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Abstract Polyolefins are the most widely produced type of plastics owing to their low production cost and favorable properties. Their polymer backbone consists solely of inert C-C bonds, making them resistant and durable materials. Although this is an extremely useful attribute during their use phase, it complicates chemical recycling. In this work, different types of polyethylenes (PEs) are converted into ketone-functionalized PEs with up to 3.4% functionalized carbon atoms, in mild conditions (≤100 °C), using a titanosilicate catalyst and tert-butyl hydroperoxide as the oxidant. Subsequently, the introduced ketones are exploited as sites for heteroatom insertion. Through Baeyer-Villiger oxidation, in-chain esters are produced with yields up to 73%. Alternatively, the ketones can be converted into the corresponding oxime, which can undergo a Beckmann rearrangement to obtain in-chain amides, with yields up to 75%. These transformations allow access to polymers that are amenable to solvolysis, thereby enhancing their potential for chemical recycling.

Summary: Background: Guidelines recommend low-dose colchicine for secondary prevention in cardiovascular disease, but uncertainty remains concerning its efficacy for stroke, efficacy in key subgroups and about uncommon but serious safety outcomes. Methods: In this trial-level meta-analysis, we searched bibliographic databases and trial registries form inception to May 16, 2024. We included randomised trials of colchicine for secondary prevention of ischaemic stroke and major adverse cardiovascular events (MACE: ischaemic stroke, myocardial infarction, coronary revascularisation, or cardiovascular death). Secondary outcomes were serious safety outcomes and mortality. A fixed-effect inverse-variance model was used to generate a pooled estimate of relative risk (RR) with 95% confidence intervals (CI). This study is registered with PROSPERO, CRD42024540320. Findings: Six trials involving 14,934 patients with prior stroke or coronary disease were included. In all patients, colchicine compared with placebo or no colchicine reduced the risk for ischaemic stroke by 27% (132 [1.8%] events versus 186 [2.5%] events, RR 0.73 [95% CI 0.58–0.90]) and MACE by 27% (505 [6.8%] events versus 693 [9.4%] events, with RR 0.73 [0.65–0.81]). Efficacy was consistent in key subgroups (females versus males, age below versus above 70, with versus without diabetes, statin versus non-statin users). Colchicine was not associated with an increase in serious safety outcomes: hospitalisation for pneumonia (109 [1.5%] versus 106 [1.5%], RR 0.99 [0.76–1.30]), cancer (247 [3.5%] versus 255 [3.6%], RR 0.97 [0.82–1.15]), and gastro-intestinal events (153 [2.1%] versus 135 [1.9%]), RR 1.15 [0.91–1.44]. There was no difference in all-cause death (201 [2.7%] versus 181 [2.4%], RR 1.09 [0.89–1.33]), cardiovascular death (70 [0.9%] versus 80 [1.1%], RR 0.89 [0.65–1.23]), or non-cardiovascular death (131 [1.8%] versus 101 [1.4%], RR 1.26 [0.98–1.64]). Interpretation: In patients with prior stroke or coronary disease, colchicine reduced ischaemic stroke and MACE, with consistent treatment effect in key subgroups, and did not increase serious safety events or death. Funding: There was no funding source for this study.

IntroductionLarge genome-wide association studies (GWASs) using case–control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing the age at onset (AAO) of ischemic stroke.MethodsAnalyses were conducted in a discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value C allele was associated with a 1.29-year earlier stroke AAO (meta p-value = 2.48 x 10−11). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decrease in mortality among APOE-Є4 carriers and have no association to stroke AAO per se. A simulation study showed that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a 2-fold increase in mortality risk would lead to an observed effect of AAO that is comparable to what we found.DiscussionIn conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.

Background and Purpose We compared the outcomes of endovascular therapy (EVT) in an extended time window in patients with large-vessel occlusion (LVO) between patients with and without pre-stroke disability. Methods In this prespecified analysis of the multinational CT for Late Endovascular Reperfusion study (66 participating sites, 10 countries between 2014 and 2022), we analyzed data from patients with acute ischemic stroke with a pre-stroke modified Rankin Scale (mRS) score of 0–4 and LVO who underwent EVT 6–24 hours from the time last seen well. The primary outcome was the composite of functional independence (FI; mRS score 0–2) or return to the pre-stroke mRS score (return of Rankin, RoR) at 90 days. Outcomes were compared between patients with pre-stroke disability (pre-stroke mRS score 2–4) and those without (mRS score 0–1). Results A total of 2,231 patients (median age, 72 years; median National Institutes of Health Stroke Scale score, 16) were included in the present analysis. Of these, 564 (25%) had pre-stroke disability. The primary outcome (FI or RoR) was observed in 30.7% of patients with pre-stroke disability (FI, 16.5%; RoR, 30.7%) compared to 44.1% of patients without (FI, 44.1%; RoR, 13.0%) (P

