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Background and Purpose: Early and reliable prediction of hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS) is crucial for treatment decisions and early intervention. The purpose of this study was to conduct a systematic review and meta‐analysis on the performance of artificial intelligence (AI) and machine learning (ML) models that utilize neuroimaging to predict HT. Methods: A systematic search of PubMed, EMBASE, and Web of Science was conducted until February 19, 2024. Inclusion criteria were as follows: patients with AIS who received reperfusion therapy; AI/ML algorithm using imaging to predict HT; or presence of sufficient data on the predictive performance. Exclusion criteria were as follows: articles with less than 20 patients; articles lacking algorithms that operate solely on images; or articles not detailing the algorithm used. The quality of eligible studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies‐2 and Checklist for Artificial Intelligence in Medical Imaging. Pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated using a random‐effects model, and a summary receiver operating characteristic curve was constructed using the Reitsma method. Results: We identified six eligible studies, which included 1640 patients. Aside from an unclear risk of bias regarding flow and timing identified in two of the studies, all studies showed low risk of bias and applicability concerns in all categories. Pooled sensitivity, specificity, and DOR were.849,.878, and 45.598, respectively. Conclusion: AI/ML models can reliably predict the occurrence of HT in AIS patients. More prospective studies are needed for subgroup analyses and higher clinical certainty and usefulness. [ABSTRACT FROM AUTHOR]

Intravenous thrombolysis using recombinant tissue plasminogen activator (tPA) remains the primary treatment for patients with acute ischemic stroke (AIS). However, the mechanism of tPA-related hemorrhagic transformation (HT) remains poorly understood. Elevation of histidine-rich glycoprotein (HRG) expression was detected by nano-liquid chromatography tandem mass spectrometry at 1 h following tPA infusion as compared to baseline prior to tPA infusion (discovery cohort, n = 10), which was subsequently confirmed in a validation cohort (n = 157) by ELISA. Surprisingly, no elevation of HRG was detected in individuals who subsequently developed HT. During in vitro experiments, HRG reduced neutrophil NETosis, inflammatory cytokine production, and migration across the blood–brain barrier induced by tPA. In a photothrombotic murine AIS model, HRG administration ameliorated HT with delayed thrombolysis, by inhibiting neutrophil immune infiltration and downregulating pro-inflammatory signaling pathways. Neutrophil depletion or NETosis inhibition also alleviated HT, whereas HRG siRNA treatment exacerbated HT. In conclusion, fluctuations in HRG levels may reflect tPA therapy and its associated HT. The inhibitory effect of HRG on neutrophils may counteract tPA-induced immune abnormalities and HT in patients with AIS. Synopsis: Histidine-rich glycoprotein (HRG) was found to be increased in plasma following thrombolysis by tissue plasminogen activator (tPA) infusion, which counteracted the hemorrhagic-prone state through inhibiting neutrophil NETosis and migration, ultimately reducing the risk of hemorrhage. Plasma levels of HRG increase following tPA treatment in patients with acute ischemic stroke. Elevated HRG levels in patients with AIS correlated with reduced hemorrhagic transformation after thrombolysis. HRG administration inhibited neutrophil NETosis and migration through the blood–brain barrier in vitro and in an animal model of middle cerebral artery occlusion, ultimately reducing hematoma and neurological deficits. Histidine-rich glycoprotein (HRG) was found to be increased in plasma following thrombolysis by tissue plasminogen activator (tPA) infusion, which counteracted the hemorrhagic-prone state through inhibiting neutrophil NETosis and migration, ultimately reducing the risk of hemorrhage. [ABSTRACT FROM AUTHOR]

Background and Purpose: Hemorrhagic transformation (HT) is a common complication of endovascular thrombectomy (EVT) in patients with acute ischemic stroke (AIS). Our study aims to investigate the clinical and imaging predictors of HT and symptomatic intracranial hemorrhage (sICH) in patients who underwent EVT. Methods: A retrospective analysis of 118 patients undergoing EVT for acute anterior circulation stroke was performed. Potential clinical and imaging predictors of all patients were collected and multivariate logistic regression was performed. The risk prediction system was constructed according to the multivariate logistic regression results. Results: The incidence of HT and sICH after EVT were 46.6% and 15.3%, respectively. The multivariate logistic regression results showed that Alberta Stroke Program Early CT Score (ASPECTS) (p =.001, odds ratio [OR] = 0.367, 95% [confidence interval] CI, 0.201‐0.670), collateral status (p<.001, OR = 0.117, 95% CI, 0.042‐0.325), relative cerebral blood flow (CBF) ratio (p =.025, OR = 0.943, 95% CI, 0.895‐0.993), and blood glucose on admission (p =.012, OR = 1.258, 95% CI, 1.053‐1.504) were associated with HT. While for sICH, collateral circulation (p =.007, OR = 0.148, 95% CI, 0.037‐0.589), ASPECTS (p =.033, OR = 0.510, 95% CI, 0.274‐0.946), and blood glucose (p =.005, OR = 1.304, 95% CI, 1.082‐1.573) were independent factors. The predictive model for HT after EVT was established, and the sensitivity and specificity of it were 90.9% and 79.4%, respectively, with the area under the curve of 90.0% (84.5%‐95.4%). Conclusion: Collateral status, ASPECTS, relative CBF ratio, and blood glucose on admission were predictors for HT in AIS patients, while collateral status, ASPECTS, and blood glucose on admission were also predictors for sICH. In addition, the established predictive model showed good diagnostic value for prediction of HT after EVT. [ABSTRACT FROM AUTHOR]

