Salvador Pedraza

Introduction: In Acute Ischemic Stroke (AIS), mismatch between Diffusion-Weighted Imaging (DWI) and Fluid-Attenuated Inversion-Recovery (FLAIR) helps identify patients who can benefit from thrombolysis when stroke onset time is unknown (15% of AIS). However, visual assessment has suboptimal observer agreement. Our study aims to develop and validate a Deep-Learning model for predicting DWI-FLAIR mismatch using solely DWI data. Patients and methods: This retrospective study included AIS patients from ETIS registry (derivation cohort, 2018–2024) and WAKE-UP trial (validation cohort, 2012–2017). DWI-FLAIR mismatch was rated visually. We trained a model to predict manually-labeled FLAIR visible areas (FVA) matching the DWI lesion on baseline and early follow-up MRIs, using only DWI as input. FVA-index was defined as the volume of predicted regions. Area under the ROC curve (AUC) and optimal FVA-index cutoff to predict DWI-FLAIR mismatch in the derivation cohort were computed. Validation was performed using baseline MRIs of the validation cohort. Results: The derivation cohort included 3605 MRIs in 2922 patients and the validation cohort 844 MRIs in 844 patients. FVA-index demonstrated strong predictive value for DWI-FLAIR mismatch in baseline MRIs from the derivation (n = 2453, AUC = 0.85, 95%CI: 0.84–0.87) and validation cohort (n = 844, AUC = 0.86, 95%CI: 0.84–0.89). With an optimal FVA-index cutoff at 0.5, we obtained a kappa of 0.54 (95%CI: 0.48–0.59), 70% sensitivity (378/537, 95%CI: 66–74%) and 88% specificity (269/307, 95%CI: 83–91%) in the validation cohort. Discussion and conclusion: The model accurately predicts DWI-FLAIR mismatch in AIS patients with unknown stroke onset. It could aid readers when visual rating is challenging, or FLAIR unavailable.

Introduction: In Acute Ischemic Stroke (AIS), mismatch between Diffusion-Weighted Imaging (DWI) and Fluid-Attenuated Inversion-Recovery (FLAIR) helps identify patients who can benefit from thrombolysis when stroke onset time is unknown (15% of AIS). However, visual assessment has suboptimal observer agreement. Our study aims to develop and validate a Deep-Learning model for predicting DWI-FLAIR mismatch using solely DWI data. Patients and methods: This retrospective study included AIS patients from ETIS registry (derivation cohort, 2018–2024) and WAKE-UP trial (validation cohort, 2012–2017). DWI-FLAIR mismatch was rated visually. We trained a model to predict manually-labeled FLAIR visible areas (FVA) matching the DWI lesion on baseline and early follow-up MRIs, using only DWI as input. FVA-index was defined as the volume of predicted regions. Area under the ROC curve (AUC) and optimal FVA-index cutoff to predict DWI-FLAIR mismatch in the derivation cohort were computed. Validation was performed using baseline MRIs of the validation cohort. Results: The derivation cohort included 3605 MRIs in 2922 patients and the validation cohort 844 MRIs in 844 patients. FVA-index demonstrated strong predictive value for DWI-FLAIR mismatch in baseline MRIs from the derivation ( n = 2453, AUC = 0.85, 95%CI: 0.84–0.87) and validation cohort ( n = 844, AUC = 0.86, 95%CI: 0.84–0.89). With an optimal FVA-index cutoff at 0.5, we obtained a kappa of 0.54 (95%CI: 0.48–0.59), 70% sensitivity (378/537, 95%CI: 66–74%) and 88% specificity (269/307, 95%CI: 83–91%) in the validation cohort. Discussion and conclusion: The model accurately predicts DWI-FLAIR mismatch in AIS patients with unknown stroke onset. It could aid readers when visual rating is challenging, or FLAIR unavailable.