Background and Purpose Posterior cerebral artery occlusion (PCAo) can cause long-term disability, yet randomized controlled trials to guide optimal reperfusion strategy are lacking. We compared the outcomes of PCAo patients treated with endovascular thrombectomy (EVT) with or without intravenous thrombolysis (IVT) to patients treated with IVT alone. Methods From the multicenter retrospective Posterior cerebraL ArTery Occlusion (PLATO) registry, we included patients with isolated PCAo treated with reperfusion therapy within 24 hours of onset between January 2015 and August 2022. The primary outcome was the distribution of the modified Rankin Scale (mRS) at 3 months. Other outcomes comprised 3-month excellent (mRS 0–1) and independent outcome (mRS 0–2), early neurological improvement (ENI), mortality, and symptomatic intracranial hemorrhage (sICH). The treatments were compared using inverse probability weighted regression adjustment. Results Among 724 patients, 400 received EVT+/-IVT and 324 IVT alone (median age 74 years, 57.7% men). The median National Institutes of Health Stroke Scale score on admission was 7, and the occluded segment was P1 (43.9%), P2 (48.3%), P3–P4 (6.1%), bilateral (1.0%), or fetal posterior cerebral artery (0.7%). Compared to IVT alone, EVT+/-IVT was not associated with improved functional outcome (adjusted common odds ratio [OR] 1.07, 95% confidence interval [CI] 0.79–1.43). EVT increased the odds for ENI (adjusted OR [aOR] 1.49, 95% CI 1.05–2.12), sICH (aOR 2.87, 95% CI 1.23–6.72), and mortality (aOR 1.77, 95% CI 1.07–2.95). Conclusion Despite higher odds for early improvement, EVT+/-IVT did not affect functional outcome compared to IVT alone after PCAo. This may be driven by the increased risk of sICH and mortality after EVT.

Background With the expanding eligibility for endovascular therapy (EVT) of patients presenting in the late window (6–24 hours after last known well), we aimed to derive a score to predict favorable outcomes associated with EVT versus best medical management. Methods and Results A multinational observational cohort of patients from the CLEAR (Computed Tomography for Late Endovascular Reperfusion) study with proximal intracranial occlusion (2014–2022) was queried (n=58 sites). Logistic regression analyses were used to derive a 9‐point score for predicting good functional outcome (modified Rankin Scale score 0–2 or return to premorbid modified Rankin Scale score) at 90 days, with sensitivity analyses for prespecified subgroups conducted using bootstrapped random forest regressions. Secondary outcomes included 90‐day functional independence (modified Rankin Scale score 0–2), poor outcome (modified Rankin Scale score 5–6), and 90‐day survival. The score was externally validated with a single‐center cohort (2014–2023). Of the 3231 included patients (n=2499 EVT), a 9‐point score included age, early computed tomography ischemic changes, and stroke severity, with higher points indicating a higher probability of a good functional outcome. The areas under the curve for the primary outcome among EVT and best medical management subgroups were 0.72 (95% CI, 0.70–0.74) and 0.87 (95% CI, 0.84–0.90), respectively, with similar performance in the external validation cohort (area under the curve, 0.71 [95% CI, 0.66–0.76]). There was a significant interaction between the score and EVT for good functional outcome, functional independence, and poor outcome (all Pinteraction

Fifteen to 20% of patients with an acute ischaemic stroke have a tandem lesion defined by the combination of an intracranial large vessel thrombo-embolic occlusion and a high grade stenosis or occlusion of the ipsilateral internal carotid artery. These patients tend to have worse outcomes than patients with isolated intracranial occlusions, with higher rates of disability and death. The introduction of endovascular thrombectomy to treat the intracranial lesion clearly improved the outcome compared with treatment with intravenous thrombolysis alone. However, the best treatment strategy for managing the extracranial carotid artery lesion in patients with tandem lesions remains unknown. Current guidelines recommend carotid endarterectomy for patients with transient ischaemic attack or non-disabling stroke and moderate or severe stenosis of the internal carotid artery, within two weeks of the initial event, to prevent major stroke recurrence and death. Alternatively, the symptomatic carotid artery could be treated by endovascular placement of a stent during endovascular thrombectomy (EVT). This would negate the need for a second procedure, immediately reduce the risk of stroke recurrence, increase patient satisfaction, and could be cost effective. However, the administration of dual antiplatelet therapy could potentially increase the risk of symptomatic intracranial haemorrhage in patients with acute ischaemic stroke. Randomised controlled trials evaluating the efficacy and safety of immediate carotid artery stenting during EVT in acute stroke patients with tandem lesions are currently ongoing and will impact the current guidelines regarding the treatment of patients with acute ischaemic stroke due to these tandem lesions.

Abstract Background Based on the lack of literature to support any treatment strategy in patients with foot drop due to peroneal nerve entrapment, a prospective study randomizing patients between surgery and conservative treatment is warranted. Since studies comparing surgery to no surgery are often challenging, we first examined the feasibility of such a randomized controlled trial. Methods/design An internal feasibility pilot study was conducted to assess several aspects of process, resource, management, and scientific feasibility. The main objective was the assessment of the recruitment rate. The criterion to embark on a full study was the recruitment of at least 14 patients in 6 participating centers within 6 months. Cross-over rate, blinding measures, training strategies, and trial assessments were evaluated. The trial was entirely funded by the KCE Trials public funding program of the Belgian Health Care Knowledge Centre (ID KCE19-1232). Results The initial duration was prolonged due to the COVID-19 pandemic. Between April 2021 and October 2022, we included 19 patients of which 15 were randomized. Fourteen patients were treated as randomized. One drop-out occurred after randomization, prior to surgery. We did not document any cross-over or accidental unblinding. Training strategies were successful. Patients perceived the quality of life questionnaire as the least relevant assessment. Assessment of ankle dorsiflexion range of motion was prone to interobserver variability. All other trial assessments were adequate. Discussion Recruitment of the anticipated 14 patients was feasible although slower than expected. The Short-Form Health Survey (SF-36) and assessment of ankle dorsiflexion range of motion will no longer be included in the full-scale FOOTDROP trial. Conclusion The FOOTDROP study is feasible. Trial registration ClinicalTrials.gov, identifier NCT04695834 . Registered 4 January 2021.