Background and Purpose: Hemorrhagic transformation (HT) has been reported in up to 50% of acute ischemic stroke (AIS) patients with a large vessel occlusion (LVO) treated with endovascular thrombectomy (EVT). HT may be driven by postrecanalization hyperperfusion injury and is independently associated with worse functional outcomes. Strategies to identify patients at risk for HT may assist in developing preventive therapies. Methods: We prospectively included adult AIS patients with an anterior circulation LVO achieving successful recanalization after EVT. Consenting participants received transcranial Doppler ultrasound (TCD) within 18 hours of procedure completion. We compared flow velocities according to the presence of HT on the computed tomography scan performed within the first 24±12 hours from the end of EVT. We also evaluated the association of flow velocities with systemic blood pressure (BP) readings at the time of insonation. Results: A total of 48 patients consented to participate in the study. Six (12%) were excluded due to the absence of temporal windows. HT was detected in 20 participants (48%). Those with HT had higher peak systolic velocities on the middle cerebral arteries compared to those without HT for both the symptomatic (107±42 vs. 82±25 cm/second, p =.024) and asymptomatic (97±21 vs. 81±25 cm/second, p =.040) sides. No correlation of flow velocities on either the symptomatic or asymptomatic side and BP measurements at the time of insonation was detected. Conclusion: TCD can identify patients at risk of HT following successful EVT. TCD could serve as an inexpensive ancillary test to guide participant selection for clinical trials targeting postprocedural reperfusion injury. [ABSTRACT FROM AUTHOR]

Aims: This review focuses on the recent literature regarding the role of the gut‐brain axis (GBA) following ischemic stroke. Discussion: Stroke is the 5th leading cause of death and disability in the United States; however, few therapies have been developed to improve prognoses. There is a plethora of evidence suggesting peripheral inflammatory responses play a large role in the pathogenesis of stroke. Additionally, hyperglycemic conditions may play a significant role in worsening stroke outcomes due to microbiome dysbiosis. Conclusion: Recent research has illuminated the vital role of the GBA in propagating poor clinical outcomes, such as hemorrhagic transformation, following ischemic stroke. Considering this detrimental consequence of stroke, and the apparent role of the GBA role, future therapeutics should aim to mitigate this peripheral contribution to stroke complications. [ABSTRACT FROM AUTHOR]

Hemorrhagic transformation (HT) is one of the most serious complications after endovascular thrombectomy (EVT) in acute ischemic stroke (AIS) patients. The purpose of this study is to develop and validate deep‐learning (DL) models based on multiparametric magnetic resonance imaging (MRI) to automatically predict HT in AIS patients. Multiparametric MRI and clinical data of AIS patients with EVT from two centers (data set 1 for training and testing: n = 338; data set 2 for validating: n = 54) were used in the DL models. The acute infarction area of diffusion‐weighted imaging (DWI) and hypoperfusion of perfusion‐weighted imaging (PWI) was labeled manually. Two forms of data sets (volume of interest [VOI] data sets and slice data sets) were analyzed, respectively. The models based on single parameter and multiparameter models were developed and validated to predict HT in AIS patients after EVT. Performance was evaluated by area under the receiver‐operating characteristic curve (AUC), accuracy (ACC), sensitivity, specificity, negative predictive value, and positive predictive value. The results showed that the performance of single parameter model based on MTT (VOI data set: AUC = 0.933, ACC = 0.843; slice data set: AUC = 0.945, ACC = 0.833) and TTP (VOI data set: AUC = 0.916, ACC = 0.873; slice data set: AUC = 0.889, ACC = 0.818) were better than the other single parameter model. The multiparameter model based on DWI & MTT & TTP & Clinical (DMTC) had the best performance for predicting HT (VOI data set: AUC = 0.948, ACC = 0.892; slice data set: AUC = 0.932, ACC = 0.873). The DMTC model in the external validation set achieved similar performance with the testing set (VOI data set: AUC = 0.939, ACC = 0.884; slice data set: AUC = 0.927, ACC = 0.871) (p > 0.05). The proposed clinical, DWI, and PWI multiparameter DL model has great potential for assisting the periprocedural management in the early prediction HT of the AIS patients with EVT. [ABSTRACT FROM AUTHOR]

Background: Recent advancements in animal studies have demonstrated the potential of normobaric hyperoxia (NBO) as a promising intervention for preserving the integrity of the blood-brain barrier (BBB). However, there is still limited understanding of the effects of NBO on BBB function in patients with clinical stroke. Therefore, the objective of this study was to investigate the efficacy of NBO therapy in attenuating BBB damage and reducing brain injury in individuals undergoing endovascular treatment (EVT) for acute stroke., Methods and Results: This study enrolled patients from the OPENS-1 (Normobaric Hyperoxia Combined With Reperfusion for Acute Ischemic Stroke) study, with 43 patients receiving NBO combined with EVT and 43 patients receiving EVT alone. The main outcome measures included serum levels of occludin, MMP-9 (matrix metalloproteinase-9), NSE (neuron-specific enolase), and S100b at 24 hours and 7 days, as well as the intracranial extravasation rate at 24 hours. Serum markers were assessed using ELISA, and intracranial contrast extravasation was visualized using dual-energy computed tomography scan. We analyzed a total of 86 patients and found that the 24-hour serum markers levels of BBB damage and brain injury were significantly lower in the group receiving NBO therapy combined with EVT compared with the group receiving EVT alone. Similarly, at 7 days, the levels of occludin, MMP-9, and NSE were lower in the NBO+EVT group. We also found that the 24-hour serum levels of occludin and MMP-9 were correlated with intracranial contrast extravasation. Additionally, the incidence of intracranial contrast extravasation was lower in the NBO+EVT group compared with the EVT group (35.9% versus 60.5%, P =0.031)., Conclusions: This study offers valuable insights into the positive impact of NBO on maintaining BBB integrity and reducing brain injury in patients with acute stroke undergoing EVT.

