in inflammatory diseases: atherosclerotic mouse models with disrupted CD40 signalling develop lesions of reduced size with a more stable plaque profile. This study investigated the potential of plasma and intraplaque levels of CD40 and CD40L as markers for cardiovascular disease (CVD) in humans and their association with plaque stability.
Methods
Soluble CD40 and CD40L (sCD40L) were measured in plasma in 1,437 subjects from The SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) cohort. Intra-plaque levels of sCD40 and sCD40L were measured in atherosclerotic plaque homogenates from 199 subjects of the Carotid Plaque Imaging Project (CPIP) cohort.
Results
Both plasma sCD40 and sCD40L levels were elevated in individuals with prevalent stroke, while sCD40 levels also were higher in individuals with a prior acute myocardial infarction. Plasma levels of sCD40 correlated with carotid intima-media thickness and total carotid plaque area and were associated with risk of cardiovascular events over a 3-year follow-up period. Intra-plaque levels of sCD40 and sCD40L were associated with plaque components characteristic for plaque vulnerability and extracellular matrix remodelling.
Conclusions
Higher plasma sCD40 and sCD40L levels are associated with prevalent CVD. Plasma sCD40 levels also correlate with the severity of carotid atherosclerosis and predict future cardiovascular events, while intra-plaque levels correlate with a vulnerable plaque phenotype. Our findings thus demonstrate that elevated levels of sCD40 and sCD40L are markers of CVD.



J Stroke: 30 Aug 2021; 23:367-376
Shami A, Edsfeldt A, Bengtsson E, Nilsson J, ... Lutgens E, Gonçalves I
J Stroke: 30 Aug 2021; 23:367-376 | PMID: 34649381
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Abstract

Mechanical Thrombectomy in Patients with a Large Ischemic Volume at Presentation: Systematic Review and Meta-Analysis.

Kerleroux B, Janot K, Hak JF, Kaesmacher J, ... Cagnazzo F, Boulouis G
The benefits of mechanical thrombectomy (MT) for patients with acute ischemic stroke (AIS) and a large ischemic core (LIC) at presentation are uncertain. We aimed to obtain up-to-date aggregate estimates of the outcomes following MT in patients with volumetrically assessed LIC. We conducted a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-conformed, PROSPERO-registered, systematic review and meta-analysis of studies that included patients with AIS and a baseline LIC treated with MT, reported ischemic core volume quantitatively, and included patients with a LIC defined as a core volume ≥50 mL. The search was restricted to studies published between January 2015 and June 2020. Random-effects-meta-analysis was used to assess the effect of MT on 90-day unfavorable outcome (i.e., modified Rankin Scale [mRS] 3-6), mortality, and symptomatic intracranial hemorrhage (sICH) occurrence. Sensitivity analyses were performed for imaging-modality (computed tomography-perfusion or magnetic resonance-diffusion weighted imaging) and LIC-definition (≥50 or ≥70 mL). We analyzed 10 studies (954 patients), including six (682 patients) with a control group, allowing to compare 332 patients with MT to 350 who received best-medical-management alone. Overall, after MT the rate of patients with mRS 3-6 at 90 days was 74% (99% confidence interval [CI], 67 to 84; Z-value=7.04; I2=92.3%) and the rate of 90-day mortality was 36% (99% CI, 33 to 40; Z-value=-7.07; I2=74.5). Receiving MT was associated with a significant decrease in mRS 3-6 odds ratio (OR) 0.19 (99% CI, 0.11 to 0.33; P<0.01; Z-value=-5.92; I2=62.56) and in mortality OR 0.60 (99% CI, 0.34 to 1.06; P=0.02; Z-value=-2.30; I2=58.72). Treatment group did not influence the proportion of patients experiencing sICH, OR 0.96 (99% CI, 0.2 to 1.49; P=0.54; Z-value=-0.63; I2=64.74). Neither imaging modality for core assessment, nor LIC definition influenced the aggregated outcomes. Using aggregate estimates, MT appeared to decrease the risk of unfavorable functional outcome in patients with a LIC assessed volumetrically at baseline.



J Stroke: 30 Aug 2021; 23:358-366
Kerleroux B, Janot K, Hak JF, Kaesmacher J, ... Cagnazzo F, Boulouis G
J Stroke: 30 Aug 2021; 23:358-366 | PMID: 34649380
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Impact:
Abstract

Hemodynamics of Leptomeningeal Collaterals after Large Vessel Occlusion and Blood Pressure Management with Endovascular Treatment.

Kim BJ, Singh N, Menon BK
Endovascular therapy (EVT) is an effective treatment for ischemic stroke due to large vessel occlusion (LVO). Unlike intravenous thrombolysis, EVT enables visualization of the restoration of blood flow, also known as successful reperfusion in real time. However, until successful reperfusion is achieved, the survival of the ischemic brain is mainly dependent on blood flow from the leptomeningeal collaterals (LMC). It plays a critical role in maintaining tissue perfusion after LVO via pre-existing channels between the arborizing pial small arteries or arterioles overlying the cerebral hemispheres. In the ischemic territory where the physiologic cerebral autoregulation is impaired and the pial arteries are maximally dilated within their capacity, the direction and amount of LMC perfusion rely on the systemic perfusion, which can be estimated by measuring blood pressure (BP). After the EVT procedure, treatment focuses on mitigating the risk of hemorrhagic transformation, potentially via BP reduction. Thus, BP management may be a key component of acute care for patients with LVO stroke. However, the guidelines on BP management during and after EVT are limited, mostly due to the scarcity of high-level evidence on this issue. In this review, we aim to summarize the anatomical and physiological characteristics of LMC to maintain cerebral perfusion after acute LVO, along with a landscape summary of the literature on BP management in endovascular treatment. The objective of this review is to describe the mechanistic association between systemic BP and collateral perfusion after LVO and thus provide clinical and research perspectives on this topic.