Abstract Acoustic and phonemic processing are understudied in aphasia, a language disorder that can affect different levels and modalities of language processing. For successful speech comprehension, processing of the speech envelope is necessary, which relates to amplitude changes over time (e.g., the rise times). Moreover, to identify speech sounds (i.e., phonemes), efficient processing of spectro-temporal changes as reflected in formant transitions is essential. Given the underrepresentation of aphasia studies on these aspects, we tested rise time processing and phoneme identification in 29 individuals with post-stroke aphasia and 23 healthy age-matched controls. We found significantly lower performance in the aphasia group than in the control group on both tasks, even when controlling for individual differences in hearing levels and cognitive functioning. Further, by conducting an individual deviance analysis, we found a low-level acoustic or phonemic processing impairment in 76% of individuals with aphasia. Additionally, we investigated whether this impairment would propagate to higher-level language processing and found that rise time processing predicts phonological processing performance in individuals with aphasia. These findings show that it is important to develop diagnostic and treatment tools that target low-level language processing mechanisms.

Introduction: Decision-making for the treatment of ruptured aneurysms is an intricate process, which involves several factors. There has been a rapid advancement in endovascular, but also in the surgical treating field of ruptured intracranial aneurysms, with a growing body of evidence for either treatment technique. Research question: As there is a wide variety of treatment possibilities, it can be hard to understand the intricacies which lie behind the decision-making process for a given aneurysm. Materials and methods: An overview of the most relevant literature in decision-making on ruptured intracranial aneurysms is given. Results: Different decision-altering factors were identified, which can be divided into information from the general evidence, to influential factors such as the patient's age, initial presenting status, and aneurysmal factors such as size, morphology and aneurysmal location. Discussion and conclusion: This review provides an evidence-based overview of the most pertinent literature on these different aspects of decision-making in ruptured aneurysm cases and provides some recommendations after each of these segments. As always, all different aspects of the patient and aneurysmal factors should be taken into consideration before coming to a conclusion, as to obtain the best possible result for an individual patient.

Background: Outcome data regarding the administration of tenecteplase (TNK) to acute ischemic stroke (AIS) patients presenting in the extended time window are limited. Objectives: We aimed to assess the current evidence regarding the efficacy and safety of TNK at a dose of 0.25 mg/kg for AIS treatment in the extended time window. Design: A systematic review and meta-analysis was conducted including all available randomized-controlled clinical trials (RCTs) that compared TNK 0.25 mg/kg versus no thrombolysis in AIS patients presenting in the extended time window (>4.5 h after last-seen-well or witnessed onset). Data sources and methods: Eligible studies were identified by searching Medline, Scopus, and international conference abstracts. The predefined efficacy outcomes of interest were 3-month excellent functional outcome [defined as the modified Rankin Scale (mRS) score ⩽1; primary outcome], 3-month good functional outcome (mRS ⩽ 2), 3-month reduced disability (⩾1-point reduction across all mRS scores). We determined symptomatic intracranial hemorrhage (sICH), any ICH and 3-month mortality as safety endpoints. A random-effects model was used to calculate risk ratios (RRs) and common odds ratios (cORs) with corresponding 95% confidence intervals (CIs). Results: Three RCTs were included comprising 556 patients treated with TNK versus 560 controls. TNK 0.25 mg/kg was associated with a higher likelihood of 3-month excellent functional outcome compared to controls (RR = 1.17; 95% CI = 1.01–1.36; I 2 = 0%), whereas there was no difference regarding good functional outcome (RR = 1.05; 95% CI = 0.94–1.17; I 2 = 0%) and reduced disability (adjusted cOR = 1.14; 95% CI = 0.92–1.40; I 2 = 0%) at 3 months. The risks of sICH (RR = 1.67; 95% CI = 0.70–4.00; I 2 = 0%), any ICH (RR = 1.08; 95% CI = 0.90–1.29; I 2 = 0%) and 3-month mortality (RR = 1.10; 95% CI = 0.81–1.49; I 2 = 0%) were similar between the groups. Conclusion: Based on data from three RCTs showing increased efficacy and a favorable safety profile of TNK in the treatment of AIS in the extended time window, continuing efforts of ongoing RCTs in the field are clearly supported. Trial registration: PROSPERO registration ID: CRD42023448707.

IntroductionCurrent guidelines recommend that patients with cerebral venous thrombosis (CVT) should be treated with vitamin K antagonists (VKAs) for 3–12 months. Direct oral anticoagulants (DOACs), however, are increasingly used in clinical practice. An exploratory randomized controlled trial including 120 patients with CVT suggested that the efficacy and safety profile of dabigatran (a DOAC) is similar to VKAs for the treatment of CVT, but large-scale prospective studies from a real-world setting are lacking.MethodsDOAC-CVT is an international, prospective, observational cohort study comparing DOACs to VKAs for the prevention of recurrent venous thrombotic events after acute CVT. Patients are eligible if they are 18 years or older, have a radiologically confirmed CVT, and have started oral anticoagulant treatment (DOAC or VKA) within 30 days of CVT diagnosis. Patients with an absolute contra-indication for DOACs, such as pregnancy or severe renal insufficiency, are excluded from the study. We aim to recruit at least 500 patients within a three-year recruitment period. The primary endpoint is a composite of recurrent venous thrombosis and major bleeding at 6 months of follow-up. We will calculate an adjusted odds ratio for the primary endpoint using propensity score inverse probability treatment weighting.DiscussionDOAC-CVT will provide real-world data on the comparative efficacy and safety of DOACs versus VKAs for the treatment of CVT.Clinical trial registrationClinicalTrials.gov, NCT04660747.