Objective: Hemorrhagic transformation (HT) is a life‐threatening complication of stroke. Whether changes in gut microbial composition underlie the development of HT remains unknown. This study aimed to investigate whether the gut microbiota is altered in HT rats and examine the association between these changes and inflammatory responses. Methods: HT was successfully established in rats injected with 50% glucose (6 ml/Kg, i.p.) 15 min before middle cerebral artery occlusion (MCAO, 90 min occlusion) with reperfusion. After 5 days, rats were euthanized, and their brains used to estimate infarct volume. The inflammatory factors, the analysis of gut microbiota, and short‐chain fatty acids (SCFA) were assessed. Results: In contrast with non‐HT rats, gut microbiota sequencing showed an elevation in the relative abundance of Proteobacteria and Actinobacteria in HT rats. Total SCFAs, especially butyrate and valeric acid, were significantly lower in the cecal contents of HT rats than in those of non‐HT rats. Hyperglycemia‐induced HT exacerbation was not observed when rats were treated with antibiotics, suggesting that altered microbiota play a critical role in hyperglycemic HT pathogenesis. Furthermore, rats whose gut was colonized with HT rat microbiota showed increased susceptibility to HT. Conclusion: This study provides important information about the gut microbiota profiles and SCFA levels of MCAO rats with HT or non‐HT. The susceptibility to HT in MCAO rats is associated with inflammation and gut microbiota modulation. [ABSTRACT FROM AUTHOR]

Background and purpose: In patients with acute ischemic stroke treated with reperfusion therapy we aimed to evaluate whether pretreatment blood–brain barrier (BBB) leakage is associated with subsequent hemorrhagic transformation (HT). Methods: We prospectively screened patients with acute ischemic stroke treated with intravenous thrombolysis and/or endovascular treatment. Before treatment, each patient received computed tomography (CT), CT angiography, and CT perfusion. We assessed pretreatment BBB leakage within the ischemic area using the volume transfer constant (Ktrans) value. Our primary outcome was relevant HT, defined as hemorrhagic infarction type 2 or parenchymal hemorrhage type 1 or 2. We evaluated independent associations between BBB leakage and HT using logistic regression, adjusting for age, sex, baseline stroke severity, Alberta Stroke Program Early CT Score (ASPECTS) ≥ 6, treatment type, and onset‐to‐treatment time. Results: We enrolled 171 patients with available assessment of BBB leakage. The patients' mean (±SD) age was 75.5 (±11.8) years, 86 (50%) were men, and the median (interquartile range) National Institutes of Health Stroke Scale score was 18 (12–23). A total of 32 patients (18%) received intravenous thrombolysis, 102 (60%) underwent direct endovascular treatment, and 37 (22%) underwent both. Patients with relevant HT (N = 31;18%) had greater mean BBB leakage (Ktrans 0.77 vs. 0.60; p = 0.027). After adjustment in the logistic regression model, we found that BBB leakage was associated both with a more than twofold risk of relevant HT (odds ratio [OR] 2.50; 95% confidence interval [CI] 1.03–6.03 per Ktrans point increase; OR 2.34; 95% CI 1.06–5.17 for Ktrans values > 0.63 [mean BBB leakage value]) and with symptomatic intracerebral hemorrhage (OR 4.30; 95% CI 1.13–13.77 per Ktrans point increase). Conclusion: Pretreatment BBB leakage before reperfusion therapy was associated with HT, and may help to identify patients at risk of HT. [ABSTRACT FROM AUTHOR]

Background: Hemorrhagic transformation (HT) after stroke, related to atrial fibrillation (AF), is a frequent complication, and it can be associated with a delay in the (re‐)initiation of oral anticoagulation therapy. We investigated the effect of the presence and severity of white matter disease (WMD) on early HT after stroke related to AF. Methods: A consecutive series of patients with recent (<4 weeks) ischemic stroke and AF, treated at the Hyper Acute Stroke Unit of the Imperial College London between 2010 and 2017, were enrolled. Patients with brain MRI performed 24–72 h from stroke onset and not yet started on anticoagulant treatment were included. WMD was graded using the Fazekas score. Results: Among the 441 patients eligible for the analysis, 91 (20.6%) had any HT. Patients with and without HT showed similar clinical characteristics. Patients with HT had a larger diffusion‐weighted imaging (DWI) infarct volume compared to patients without HT (p <.001) and significant difference in the distribution of the Fazekas score (p =.001). On multivariable analysis, HT was independently associated with increasing DWI infarct volume (odd ratio (OR), 1.03; 95% confidence interval (CI), 1.01–1.05; p <.001), higher Fazekas scores (OR, 1.94; 95% CI, 1.47–2.57; p <.001) and history of previous intracranial hemorrhage (OR, 4.80; 95% CI, 1.11–20.80; p =.036). Conclusions: Presence and severity of WMD is associated with increased risk of development of early HT in patients with stroke and AF. Further evidence is needed to provide reliable radiological predictors of the risk of HT in cardioembolic stroke. [ABSTRACT FROM AUTHOR]

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by risks of hemorrhagic transformation (HT). We have reported that a new 12/15‐lipoxygenase (12/15‐LOX) inhibitor ML351 reduced tPA related HT in mice subjected to experimental stroke under anticoagulation. In this study, we asked whether ML351 can ameliorate tPA induced HT in an embolic stroke model. Rats were subjected to embolic middle cerebral artery occlusion with 2 or 3 hr ischemia and tPA infusion, with or without ML351. Regional cerebral blood flow was monitored 2 hr after ischemia and continuously monitored for 1 hr after treatment for determining reperfusion. Hemoglobin was determined in brain homogenates and infarct volume was quantified at 24 hr after stroke.12/15‐LOX, cluster of differentiation 68(CD68), immunoglobulin G (IgG), and tight junction proteins expression was detected by immunohistochemistry. ML351 significantly reduced tPA related hemorrhage after stroke without affecting its thrombolytic efficacy. ML351 also reduced blood–brain barrier disruption and improved preservation of junction proteins. ML351 and tPA combination improved neurological deficit of rats even though ML351 did not further reduce the infarct volume compared to tPA alone treated animals. Pro‐inflammatory cytokines were suppressed by ML351 both in vivo and in vitro experiments. We further showed that ML351 suppressed the expression of c‐Jun‐N‐terminal kinase (JNK) in brains and microglia cultures, whereas exogenous 12‐HETE attenuated this effect in vitro. In conclusion, ML351 and tPA combination therapy is beneficial in ameliorating HT after ischemic stroke. This protective effect is probably because of 12/15‐LOX inhibition and suppression of JNK‐mediated microglia/macrophage activation. [ABSTRACT FROM AUTHOR]