J Stroke: 30 Aug 2021; 23:343-357
Kim BJ, Singh N, Menon BK
J Stroke: 30 Aug 2021; 23:343-357 | PMID: 34649379
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Abstract

Clot Composition Analysis as a Diagnostic Tool to Gain Insight into Ischemic Stroke Etiology: A Systematic Review.

Aliena-Valero A, Baixauli-Martín J, Torregrosa G, Tembl JI, Salom JB
Mechanical thrombectomy renders the occluding clot available for analysis. Insights into thrombus composition could help establish the stroke cause. We aimed to investigate the value of clot composition analysis as a complementary diagnostic tool in determining the etiology of large vessel occlusion (LVO) ischemic strokes (International Prospective Register of Systematic Reviews [PROSPERO] registration # CRD42020199436). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we ran searches on Medline (using the PubMed interface) and Web of Science for studies reporting analyses of thrombi retrieved from LVO stroke patients subjected to mechanical thrombectomy (January 1, 2006 to September 21, 2020). The PubMed search was updated weekly up to February 22, 2021. Reference lists of included studies and relevant reviews were hand-searched. From 1,714 identified studies, 134 eligible studies (97 cohort studies, 31 case reports, and six case series) were included in the qualitative synthesis. Physical, histopathological, biological, and microbiological analyses provided information about the gross appearance, mechanical properties, structure, and composition of the thrombi. There were non-unanimous associations of thrombus size, structure, and composition (mainly proportions of fibrin and blood formed elements) with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) etiology and underlying pathologies, and similarities between cryptogenic thrombi and those of known TOAST etiology. Individual thrombus analysis contributed to the diagnosis, mainly in atypical cases. Although cohort studies report an abundance of quantitative rates of main thrombus components, a definite clot signature for accurate diagnosis of stroke etiology is still lacking. Nevertheless, the qualitative examination of the embolus remains an invaluable tool for diagnosing individual cases, particularly regarding atypical stroke causes.



J Stroke: 30 Aug 2021; 23:327-342
Aliena-Valero A, Baixauli-Martín J, Torregrosa G, Tembl JI, Salom JB
J Stroke: 30 Aug 2021; 23:327-342 | PMID: 34649378
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Abstract

Mechanisms of Preconditioning Exercise-Induced Neurovascular Protection in Stroke.

Hafez S, Eid Z, Alabasi S, Darwiche Y, Channaoui S, Hess DC
Ischemic stroke is a leading cause of death and disability. Tissue plasminogen activator is the only U.S. Food and Drug Administration approved thrombolytic therapy for ischemic stroke patients till date. However, its use is limited due to increased risk of bleeding and narrow therapeutic window. Most of the preclinically tested pharmacological agents failed to be translated to the clinic. This drives the need for alternative therapeutic approaches that not only provide enhanced neuroprotection, but also reduce the risk of stroke. Physical exercise is a sort of preconditioning that provides the body with brief ischemic episodes that can protect the body from subsequent severe ischemic attacks like stroke. Physical exercise is known to improve cardiovascular health. However, its role in providing neuroprotection in stroke is not clear. Clinical observational studies showed a correlation between regular physical exercise and reduced risk and severity of ischemic stroke and better outcomes after stroke. However, the underlying mechanisms through which prestroke exercise can reduce the stroke injury and improve the outcomes are not completely understood. The purpose of this review is to: demonstrate the impact of exercise on stroke outcomes and show the potential role of exercise in stroke prevention and recovery; uncover the underlying mechanisms through which exercise reduces the neurovascular injury and improves stroke outcomes aiming to develop novel therapeutic approaches.



J Stroke: 30 Aug 2021; 23:312-326
Hafez S, Eid Z, Alabasi S, Darwiche Y, Channaoui S, Hess DC
J Stroke: 30 Aug 2021; 23:312-326 | PMID: 34649377
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Abstract

Post-Stroke Cognitive Impairment: Pathophysiological Insights into Brain Disconnectome from Advanced Neuroimaging Analysis Techniques.

Lim JS, Lee JJ, Woo CW
The neurological symptoms of stroke have traditionally provided the foundation for functional mapping of the brain. However, there are many unresolved aspects in our understanding of cerebral activity, especially regarding high-level cognitive functions. This review provides a comprehensive look at the pathophysiology of post-stroke cognitive impairment in light of recent findings from advanced imaging techniques. Combining network neuroscience and clinical neurology, our research focuses on how changes in brain networks correlate with post-stroke cognitive prognosis. More specifically, we first discuss the general consequences of stroke lesions due to damage of canonical resting-state large-scale networks or changes in the composition of the entire brain. We also review emerging methods, such as lesion-network mapping and gradient analysis, used to study the aforementioned events caused by stroke lesions. Lastly, we examine other patient vulnerabilities, such as superimposed amyloid pathology and blood-brain barrier leakage, which potentially lead to different outcomes for the brain network compositions even in the presence of similar stroke lesions. This knowledge will allow a better understanding of the pathophysiology of post-stroke cognitive impairment and provide a theoretical basis for the development of new treatments, such as neuromodulation.



J Stroke: 30 Aug 2021; 23:297-311
Lim JS, Lee JJ, Woo CW
J Stroke: 30 Aug 2021; 23:297-311 | PMID: 34649376
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Impact:

This program is still in alpha version.