Abstract Background High-quality evidence is lacking to support one treatment strategy over another in patients with foot drop due to peroneal nerve entrapment. This leads to strong variation in daily practice. Methods/design The FOOTDROP (Follow-up and Outcome of Operative Treatment with Decompressive Release Of The Peroneal nerve) trial is a randomized, multi-centre study in which patients with peroneal nerve entrapment and persistent foot drop, despite initial conservative treatment, will be randomized 10 (± 4) weeks after onset between non-invasive treatment and surgical decompression. The primary endpoint is the difference in distance covered during the 6-min walk test between randomization and 9 months later. Time to recovery is the key secondary endpoint. Other secondary outcome measures encompass ankle dorsiflexion strength (MRC score and isometric dynamometry), gait assessment (10-m walk test, functional ambulation categories, Stanmore questionnaire), patient-reported outcome measures (EQ5D-5L), surgical complications, neurological deficits (sensory changes, motor scores for ankle eversion and hallux extension), health economic assessment (WPAI) and electrodiagnostic assessment. Discussion The results of this randomized trial may elucidate the role of surgical decompression of the peroneal nerve and aid in clinical decision-making. Trial registration ClinicalTrials.gov NCT04695834. Registered on 4 January 2021.

A large proportion of chronic stroke survivors still struggle with upper limb (UL) problems in daily activities, typically reaching tasks. During three-dimensional reaching movements, the deXtreme robot offers error enhancement forces. Error enhancement aims to improve the quality of movement. We investigated clinical and patient-reported outcomes and assessed the quality of movement before and after a 5 h error enhancement training with the deXtreme robot. This pilot study had a pre-post intervention design, recruiting 22 patients (mean age: 57 years, mean days post-stroke: 1571, male/female: 12/10) in the chronic phase post-stroke with UL motor impairments. Patients received 1 h robot treatment for five days and were assessed at baseline and after training, collecting (1) clinical, (2) patient-reported, and (3) kinematic (KINARM, BKIN Technologies Ltd., Kingston, ON, Canada) outcome measures. Our analysis revealed significant improvements (median improvement (Q1–Q3)) in (1) UL Fugl–Meyer assessment (1.0 (0.8–3.0), p < 0.001) and action research arm test (2.0 (0.8–2.0), p < 0.001); (2) motor activity log, amount of use (0.1 (0.0–0.3), p < 0.001) and quality of use (0.1 (0.1–0.5), p < 0.001) subscale; (3) KINARM-evaluated position sense (−0.45 (−0.81–0.09), p = 0.030) after training. These findings provide insight into clinical self-reported and kinematic improvements in UL functioning after five hours of error enhancement UL training.

IntroductionStroke is one of the leading causes of mortality and disability. Improving patient outcomes can be achieved by improving stroke care and adherence to guidelines. Since wide variation in adherence rates for stroke guidelines still exists, we aimed to describe and compare stroke care variability within Belgian hospitals.Materials and methodsAn observational, multicenter study was performed in 29 Belgian hospitals. We retrospectively collected patient characteristics, quality indicators, and time metrics from the last 30 consecutive patients per hospital, diagnosed with ischemic stroke in 2019 with structured questionnaires. Mean adherence ratios (%) ± SD (minimum – maximum) were calculated.ResultsWe analyzed 870 patient records from 29 hospitals. Results showed large inter- and intrahospitals variations in adherence for various indicators. Almost all the patients received brain imaging (99.7%) followed by admission at a stroke unit in 82.9% of patients. Of patients not receiving thrombolysis, 92.5% of patients were started on antithrombotic drugs. Indicators with moderate median adherence but large interhospital variability were glycemia monitoring [82.3 ± 16.7% (26.7–100.0%)], performing clinical neurological examination and documentation of stroke severity [63.1 ± 36.8% (0–100%)], and screening for activities of daily living [51.1 ± 40.3% (0.0–100.0%)]. Other indicators lacked adequate adherence: swallowing function screening [37.0 ± 30.4% (0.0–93.3%)], depression screening [20.2 ± 35.8% (0.0–100%)], and timely body temperature measurement [15.1 ± 17.0% (0.0–60%)].ConclusionWe identified high adherence to guidelines for some indicators, but lower rates with large interhospital variability for other recommendations also based on robust evidence. Improvement strategies should be implemented to improve the latter.

Abstract Background Technology development for sitting balance therapy and trunk rehabilitation is scarce. Hence, intensive one-to-one therapist-patient training is still required. We have developed a novel rehabilitation prototype, specifically aimed at providing sitting balance therapy. We investigated whether technology-supported sitting balance training was feasible and safe in chronic stroke patients and we determined whether clinical outcomes improved after a four-week programme, compared with usual care. Methods In this parallel-group, assessor-blinded, randomized controlled pilot trial, we divided first-event chronic stroke participants into two groups. The experimental group received usual care plus additional therapy supported by rehabilitation technology, consisting of 12 sessions of 50 min of therapy over four weeks. The control group received usual care only. We assessed all participants twice pre-intervention and once post-intervention. Feasibility and safety were descriptively analysed. Between-group analysis evaluated the pre-to-post differences in changes in motor and functional outcomes. Results In total, 30 participants were recruited and 29 completed the trial (experimental group: n = 14; control group: n = 15). There were no between-group differences at baseline. Therapy was evaluated as feasible by participants and therapist. There were no serious adverse events during sitting balance therapy. Changes in clinical outcomes from pre- to post-intervention demonstrated increases in the experimental than in the control group for: sitting balance and trunk function, evaluated by the Trunk Impairment Scale (mean points score (SD) 7.07 (1.69) versus 0.33 (2.35); p

Acute ischemic stroke impacts men and women differently. Here, the authors show how different lesion patterns in men and women are linked to the extent of stroke severity.