Introduction: Hemorrhagic transformation (HT) is a complex and multifactorial complication among patients with acute ischemic stroke (AIS), and the inflammatory response has been considered as a risk factor for HT. We aimed to evaluate the stratification of FAR (fibrinogen‐to‐albumin ratio), an inflammatory biomarker, in HT patients. Methods: A total of 256 consecutive stroke patients with HT and 256 age‐ and gender‐matched stroke patients without HT were included in this study. HT during hospitalization was diagnosed by follow‐up imaging assessment and was classified into hemorrhagic infarction (HI) and parenchymal hematoma (PH) according to the recommendations of European Cooperative Acute Stroke Study II classification. Blood samples were obtained at admission. Results: Higher levels of FAR were observed in patients with HT compared with the non‐HT group [10.29 (8.39–12.95) vs. 8.60 (7.25–10.8), p <.001], but no significant difference was found between the PH and HI [10.88 (8.72–13.40) vs. 10.13 (8.14–12.60), p >.05]. Patients were assigned to groups of high FAR (≥9.51) and low FAR (<9.51) based on the optimal cut‐off value. After adjustment for potential confounders, the high FAR remained independently associated with the increased risk of HT (OR = 5.027, 95% CI = 5.027 (2.309–10.942), p <.001). Conclusions: High FAR was independently associated with the increased risk of HT after AIS. [ABSTRACT FROM AUTHOR]

Objective: Delayed thrombolytic therapy with recombinant tissue plasminogen activator (tPA) may exacerbate blood‐brain barrier (BBB) breakdown after ischemic stroke and lead to catastrophic hemorrhagic transformation (HT). Rosiglitazone(RSG), a widely used antidiabetic drug that activates peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), has been shown to protect against cerebral ischemia through promoting poststroke microglial polarization toward the beneficial anti‐inflammatory phenotype. However, whether RSG can alleviate HT after delayed tPA treatment remains unknown. In this study, we sort to examine the role of RSG on tPA‐induced HT after stroke. Methods and results: We used the murine suture middle cerebral artery occlusion (MCAO) models of stroke followed by delayed administration of tPA (10 mg/kg, 2 hours after suture occlusion) to investigate the therapeutic potential of RSG against tPA‐induced HT. When RSG(6 mg/kg) was intraperitoneally administered 1 hour before MCAO in tPA‐treated MCAO mice, HT in the ischemic territory was significantly attenuated 1 day after stroke. In the tPA‐treated MCAO mice, we found RSG significantly mitigated BBB disruption and hemorrhage development compared to tPA‐alone‐treated stroke mice. Using flow cytometry and immunostaining, we confirmed that the expression of CD206 was significantly upregulated while the expression of iNOS was down‐regulated in microglia of the RSG‐treated mice. We further found that the expression of Arg‐1 was also upregulated in those tPA and RSG‐treated stroke mice and the protection against tPA‐induced HT and BBB disruption in these mice were abolished in the presence of PPAR‐γ antagonist GW9662 (4 mg/kg, 1 hour before dMCAO through intraperitoneal injection). Conclusions: RSG treatment protects against BBB damage and ameliorates HT in delayed tPA‐treated stroke mice by activating PPAR‐γ and favoring microglial polarization toward anti‐inflammatory phenotype. [ABSTRACT FROM AUTHOR]

Abstract: Clinical benefit for mechanical thrombectomy (MT) in stroke was recently demonstrated in multiple large prospective studies. Acute hyperglycemia (HG) is an important risk factor of poor outcome in stroke patients, including those that underwent MT. The aim of this therapy is to achieve a complete reperfusion in a short time, given that reperfusion damage is dependent on the duration of ischemia. Here, we investigated the effects of acute HG in a mouse model of ischemic stroke induced by middle cerebral artery occlusion (MCAO). Hyperglycemic (intraperitoneal [ip] injection of glucose) and control (ip saline injection) 10‐week male C57BL6 mice were subjected to MCAO (30, 90, and 180 min) followed by reperfusion obtained by withdrawal of the monofilament. Infarct volume, hemorrhagic transformation (HT), neutrophil infiltration, and neurological scores were assessed at 24 hr by performing vital staining, ELISA immunofluorescence, and behavioral test, respectively. Glucose injection led to transient HG (blood glucose = 250–390 mg/dL) that significantly increased infarct volume, HT, and worsened neurological outcome. In addition, we report that HG promoted blood‐brain barrier disruption as shown by hemoglobin accumulation in the brain parenchyma and tended to increase neutrophil extravasation within the infarcted area. Acute HG increased neurovascular damage for all MCAO durations tested. HTs were observed as early as 90 min after ischemia under hyperglycemic conditions. This model mimics MT ischemia/reperfusion and allows the exploration of brain injury in hyperglycemic conditions. [ABSTRACT FROM AUTHOR]

Background and purpose The prognostic value of contrast accumulation from non-contrast brain computed tomography taken immediately after endovascular reperfusion treatment in acute ischaemic stroke patients to predict symptomatic hemorrhage was studied. Methods Between July 2007 and August 2014, acute anterior circulation ischaemic stroke patients who were treated by intra-arterial thrombolysis or thrombectomy were included. Contrast accumulation was defined as a high attenuation area from non-contrast brain computed tomography immediately taken after endovascular reperfusion treatment, and patients were categorized into three groups according to the presence and location of contrast: (i) negative, (ii) cortical involvement and (iii) non-cortical involvement. The rates of symptomatic hemorrhage after 24 h and functional outcome at discharge were compared between patients with and without cortical involvement. Results Of 64 patients who were treated by endovascular intervention, contrast accumulation was detected in 56, including 33 patients with cortical involvement and 23 patients without cortical involvement. The cortical involvement pattern was more frequently associated with symptomatic hemorrhage (13 vs. 1 patient, P = 0.003) and with grave outcome at discharge with modified Rankin Scale 5 or 6 (14 vs. 4, P = 0.048) than the non-cortical involvement group. Multivariate logistic regression analysis including initial collateral status and occlusion site disclosed that cortical involvement pattern independently predicted symptomatic hemorrhage after endovascular treatment (odds ratio 19.0, confidence interval 1.6-227.6, P = 0.020). Conclusion Our study provides evidence that the cortical involvement of contrast accumulation is associated with symptomatic hemorrhage after endovascular reperfusion treatment. [ABSTRACT FROM AUTHOR]