BACKGROUND: Blood-brain barrier (BBB) leakage measured with dynamic susceptibility contrast-enhanced magnetic resonance imaging (MRI) has been associated with hemorrhagic transformation in acute ischemic stroke. However, the influence of prethrombolysis BBB leakage on infarct growth has not been studied. Therefore, we aimed to characterize BBB integrity according to tissue state at admission and tissue fate on follow-up MRI. METHODS: This is a post hoc analysis of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke). Ischemic cores were segmented on diffusion-weighted imaging at baseline and on fluid-attenuated inversion recovery images at follow-up (22–36 hours). Dynamic susceptibility contrast-enhanced–MRI provided penumbra masks (time to maximum of the tissue residue function >6 s minus ischemic core) and BBB leakage (extraction fraction [EF], Z scored) maps via automated analysis. EF was averaged within the ischemic core, total penumbra, 2 penumbra subtypes (salvaged/infarcted penumbra), and normal tissue. Adjusted linear mixed-effects models tested for differences between tissue types and associations of EF with clinical/imaging outcomes. Complementary voxel-wise analyses were performed. RESULTS: Of 503 patients enrolled in the trial, 165 with suitable dynamic susceptibility contrast-enhanced–MRI data were included in this analysis (mean age 66 years, 38% women, median National Institutes of Health Stroke Scale score of 6; 53% receiving alteplase). EF was significantly increased in the ischemic core and penumbra relative to normally perfused tissue, while differences between total penumbra and ischemic core were statistically nonsignificant. Infarcted penumbra exhibited higher EF than salvaged penumbra, even after adjusting for hypoperfusion severity ( P <0.001, n=79 with baseline penumbral tissue and follow-up MRI). Voxel-wise analyses showed a significant association between EF and voxel-level infarction in the placebo group only. EF did not predict hemorrhagic transformation or functional outcomes. CONCLUSIONS: Penumbral BBB leakage may identify tissue at increased risk of infarction. Larger, prospective studies are needed to determine the clinical relevance of BBB leakage as an imaging marker of tissue fate. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu/ ; Unique identifier: 2011-005906-32.

Data from randomized trials on the treatment effect of pure thrombolysis in patients with vessel occlusion are lacking. We examined data from a corresponding subsample of patients from the multicenter, randomized, placebo-controlled WAKE-UP trial to determine whether MRI-guided IV thrombolysis with alteplase in unknown-onset ischemic stroke benefits patients presenting with vessel occlusion. Patients with an acute ischemic lesion visible on MRI diffusion-weighted imaging but no marked parenchymal hyperintensity on fluid-attenuated inversion recovery images were randomized to treatment with IV alteplase or placebo. The primary end point was a favorable outcome defined by a modified Rankin Scale score of 0-1 at 90 days after stroke. We investigated the interaction between vessel status and treatment effect using an unconditional logistic regression model. Treatment effects (adjusted odds ratio [aOR]) and their 95% CI were compared in patients with and without any vessel occlusion (AVO) and large vessel occlusion (LVO). 185 patients (mean age 64.5 years, 46% female, median NIH Stroke Scale score 9, median time between last seen well and MRI 10.26 hours) received treatment and presented with an occlusion. 98 (20%) had LVO (defined as occlusion of the internal carotid artery, middle cerebral artery trunk, or combination). A favorable outcome was observed in 30 of 94 patients with AVO (31.9%) in the alteplase group and in 18 of 91 (19.8%) in the placebo group (aOR 2.04, 95% CI 1.00-4.18). In the subgroup of patients with LVO, a favorable outcome was observed in 16 of 53 (30.2%) in the alteplase group and in 7 of 44 (15.9%) in the placebo group (aOR 2.08, 95% CI 0.71-6.10). Treatment with alteplase was associated with higher odds of favorable outcomes with no heterogeneity of treatment effect between patients with AVO and patent vessel (p = 0.56), or between patients with and without LVO (p = 0.69). Although the WAKE-UP study was not powered to demonstrate treatment efficacy in patient subpopulations, this subgroup analysis points to a benefit of MRI-guided thrombolysis in patients with unknown-onset ischemic stroke, independent of vessel occlusion. Registered at ClinicalTrials.gov with unique identifier NCT01525290 (clinicaltrials.gov/study/NCT01525290). The study was first posted on February 2, 2012; the first patient was enrolled on September 24, 2012. This study provides Class II evidence that for patients with unknown-onset ischemic stroke with AVO, MRI-guided treatment with IV tissue plasminogen activator improves outcomes.

BACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are the most prominent imaging feature of cerebral small vessel disease (cSVD). Previous studies suggest a link between cSVD burden and intracerebral hemorrhage and worse functional outcome after thrombolysis in acute ischemic stroke. We aimed to determine the impact of WMH burden on efficacy and safety of thrombolysis in the MRI-based randomized controlled WAKE-UP trial of intravenous alteplase in unknown onset stroke. METHODS: The design of this post hoc study was an observational cohort design of a secondary analysis of a randomized trial. WMH volume was quantified on baseline fluid-attenuated inversion recovery images of patients randomized to either alteplase or placebo in the WAKE-UP trial. Excellent outcome was defined as score of 0-1 on the modified Rankin Scale after 90 days. Hemorrhagic transformation was assessed on follow-up imaging 24-36 hours after randomization. Treatment effect and safety were analyzed by fitting multivariable logistic regression models. RESULTS: Quality of scans was sufficient in 441 of 503 randomized patients to delineate WMH. Median age was 68 years, 151 patients were female, and 222 patients were assigned to receive alteplase. Median WMH volume was 11.4 mL. Independent from treatment, WMH burden was statistically significantly associated with worse functional outcome (odds ratio, 0.72 [95% CI, 0.57–0.92]), but not with higher chances of any hemorrhagic transformation (odds ratio, 0.78 [95% CI, 0.60–1.01]). There was no interaction of WMH burden and treatment group for the likelihood of excellent outcome ( P =0.443) or any hemorrhagic transformation ( P =0.151). In a subgroup of 166 patients with severe WMH, intravenous thrombolysis was associated with higher odds of excellent outcome (odds ratio, 2.40 [95% CI, 1.19–4.84]) with no significant increase in the rate of hemorrhagic transformation (odds ratio, 1.96 [95% CI, 0.80–4.81]). CONCLUSIONS: Although WMH burden is associated with worse functional outcome, there is no association with treatment effect or safety of intravenous thrombolysis in patients with ischemic stroke of unknown onset. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01525290.

Background: Reversibility of the diffusion-weighted imaging (DWI) lesion means that not all of the DWI lesion represents permanently injured tissue. We investigated DWI reversibility and the association with thrombolysis, reperfusion and functional outcome in patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging–Based Thrombolysis in Wake-Up Stroke). Methods: In this retrospective analysis of WAKE-UP, a randomized controlled trial (RCT) between September 2012 and June 2017 in Belgium, Denmark, France, Germany, Spain and United Kingdom, a convolutional neural network segmented the DWI lesions (b=1000 s/mm ² ) at baseline and follow-up (24 hours). We calculated absolute and relative DWI reversibility in 2 ways: first, a volumetric (baseline volume−24-hour volume >0) and second, a voxel-based (part of baseline lesion not overlapping with 24-hour lesion) approach. We additionally defined relative voxel-based DWI-reversibility >50% to account for coregistration inaccuracies. We calculated the odds ratio for reversibility according to treatment arm. We analyzed the association of reversibility with excellent functional outcome (modified Rankin Scale score of 0–1), in a multivariable model. Results: In 363 patients, the median DWI volume was 3 (1–10) mL at baseline and 6 (2–20) mL at follow-up. Volumetric DWI reversibility was present in 19% (69/363) with a median absolute reversible volume of 1 mL (0–2) or 28% (14–50) relatively. Voxel-based DWI reversibility was present in 358/363 (99%) with a median absolute volume of 1 mL (0–2), or 22% (9–38) relatively. In 18% of the patients (67/363), relative voxel-based DWI reversibility >50% was present. Volumetric DWI reversibility and relative voxel-based DWI reversibility >50% was more frequent in patients treated with alteplase versus placebo (OR, 1.86 [95% CI, 1.09–3.17] and OR, 2.03 [95% CI, 1.18–3.50], respectively). Relative voxel-based DWI reversibility >50% was associated with excellent functional outcome (OR, 2.30 [95% CI, 1.17–4.51]). Conclusions: Small absolute volumes of DWI reversibility were present in a large proportion of randomized patients in the WAKE-UP trial. Reversibility was more often present after thrombolysis.

Introduction: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. Methods: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0–1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. Results: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954–1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932–0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989–0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9–96%) of the treatment effect. Conclusion: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.

Growing evidence implicates the gut microbiome in cognition. Blastocystis is a common gut single-cell eukaryote parasite frequently detected in humans but its potential involvement in human pathophysiology has been poorly characterized. Here we describe how the presence of Blastocystis in the gut microbiome was associated with deficits in executive function and altered gut bacterial composition in a discovery (n = 114) and replication cohorts (n = 942). We also found that Blastocystis was linked to bacterial functions related to aromatic amino acids metabolism and folate-mediated pyrimidine and one-carbon metabolism. Blastocystis-associated shifts in bacterial functionality translated into the circulating metabolome. Finally, we evaluated the effects of microbiota transplantation. Donor’s Blastocystis subtypes led to altered recipient’s mice cognitive function and prefrontal cortex gene expression. In summary, Blastocystis warrant further consideration as a novel actor in the gut microbiome-brain axis.