Abstract Stroke has a deleterious impact on quality of life. However, it is less well known if stroke lesions in different brain regions are associated with reduced quality of life (QoL). We therefore investigated this association by multivariate lesion-symptom mapping. We analyzed magnetic resonance imaging and clinical data from the WAKE-UP trial. European Quality of Life 5 Dimensions (EQ-5D) 3 level questionnaires were completed 90 days after stroke. Lesion symptom mapping was performed using a multivariate machine learning algorithm (support vector regression) based on stroke lesions 22–36 h after stroke. Brain regions with significant associations were explored in reference to white matter tracts. Of 503 randomized patients, 329 were included in the analysis (mean age 65.4 years, SD 11.5; median NIHSS = 6, IQR 4–9; median EQ-5D score 90 days after stroke 1, IQR 0–4, median lesion volume 3.3 ml, IQR 1.1–16.9 ml). After controlling for lesion volume, significant associations between lesions and EQ-5D score were detected for the right putamen, and internal capsules of both hemispheres. Multivariate lesion inference analysis revealed an association between injuries of the cortico-spinal tracts with worse self-reported quality of life 90 days after stroke in comparably small stroke lesions, extending previous reports of the association of striato-capsular lesions with worse functional outcome. Our findings are of value to identify patients at risk of impaired QoL after stroke.

Background purposeA substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort.Materials and methodsAnalyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome.ResultsWe analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, pFDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, pFDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL.ConclusionMultiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only.

Background An increase in beat‐to‐beat variability of repolarization (BVR) predicts arrhythmia onset in experimental models, but its clinical translation is not well established. We investigated the temporal changes in BVR before nonsustained ventricular tachycardia (nsVT) in patients with implantable cardioverter defibrillator (ICD). Methods and Results Patients with nsVT on 24‐hour Holter before ICD implantation for ischemic cardiomyopathy (ischemic cardiomyopathy+nsVT, n=43) or dilated cardiomyopathy (dilated cardiomyopathy+nsVT, n=37), matched ICD candidates without nsVT (ischemic cardiomyopathy‐nsVT, n=29 and dilated cardiomyopathy‐nsVT, n=26), and patients without ICD without structural heart disease (n=50) were studied. Digital Holter recordings from these patients were analyzed using a modified fiducial segment averaging technique to detect the QT interval. The nsVT episodes were semi‐automatically identified and QT‐BVR was assessed 1‐, 5‐, and 30‐minutes before nsVT, and at rest (at 3:00 am). Resting BVR was higher in ICD patients compared with controls without structural heart disease. In ICD patients with nsVT, BVR increased significantly 1‐minute pre‐nsVT in ischemic cardiomyopathy (2.21±0.59 ms, versus 5 minutes pre‐nsVT: 1.78±0.50 ms, P

IntroductionHigher white blood cell (WBC) count is associated with poor functional outcome in acute ischemic stroke (AIS). However, little is known about whether the association is modified by treatment with intravenous alteplase.MethodsWAKE-UP was a randomized controlled trial of the efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in unknown onset stroke. WBC count was measured on admission and again at 22–36 h after randomization to treatment (follow-up). Favorable outcome was defined by a score of 0 or 1 on the modified Rankin scale (mRS) 90 days after stroke. Further outcome were stroke volume and any hemorrhagic transformation (HT) that were assessed on follow-up CT or MRI. Multiple logistic regression analysis was used to assess the association between outcome and WBC count and treatment group.ResultsOf 503 randomized patients, WBC count and baseline parameters were available in 437 patients (μ = 64.7 years, 35.2% women) on admission and 355 patients (μ = 65.1 years, 34.1% women) on follow-up. Median WBC count on admission was 7.6 × 109/L (interquartile range, IQR, 6.1–9.4 × 109/L) and 8.2 × 109/L (IQR, 6.7–9.7 × 109/L) on follow-up. Higher WBC count both on admission and follow-up was associated with lower odds of favorable outcome, adjusted for age, National Institutes of Health (NIH) Stroke Scale Score, temperature, and treatment (alteplase vs. placebo, adjusted odds ratio, aOR 0.85, 95% confidence interval [CI] 0.78–0.94 and aOR 0.88, 95% CI 0.79–0.97). No interaction between WBC count and treatment group was observed (p = 0.11). Furthermore, WBC count on admission and follow-up was significantly associated with HT (aOR 1.14, 95% CI 1.05–1.24 and aOR 1.13, 95% CI 1.00–1.26). Finally, WBC count on follow-up was associated with larger stroke volume (aOR 2.57, 95% CI 1.08–6.07).ConclusionHigher WBC count is associated with unfavorable outcome, an increased risk of HT, and larger stroke volume, independent of treatment with alteplase. Whether immunomodulatory manipulation of WBC count improves stroke outcome needs to be tested.Trial RegistrationClinicalTrials.gov Identifier: NCT01525290.

The effects of thrombolysis therapy in stroke on structural connectivity are not well understood. Here, the authors show with causal mediation analysis that the clinical benefits of thrombolysis in anterior circulation stroke are mediated via structural connectivity.