Purpose: Intravenous thrombolysis can improve clinical outcome in acute ischemic stroke patients but increases the risk of hemorrhagic transformation (HT). Blood-brain barrier damage, which can be quantified by the vascular permeability for contrast agents, is a potential predictor for HT. This study aimed to assess whether this prediction can be improved by measuring vascular permeability using a novel fast nonlinear regression (NLR) method instead of Patlak analysis. Methods: From a prospective ischemic stroke multicenter cohort study, 20 patients with HT on follow-up imaging and 40 patients without HT were selected. The permeability transfer constant Ktrans was measured in three ways; using standard Patlak analysis, Patlak analysis with a fixed offset, and the NLR method. In addition, the permeability-surface (PS) area product and the conventional perfusion parameters (blood volume, flow, and mean transit time) were measured using the NLR method. Relative values were calculated in two ways, i.e., by dividing the average in the infarct core by the average in the contralateral hemisphere, and by dividing the average in the ipsilateral hemisphere by the average in the contralateral hemisphere. Mann-Whitney U tests and receiver operating characteristic (ROC) analyses were performed to assess the discriminative power of each of the relative parameters. Results: Both the infarct-core and whole-hemisphere averaged relative Ktrans (rKtrans) values, measured with the NLR method, were significantly higher in the patients who developed HT as compared with those who did not. The rKtrans measured with standard Patlak analysis was not significantly different. The relative PS (rPS), measured with NLR, had the highest discriminative power (P = 0.002). ROC analysis of rPS showed an area under the curve (AUC) of 0.75 (95% confidence interval: 0.62-0.89) and a sensitivity of 0.75 at a specificity of 0.75. The AUCs of the Patlak rKtrans, the Patlak rKtrans with fixed offset, and the NLR rKtrans were 0.58, 0.66, and 0.67, respectively. Conclusions: CT perfusion analysis may aid in predicting HT, but standard Patlak analysis did not provide estimates for rKtrans that were significantly higher in the HT group. The rPS, measured in the infarct core with NLR, had superior discriminative power compared with Ktrans measured with either Patlak analysis with a fixed offset or NLR, and conventional perfusion parameters. [ABSTRACT FROM AUTHOR]

Aim Anticoagulants are commonly used to treat ischemic stroke. Its impact on cerebellar infarction has not been fully understood. Methods In the clinical study, we reviewed a consecutive series of patients with large-sized cerebellar infarction (diameter > 3 cm, n = 30) treated with or without anticoagulation. In animal study, cerebellar infarction operation was performed in 12 Cynomolgus monkeys. Then the animals were administrated with low molecular weight heparin ( LMWH) or vehicle for 14 days. Results Six patients died during the following treatment. All the subjects that died received anticoagulation therapy, while nobody in the survival group received such a therapy. Compared with sham-operated animals, all monkeys with cerebellar infarction have obvious neurological deficits. The number and size of the Purkinje cells in the cerebellar area were also reduced. Two animals in the LMWH group (33%) died, while all animals in the vehicle control group survived. Compared with the vehicle group, the neurological score in the LMWH group was significantly increased ( P < 0.05). The water content in the cerebella was also significantly higher ( P < 0.05). Edema, hemorrhage, and subarachnoid hemorrhage occurred in the cerebella as well as brainstem of all the LMWH treated animals. Conclusions These results indicated the harmful effects of anticoagulation therapy on large-sized cerebellar infarction. [ABSTRACT FROM AUTHOR]

Resolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A4 ( LXA4) is an anti-inflammatory, pro-resolution lipid mediator with high affinity binding to ALX, the lipoxin A4 receptor. Since LXA4 is rapidly inactivated, potent analogs have been created, including the ALX agonist BML-111. We hypothesized that post-ischemic intravenous administration of BML-111 would provide protection to the neurovascular unit and reduce neuroinflammation in a rat stroke model. Animals were subjected to 90 min of middle cerebral artery occlusion ( MCAO) and BML-111 was injected 100 min and 24 h after stroke onset and animals euthanized at 48 h. Post-ischemic treatment with BML-111 significantly reduced infarct size, decreased vasogenic edema, protected against blood-brain barrier disruption, and reduced hemorrhagic transformation. Matrix metalloproteinase-9 and matrix metalloproteinase-3 were significantly reduced following BML-111 treatment. Administration of BML-111 dramatically decreased microglial activation, as seen with CD68, and neutrophil infiltration and recruitment, as assessed by levels of myeloperoxidase and intracellular adhesion molecule-1. The tight junction protein zona occludens-1 was protected from degradation following treatment with BML-111. These results indicate that post-ischemic activation of ALX has pro-resolution effects that limit the inflammatory damage in the cerebral cortex and helps maintain blood-brain barrier integrity after ischemic stroke. [ABSTRACT FROM AUTHOR]

Aims Statins may afford neuroprotection against ischemic injury, but it remains controversial whether combined treatment with tissue plasminogen activator (tPA) after stroke increases the risk of hemorrhagic transformation ( HT), the major tPA-related complication. We evaluated the safety of combining statin with tPA administration during the acute phase of both experimental and human stroke. Methods The occurrence and severity of HT, infarct volume, and neurological outcome were evaluated in spontaneous hypertensive rats (SHR) subjected to embolic middle cerebral arterial occlusion (MCAO), which received vehicle or simvastatin (20 mg/kg), 15 min after ischemia and tPA (9 mg/kg) 3 h after ischemia. Additionally, HT rate was evaluated in stroke patients who were treated with tPA (0.9 mg/kg) within 3 h after symptom onset, considering whether or not were under statins treatment when the stroke occurred. Results In the experimental study, no differences in HT rates and severity were found between treatment groups, neither regarding mortality, neurological deficit, infarct volume, or metalloproteinases ( MMPs) brain content. In the clinical study, HT rates and hemorrhage type were similar in stroke patients who were or not under statins treatment. Conclusion This study consistently confirms that the use of statins does not increase HT rates and severity when is combined with tPA administration. [ABSTRACT FROM AUTHOR]

Background and purpose Hemorrhagic transformation (HT) is one of the most problematic complications to arise from intravenous thrombolysis ( IVT). This study was conducted to assess whether micro- and macroalbuminuria could be associated with HT after IVT in patients with acute ischaemic stroke, and to investigate whether the value of urinary albumin-to-creatinine ratios would correlate with the degree of HT. Methods This was a retrospective study of stroke patients who had undergone IVT within 3 h of symptom onset. Albuminuria assessment was based on random morning spot urine collection with patients in a fasting state, the first morning after IVT. Multiple logistic regression analysis was used to evaluate whether the presence of micro- and macroalbuminuria might be independent predictors of HT. Results One-hundred and fifty-four patients were included in the study. Fifty-one patients had HT. The presence of micro- or macroalbuminuria was associated with HT after adjustment for variables with clinical significance (adjusting for age, atrial fibrillation, platelet counts, baseline National Institutes of Health Stroke Scale score, hypertension and diabetes mellitus; odds ratio, 2.542; 95% confidence interval, 1.106-5.841; P = 0.028). There were significant relationships between the presence of micro- and macroalbuminuria and types of HT. Conclusion In conclusion, the results of this study suggest that the presence of micro- and macroalbuminuria after IVT could be a predictor of severe HT in patients with acute ischaemic stroke. [ABSTRACT FROM AUTHOR]

Background and purpose Absence of FLAIR hyperintensity within an acute infarct is associated with stroke onset <4.5 h. However, some patients rapidly develop FLAIR hyperintensity within this timeframe. We hypothesized that development of early infarct FLAIR hyperintensity would predict hemorrhagic transformation ( HT) in patients treated with tissue plasminogen activator (tPA) < 4.5 h after onset. Methods Consecutive acute stroke patients treated with intravenous tPA <4.5 h after onset who had MRI before and 1 day after thrombolysis were included. Two raters (blind to HT) independently identified FLAIR hyperintensity with reference to the diffusion-weighted image (DWI) lesion. HT was assessed using T2* MRI at 24 h. Hemorrhagic infarction ( HI) was defined as petechial HT without mass effect, and parenchymal hematoma ( PH) as HT with mass effect. Multivariable logistic regression analysis for HT included FLAIR status, baseline National Institutes of Health Stroke Scale and DWI lesion volume, leukoaraiosis ( Wahlund score), serum glucose and reperfusion. Results Of 109 patients, 33 (30%) had acute FLAIR hyperintensity. HT occurred in 17 patients (15.6%; 15 HI, 2 PH). HT was more common in FLAIR-positive patients than FLAIR-negative patients (33.3% vs. 9.2%, P = 0.009). Median time-to-scan and median time-to-thrombolysis did not differ significantly between patients with HT and without [97 IQR(68, 155) vs. 90 IQR(73, 119), P = 0.5; 120 IQR(99, 185) vs. 125 IQR(95, 150), P = 0.6, respectively]. In multivariable analysis, only FLAIR hyperintensity was independently associated with HT after thrombolysis ( OR 18; 95% CI 2-175, P = 0.013). Conclusions Early development of FLAIR hyperintensity within the area of diffusion restriction is associated with increased risk of HT after thrombolysis in acute stroke patients. [ABSTRACT FROM AUTHOR]

ABSTRACT PURPOSE Multimodal CT with CT angiography (CTA) and CT perfusion (CTP) are increasingly used in stroke triage. Our aim was to identify parameters most predictive of hemorrhagic transformation (HT), especially symptomatic intracerebral hemorrhage (SICH). METHODS This retrospective study included patients evaluated by baseline multimodal CT ≤ 9 hours from ictus with acute nonlacunar middle cerebral artery (MCA) territory infarction. Two readers independently evaluated CTP maps for ischemic severity and CTA source images (CTA-SI) for infarct extent (as measured by ASPECTS). Presence of proximal occlusion (ICA or M1) and degree of collateralization (collateral score) were also assessed on CTA. HT was defined as SICH if associated with deterioration ≥ 4-points on NIHSS. Multivariate logistic regression analysis identified independent predictors of SICH. ROC curves selected optimal thresholds. RESULTS Of 84 patients reviewed, HT occurred in 22 (26.2%) and SICH in 8 (9.5%). Univariate predictors for SICH were proximal occlusion (OR = 8.65, P= .049), collateral score (OR = .34, P= .017), ASPECTS (OR = .46, P= .001), and CBV (OR = .001, P= .005). Multivariate analysis revealed ASPECTS as the only independent predictor with optimal threshold ≤ 5 and sensitivity and specificity of 75.0% and 85.5%, respectively. CONCLUSION For acute MCA infarcts ≤ 9 hours, the strongest predictor of SICH on multimodal CT was ASPECTS on CTA-SI. J Neuroimaging 2012;22:160-166 [ABSTRACT FROM AUTHOR]

Previous studies have suggested a greater ischemic tolerance in posterior circulation as compared to anterior cerebral circulation. We aimed to investigate whether a differential response exists between anterior and posterior circulation strokes. Two hundred and four middle cerebral artery (MCA) patients and 28 basilar artery occlusion (BAO) patients treated with intravenous recombinant tissue plasminogen activator were included. Transcranial Doppler assessed recanalization at different time points. Patients were divided in three groups: total time of ischemia (TTI) <6, 6-24, or >24 hours. We calculated the percentage of recovery (admission National Institutes of Health Stroke Scale [NIHSS]– discharge NIHSS/admission NIHSS) × 100. Mean time to treatment was longer in BAO patients (P = .031). Early recanalization was more frequent among MCA occlusions (41% vs 29%; P = .039); the rate of persisting occlusion at 24 hours was similar (P = .933). Clinical recovery according to TTI was similar in each group: <6 hours: BAO 84%/MCA 69%; 6-24 hours: BAO 63%/MCA 61%; >24 hours: BAO −44%/MCA 11% (P = .23). For each hour of ischemia MCA patients worsened 1.78% (P = .035) and BAO 1.76% (P = .421). MCA occlusions compared to BAO were independently associated with hemorrhagic transformation (OR: 8.2; P = .043). Our data do not support the theory of increased ischemic tolerance in posterior circulation. Despite longer time-to-treatment, BAO were more resistant to hemorrhagic transformations. [ABSTRACT FROM AUTHOR]