Abstract Background One quarter to one third of patients eligible for systemic thrombolysis are on antiplatelet therapy at presentation. In this study, we aimed to assess the safety and efficacy of intravenous thrombolysis in stroke patients on prescribed antiplatelet therapy in the WAKE-UP trial. Methods WAKE-UP was a multicenter, randomized, double-blind, placebo-controlled clinical trial to study the efficacy and safety of MRI-guided intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time. The medication history of all patients randomized in the WAKE-UP trial was documented. The primary safety outcome was any sign of hemorrhagic transformation on follow-up MRI. The primary efficacy outcome was favorable functional outcome defined by a score of 0–1 on the modified Rankin scale at 90 days after stroke, adjusted for age and baseline stroke severity. Logistic regression models were fitted to study the association of prior antiplatelet treatment with outcome and treatment effect of intravenous alteplase. Results Of 503 randomized patients, 164 (32.6%) were on antiplatelet treatment. Patients on antiplatelet treatment were older (70.3 vs. 62.8 years, p

Abstract Background The anatomical distribution of acute lacunar infarcts has mainly been studied for supratentorial lesions. In addition, little is known about the association with distinct stroke symptoms, not summarized as classical lacunar syndromes. We aimed to describe the spatial lesion distribution of acute supra- and infratentorial lacunar infarcts and their association with stroke symptoms in patients eligible for thrombolysis. Methods All patients enrolled in the WAKE-UP trial (efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in wake-up stroke) were screened for lacunar infarcts on diffusion-weighted imaging (DWI). The relationship between the anatomical distribution of supra- and infratentorial lacunar infarcts, their demographic characteristics and acute stroke symptoms, defined by the National Institutes of Health Stroke Scale (NIHSS) score, were correlated and compared. Results Maps of lesion distribution from 224 lacunar infarct patients (76 [33.9%] females, mean age [standard deviation] of 63.4 [11.5] years) were generated using computational image mapping methods. Median infarct volume was 0.73 ml (interquartile range [IQR] 0.37–1.15 ml). Median NIHSS sum score on hospital arrival was 4 (IQR 3–6). 165 (73.7%) patients had lacunar infarcts in the supratentorial deep white or grey matter, while 59 (26.3%) patients had infratentorial lacunar infarcts. Patients with supratentorial lacunar infarcts presented with a significantly lower occurrence of deficits in the NIHSS items gaze (p

A disruption of white matter connectivity is negatively associated with language (recovery) in patients with aphasia after stroke, and behavioral gains have been shown to coincide with white matter neuroplasticity. However, most brain-behavior studies have been carried out in the chronic phase after stroke, with limited generalizability to earlier phases. Furthermore, few studies have investigated neuroplasticity patterns during spontaneous recovery (i.e., not related to a specific treatment) in the first months after stroke, hindering the investigation of potential early compensatory mechanisms. Finally, the majority of previous research has focused on damaged left hemisphere pathways, while neglecting the potential protective value of their right hemisphere counterparts for language recovery. To address these outstanding issues, we present a longitudinal study of thirty-two patients with aphasia (21 males and 11 females, M = 69.47 years, SD = 10.60 years) who were followed up for a period of 1 year with test moments in the acute (1–2 weeks), subacute (3–6 months) and chronic phase (9–12 months) after stroke. Constrained Spherical Deconvolution-based tractography was performed in the acute and subacute phase to measure Fiber Bundle Capacity (FBC), a quantitative connectivity measure that is valid in crossing fiber regions, in the bilateral dorsal arcuate fasciculus (AF) and the bilateral ventral inferior fronto-occipital fasciculus (IFOF). First, concurrent analyses revealed positive associations between the left AF and phonology, and between the bilateral IFOF and semantics in the acute – but not subacute - phase, supporting the dual-stream language model. Second, neuroplasticity analyses revealed a decrease in connection density of the bilateral AF – but not the IFOF – from the acute to the subacute phase, possibly reflecting post stroke white matter degeneration in areas adjacent to the lesion. Third, predictive analyses revealed no contribution of acute FBC measures to the prediction of later language outcomes over and above the initial language scores, suggesting no added value of the diffusion measures for language prediction. Our study provides new insights on (changes in) connectivity of damaged and undamaged language pathways in patients with aphasia in the first months after stroke, as well as if/how such measures are related to language outcomes at different stages of recovery. Individual results are discussed in the light of current frameworks of language processing and aphasia recovery.

Although several studies have aimed for accurate predictions of language recovery in post stroke aphasia, individual language outcomes remain hard to predict. Large-scale prediction models are built using data from patients mainly in the chronic phase after stroke, although it is clinically more relevant to consider data from the acute phase. Previous research has mainly focused on deficits, i.e., behavioral deficits or specific brain damage, rather than compensatory mechanisms, i.e., intact cognitive skills or undamaged brain regions. One such unexplored brain region that might support language (re)learning in aphasia is the hippocampus, a region that has commonly been associated with an individual’s learning potential, including statistical learning. This refers to a set of mechanisms upon which we rely heavily in daily life to learn a range of regularities across cognitive domains. Against this background, thirty-three patients with aphasia (22 males and 11 females, M = 69.76 years, SD = 10.57 years) were followed for 1 year in the acute (1–2 weeks), subacute (3–6 months) and chronic phase (9–12 months) post stroke. We evaluated the unique predictive value of early structural hippocampal measures for short-term and long-term language outcomes (measured by the ANELT). In addition, we investigated whether statistical learning abilities were intact in patients with aphasia using three different tasks: an auditory-linguistic and visual task based on the computation of transitional probabilities and a visuomotor serial reaction time task. Finally, we examined the association of individuals’ statistical learning potential with acute measures of hippocampal gray and white matter. Using Bayesian statistics, we found moderate evidence for the contribution of left hippocampal gray matter in the acute phase to the prediction of long-term language outcomes, over and above information on the lesion and the initial language deficit (measured by the ScreeLing). Non-linguistic statistical learning in patients with aphasia, measured in the subacute phase, was intact at the group level compared to 23 healthy older controls (8 males and 15 females, M = 74.09 years, SD = 6.76 years). Visuomotor statistical learning correlated with acute hippocampal gray and white matter. These findings reveal that particularly left hippocampal gray matter in the acute phase is a potential marker of language recovery after stroke, possibly through its statistical learning ability.