As hemorrhagic transformation (HTr) is a frequent complication and can worsen the outcome of acute ischemic stroke, our aim was to assess the risk factors of HTr. Using the database of our neuropathological laboratory, 245 consecutive acute ischemic stroke patients were analyzed. An exploratory logistic regression procedure was carried out to find the best multiple model identifying the factors associated with HTr. The autopsy revealed ischemic infarct in 175 (71%) and ischemic infarct with HTr in 70 (29%) patients. Mean age was 71.5 ± 11.4 years (mean ± SD) and 74.8 ± 10.2 years (mean ± SD), respectively. The multiple model confirmed age in case of embolic stroke, and diabetes mellitus and infarct size as independent risk factors of HTr. It seems that not serum glucose level but diabetes mellitus in the case history is an independent predictor of HTr. [ABSTRACT FROM AUTHOR]

Melatonin protects against transient middle cerebral artery (MCA) occlusion and may be suited as an add-on therapy of tissue plasminogen activator (t-PA) thrombolysis. Herein, we examined whether melatonin would reduce postischemic increase in the blood–brain barrier (BBB) permeability and, therefore, attenuate the risk of hemorrhagic transformation after t-PA therapy in experimental stroke. Twelve mice were subjected to transient occlusion of the MCA for 1 hr, followed by 24 hr of reperfusion. Melatonin (5 mg/kg, i.p.) or vehicle was given at the beginning of reperfusion. BBB permeability was evaluated by quantitation of Evans Blue leakage. An additional 32 mice underwent photothrombotic occlusion of the distal MCA, and were administered vehicle or t-PA (10 mg/kg, i.v.), alone or in combination with melatonin (5 mg/kg, i.p.), at 6 hr postinsult. The animals were then killed after 24 hr for the determination of infarct and hemorrhage volumes. Relative to controls, melatonin-treated animals had significantly reduced BBB permeability (by 52%; P < 0.001). Additionally, we found that at 6 hr after photo-irradiation, either t-PA or melatonin, or a combined administration of t-PA plus melatonin, did not significantly affect brain infarction ( P > 0.05), compared with controls. Mice treated with t-PA alone, however, had significantly increased hemorrhagic formation ( P < 0.05), and the event was effectively reversed by co-treatment with melatonin ( P < 0.05). Thus, melatonin improved postischemic preservation of the BBB permeability and a decreased risk of adverse hemorrhagic transformation after t-PA therapy for ischemic stroke. The findings further highlight melatonin's potential role in the field of thrombolytic treatment for ischemic stroke patients. [ABSTRACT FROM AUTHOR]

Objectives: We performed this retrospective cohort study to establish which factors are mostly indicative of the appearance of hemorrhagic transformation (HT) and of its time course in a sample of nonlacunar ischemic strokes. Materials and Methods: In 402 patients with nonlacunar ischemic stroke (75.0 ± 12.7 years, 192 male), clinical, laboratory, and neuroimaging variables obtained during the first 3 days of hospitalization were compared between patients with and without HT at computer tomography scan. Results: HT was documented in 129 patients (32.1%), including 36 with parenchymal hematoma (PH), after a median time of 6 days (range 1–27). Many variables were univariately associated with HT, but only 5 of them were confirmed in Cox regression (Hazard Ratio, 95% Confidence Interval): maximum cerebral lesion diameter (CLD) in cm (1.12, 1.06–1.18; p =.0001), hemoglobin in g/dl (1.16, 1.06–1.27; p =.002), blood glucose in mmol/L (1.10, 1.03–1.18; p =.007), prior anticoagulant therapy (1.82, 1.10–3.03; p =.02), and edema with mass effect (1.72, 1.08–2.75; p =.02). Thus, the most significant predictor was CLD. The overall risk of HT was minimum for CLD < 2 cm (1.5%), intermediate for CLD ≥ 2 and < 5 cm (22%), and maximum for CLD ≥ 5 cm (58%). The residual probability of having HT decreased progressively over time, and a simple formula is proposed to predict, from CLD in cm, when the probability of HT falls below 10%. Conclusions: The main determinant of HT was CLD, a simple quantitative parameter that could prove useful, in particular, in deciding the timing of anticoagulation in cardioembolic stroke patients. [ABSTRACT FROM AUTHOR]

Background tPA (tissue-type plasminogen activator) remains the only approved drug for acute ischemic stroke, with a potentially serious adverse effect: hemorrhagic transformation. The effects of antithrombotic agents on tPA-induced hemorrhagic transformation after ischemic stroke are not clearly defined. We performed a systematic review and meta-analysis in preclinical studies aiming to evaluate the efficacy of antithrombotic agents on tPA-induced hemorrhagic transformation after ischemic stroke. Methods and Results We conducted a systematic review and meta-analysis of studies testing antithrombotic agents in animal models of tPA-induced hemorrhagic transformation. The pooled effects were calculated using random-effects models, and heterogeneity was explored through meta-regression and subgroup analyses. Publication bias was assessed using trim and fill method and the Egger test. The efficacy of 18 distinct interventions was described in 22 publications. The pooled data showed a significant improvement in cerebral hemorrhage, infarct size, and neurobehavioral outcome in treated compared with control animals (standardized mean difference, 0.45 [95% CI, 0.11-0.78]; standardized mean difference, 1.18 [95% CI, 0.73-1.64]; and standardized mean difference, 0.91 [95% CI, 0.49-1.32], respectively). Subgroup analysis indicated that quality score, random allocation, control of temperature, anesthetic used, stroke model used, route of drug delivery, time of drug administration, and time of assessment were significant factors that influenced the effects of interventions. Conclusions Administration with antiplatelet agents revealed statistically significant improvement in all the outcomes. Anticoagulant agents showed significant effects in infarct size and neurobehavioral score, but fibrinolytic agents did not show any significant improvement in all the outcomes. The conclusions should be interpreted cautiously given the heterogeneity and publication bias identified in this analysis.

Objective: The potential effect of matrix metalloproteinase‐9 (MMP‐9) variants and these variants interactions on hemorrhagic transformation (HT) risk after ischemic stroke (IS) remain unclear. The aims of present study were to investigate the associations of six variants in MMP‐9 with HT, and these variants interactions whether related to increased HT risk. Method: A total of 705 patients with IS who were admitted to the participating hospitals within 48 hr of symptom onset were consecutively enrolled between March 2014 and December 2016. HT was confirmed by brain computed tomography (CT) scan during 14 days from stroke onset. Six variants of MMP‐9 gene were measured by mass spectrometry. Interactions of gene variant–gene variant were assessed through generalized multifactor dimensionality reduction method (GMDR). Results: HT occurred in 104 (14.8%) patients. There were no differences in genotypes for the six variants between patients with and without HT using univariate analysis (all p > 0.05). GMDR analysis revealed that there was a synergistic effect of gene variant–gene variant interactions between rs3918242 and rs3787268 in MMP‐9 gene. Cox regression analysis showed that high‐risk interactions of rs3918242 and rs3787268 were associated with increased risk of HT after adjusting for covariates (hazard ratio: 2.08; 95% confidence interval: 1.34–7.85; p = 0.016). Conclusion: Incidence of HT is common in acute IS in Chinese population. The mechanisms leading to HT are most likely multifactorial. Two‐loci interactions of rs3918242 and rs3787268 in MMP‐9 gene may confer a higher risk for HT. [ABSTRACT FROM AUTHOR]

Background and purpose: Hemorrhagic transformation (HT) is a major complication of acute ischaemic stroke that is potentially related to clinical deterioration. The objective of this study was to assess whether chronic hyperglycemia is a predictive factor of HT in patients with acute anterior stroke. Methods: Patients with acute anterior stroke were included in this study. Hemoglobin A1c (HbA1c) was measured in the morning after hospitalization. HT was detected by computed tomography scans or gradient echo magnetic resonance imaging performed 4 (±2) days after onset. Univariate and multivariate logistic regression analyses were used to assess the risks for HT and short‐term outcomes. Results: Of the 426 patients included, 93 (21.8%) had HT: 61 (14.3%) presented with hemorrhagic infarction and 32 (7.5%) presented with parenchymal hematoma. A total of 54 patients received thrombolytic treatment and 18 (33.3%) were found to have HT. In the multivariate analysis, HbA1c [odds ratio (OR), 1.294; 95% confidence interval (CI), 1.097–1.528], infarction size (OR, 3.358; 95% CI, 1.748–6.449) and thrombolytic therapy (OR, 3.469; 95% CI, 1.757–6.847) were predictors of HT. The predictive effect of HbA1c on HT was still observed in both groups when patients were stratified according to the levels of fasting blood glucose. HbA1c was found to be a predictor of poor outcomes in the multilogistic regression analysis (OR, 1.482; 95% CI, 1.228–1.788). Conclusions: Higher HbA1c was independently related to HT and poor neurological outcomes in patients with ischaemic stroke. These findings have significant implications for the treatment of diabetes and glucose management in patients with diabetes mellitus and/or acute ischaemic stroke. Click here to view the accompanying paper in this volume. [ABSTRACT FROM AUTHOR]

Background In patients with acute ischemic stroke and atrial fibrillation, early anticoagulation prevents ischemic recurrence but with the risk of hemorrhagic transformation ( HT ). The aims of this study were to evaluate in consecutive patients with acute stroke and atrial fibrillation (1) the incidence of early HT, (2) the time to initiation of anticoagulation in patients with HT , (3) the association of HT with ischemic recurrences, and (4) the association of HT with clinical outcome at 90 days. Methods and Results HT was diagnosed by a second brain computed tomographic scan performed 24 to 72 hours after stroke onset. The incidence of ischemic recurrences as well as mortality or disability (modified Rankin Scale scores >2) were evaluated at 90 days. Ischemic recurrences were the composite of ischemic stroke, transient ischemic attack, or systemic embolism. Among the 2183 patients included in the study, 241 (11.0%) had HT . Patients with and without HT initiated anticoagulant therapy after a mean 23.3 and 11.6 days, respectively, from index stroke. At 90 days, 4.6% (95% confidence interval, 2.3-8.0) of the patients with HT had ischemic recurrences compared with 4.9% (95% confidence interval, 4.0-6.0) of those without HT ; 53.1% of patients with  HT were deceased or disabled compared with 35.8% of those without HT . On multivariable analysis, HT was associated with mortality or disability (odds ratio, 1.71; 95% confidence interval, 1.24-2.35). Conclusions In patients with HT , anticoagulation was initiated about 12 days later than patients without HT . This delay was not associated with increased detection of ischemic recurrence. HT was associated with increased mortality or disability.

Recombinant tissue-type plasminogen activator (rt-PA) is presently the only pharmacological treatment approved for thrombolysis in patients suffering from ischemic stroke. Although reperfusion of ischemic tissue is essential, the use of rt-PA is limited due to its narrow therapeutic window and risk of hemorrhagic transformations. Recent studies have shown that rt-PA amplifies the post-ischemic activation of the nuclear enzyme poly(ADP-ribose)polymerase (PARP). This enzyme has been shown to contribute to both the breakdown of the blood brain barrier and spontaneous hemorrhagic transformations after ischemia. We therefore examined the capacity of PJ34 ( N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-( N,N-dimethylamino) acetamide hydrochloride), a potent inhibitor of PARP, to reduce the hemorrhagic transformations that occur after rt-PA in mice with permanent focal cerebral ischemia. Ischemia was produced by intraluminal occlusion of the left middle cerebral artery and treated with vehicle, rt-PA (10 mg/kg, i.v., 6 h after occlusion) or rt-PA plus PJ34 (3, 6 or 12 mg/kg, i.p., at ischemia onset and 4 h later). Hemorrhagic transformations, neurological examination, and infarct volumes were evaluated 48 h after the onset of ischemia. Delayed administration of rt-PA resulted in increased hemorrhagic transformations and aggravated the neurological deficit. Giving PJ34 (3 mg/kg) markedly reduced the hemorrhagic transformations, an effect not owing to a modification of matrix metalloprotease activity. Furthermore, PJ34 improved the neurological functions of rt-PA-treated ischemic mice. To conclude, the PARP inhibitor PJ34 makes rt-PA safer in experimental ischemic stroke. [ABSTRACT FROM AUTHOR]