Introduction: Peroneal nerve entrapment is a frequent cause of foot drop. Despite being frequent, no guidelines exist to recommend surgical or non-invasive treatment, leading to important variations in daily practice. Research question: To map variation in daily practice. Materials and methods: An online Qualtrics survey was distributed among neurosurgeons, neurologists, orthopaedic surgeons and physical medicine and rehabilitation physicians through various national and international scientific organizations, mapping current treatment strategies. Descriptive statistics and non-parametric tests were used to analyse data with SPSS. Results: Responses from 181 out of 221 participants from 35 countries were analysed. A large majority of participants agreed that good evidence supporting any treatment strategy is lacking (77.9%) and that daily practice is mostly guided by own beliefs and experience (84.0%). Both non-invasive treatment and neurolysis are well established treatment strategies (supported by respectively 92.3% and 93.4% of physicians). Timing of neurolysis and duration of non-invasive treatment varied considerably. Duration of non-invasive treatment was significantly shorter in the group of surgeons compared to non-surgeons (p ​= ​0.033). Most physicians consider neurolysis a valid treatment option. However, significant more non-surgeons than surgeons were opposed to surgical treatment (p ​= ​0.001). Discussion and conclusion: Important differences in attitudes were observed not only between, but also within specialisms, regardless of physician experience. This survey highlights important variations in daily practice for foot drop due to peroneal entrapment and emphasizes the need for future controlled studies.

Background and PurposeThe evolution of total brain volume early after stroke is not well understood. We investigated the associations between age and imaging features and brain volume change in the first month after stroke.MethodsWe retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial. Total brain volume change from hyperacute MRI data to the first month after stroke was assessed using unified segmentation in SPM12. We hypothesized that age, ischemic brain lesion size, and white matter (WM) changes were associated with larger brain volume change. Enlarged perivascular spaces (EPVSs) and white matter hyperintensities (WMHs) were rated visually and the presence of lacunes was assessed.ResultsWe enrolled 173 patients with a mean age of 67 ± 11 years, 44% were women. There was a median 6 ml decrease in volume (25th percentile −1 ml to 75th percentile 21 ml) over time, equivalent to a median 0.5% (interquartile range [IQR], −0.07%−1.4%), decrease in brain volume. Age was associated with larger brain volume loss (per 10 years of age, 5 ml 95% CI 2–8 ml). Baseline diffusion weighted imaging (DWI) lesion volume was not associated with greater volume loss per 10 ml of lesion volume, change by 0 ml (95% CI −0.1 to 0.1 ml). Increasing Fazekas scores of deep WMH were associated with greater tissue loss (5 ml, 95% CI 1–10 ml).ConclusionsTotal brain volume changes in a heterogenous fashion after stroke. Volume loss occurs over 1 month after stroke and is associated with age and deep WM disease. We did not find evidence that more severe strokes lead to increased early tissue loss.

Background: Histopathological evidence of cerebral vascular amyloid β accumulation is the gold standard to diagnose cerebral amyloid angiopathy (CAA). Neuroimaging findings obtained with CT and MRI can suggest the presence of CAA when histopathology is lacking. We explored the role of amyloid PET in patients with lobar intracerebral hemorrhage (ICH) as this may provide molecular evidence for CAA as well. Methods: In this retrospective, monocenter analysis, we included consecutive patients with non-traumatic lobar ICH who had undergone amyloid PET. We categorized patients according to amyloid PET status and compared demographics and neuroimaging findings. We calculated sensitivity and specificity of the simplified Edinburgh criteria and amyloid PET with probable modified Boston criteria as reference standard, as well as sensitivity and specificity of the simplified Edinburgh and modified Boston criteria with amyloid PET status as molecular marker for presence or absence of CAA. Results: We included 38 patients of whom 24 (63%) were amyloid PET positive. Amyloid PET positive patients were older at presentation (p = 0.004). We observed no difference in prevalence of subarachnoid hemorrhages, fingerlike projections or microbleeds between both groups, but cortical superficial siderosis (p = 0.003) was more frequent in the amyloid PET positive group. In 5 out of 38 patients (13%), the modified Boston criteria were not fulfilled due to young age or concomitant vitamin K antagonist use with INR > 3.0. With the modified Boston criteria as reference standard, there was no difference in sensitivity nor specificity between the simplified Edinburgh criteria and amyloid PET status. With amyloid PET status as reference standard, there was also no difference in sensitivity nor specificity between the simplified Edinburgh and modified Boston criteria. Conclusions: Amyloid PET was positive in 63% of lobar ICH patients. Under certain circumstances, patients might not be diagnosed with probable CAA according to the modified Boston criteria and in these cases, amyloid PET may be useful. Accuracy to predict CAA based on amyloid PET status did not differ between the simplified Edinburgh and modified Boston criteria.

Abstract Background EphA4 is a receptor of the ephrin system regulating spine morphology and plasticity in the brain. These processes are pivotal in the pathophysiology of Alzheimer’s disease (AD), characterized by synapse dysfunction and loss, and the progressive loss of memory and other cognitive functions. Reduced EphA4 signaling has been shown to rescue beta-amyloid-induced dendritic spine loss and long-term potentiation (LTP) deficits in cultured hippocampal slices and primary hippocampal cultures. In this study, we investigated whether EphA4 ablation might preserve synapse function and ameliorate cognitive performance in the APPPS1 transgenic mouse model of AD. Methods A postnatal genetic ablation of EphA4 in the forebrain was established in the APPPS1 mouse model of AD, followed by a battery of cognitive tests at 9 months of age to investigate cognitive function upon EphA4 loss. A Golgi-Cox staining was used to explore alterations in dendritic spine density and morphology in the CA1 region of the hippocampus. Results Upon EphA4 loss in APPPS1 mice, we observed improved social memory in the preference for social novelty test without affecting other cognitive functions. Dendritic spine analysis revealed altered synapse morphology as characterized by increased dendritic spine length and head width. These modifications were independent of hippocampal plaque load and beta-amyloid peptide levels since these were similar in mice with normal versus reduced levels of EphA4. Conclusion Loss of EphA4 improved social memory in a mouse model of Alzheimer’s disease in association with alterations in spine morphology.

Background: Management of temperature, glycaemia and dysphagia, reffered to as the Fever, Sugar, Swallowing (FeSS) protocol, improves outcome in patients with acute stroke. Electronic health records can assist in efficient alignment of such clinical treatment protocol with daily patient care. Objectives: To assess the association between the implementation of the FeSS protocol, facilitated by an advanced electronic health record (EHR), and protocol adherence and outcome 90 days after hospital admission. Design: A single centre pre- and post-intervention study amongst patients presenting in the stroke unit within 48 h of onset of symptoms. Setting: The stroke unit of the comprehensive stroke centre at the University Hospitals Leuven, where a standardized care programme for stroke patients is in place. Participants: 495 patients consecutively admitted in 2018 and 2019 with a diagnosis of ischaemic stroke or intracerebral haemorrhage admitted to the stroke unit, with following criteria: (1) ≥18 years of age on admission, (2) presented within 48 h of onset of symptoms to the stroke unit. Methods: Advanced EHRs including electronic care planning and documentation offered nurses access to and support from FeSS guidelines at the point of care. We studied: (1) adherence to the protocol by nurses, (2) patient outcome as assessed by the modified Rankin Scale. Results: The rate of 90-day death and dependency (modified Rankin Scale ≥2) was lower in the post-intervention group (51.21%) compared to the pre-intervention group (60.34%) (adjusted OR 0.63, 95%CI 0.41-0.97). FeSS elements were more frequently documented in the post-intervention group, particularly temperature monitoring and glycaemia management. However, adherence remained suboptimal, and care plans within the electronic health record were frequently altered by nurses. Discussion and conclusion: A multicomponent implementation strategy comprising of traditional implementation strategies and appended by the use of electronic health records facilitated implementation and detailed evaluation of a complex intervention. This implementation was associated with reduced death and dependency. However, a better understanding of the interaction between nurses and the EHR as a means to facilitate their work is of critical importance.

Objective: To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke.Methods: We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to−6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden via modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons.Results: The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (β = 0.104, p < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), p < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), p < 0.01, respectively].Conclusion: The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health.

ObjectiveNeuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes.MethodsWe analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask–WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with stable selected features predictive of WMH burden and then related this signature to clinical variables using canonical correlation analysis (CCA).ResultsRadiomic features were predictive of WMH burden (R2 = 0.855 ± 0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p-valuesCV1–6 < 0.001, p-valueCV7 = 0.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes, CV4 by hypertension, CV5 by atrial fibrillation (AF) and diabetes, CV6 by coronary artery disease (CAD), and CV7 by CAD and diabetes.ConclusionRadiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes, suggesting different radiographical textural abnormalities per cardiovascular risk profile. Further research could evaluate radiomics to predict the progression of WMH and for the follow-up of stroke patients’ brain health.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the brainstem, spinal cord and motor cortex. ALS is characterized by genetic and clinical heterogeneity, suggesting the existence of genetic factors that modify the phenotypic expression of the disease. We previously identified the axonal guidance EphA4 receptor, member of the Eph-ephrin system, as an ALS disease-modifying factor. EphA4 genetic inhibition rescued the motor neuron phenotype in zebrafish and a rodent model of ALS. Preventing ligands from binding to the EphA4 receptor also successfully improved disease, suggesting a role for EphA4 ligands in ALS. One particular ligand, ephrin-A5, is upregulated in reactive astrocytes after acute neuronal injury and inhibits axonal regeneration. Moreover, it plays a role during development in the correct pathfinding of motor axons towards their target limb muscles. We hypothesized that a constitutive reduction of ephrin-A5 signalling would benefit disease progression in a rodent model for ALS. We discovered that in the spinal cord of control and symptomatic ALS mice ephrin-A5 was predominantly expressed in neurons. Surprisingly, reduction of ephrin-A5 levels in SOD1G93A mice accelerated disease progression and reduced survival without affecting disease onset, motor neuron numbers or innervated neuromuscular junctions in symptomatic mice. These findings suggest ephrin-A5 as a modifier of disease progression that might play a role in the later stages of the disease. Similarly, we identified a more aggressive disease progression in patients with lower ephrin-A5 protein levels in the cerebrospinal fluid without modifying disease onset. In summary, we identified reduced expression of ephrin-A5 to accelerate disease progression in a mouse model of ALS as well as in humans. Combined with our previous findings on the role of EphA4 in ALS our current data suggests different contribution for various members of the Eph-ephrin system in the pathophysiology of a motor neuron disease.

Rationale: 11C-UCB-J binds to synaptic vesicle glycoprotein 2A, a protein ubiquitously expressed in presynaptic nerve terminals, and can therefore serve as in vivo proxy of synaptic density. There are discrepancies in postmortem data on stability of synaptic density with healthy aging. In this study, healthy aging and sex as potential modifiers of 11C-UCB-J binding were investigated in healthy volunteers over 7 adult decades, assuming that the number of SV2A vesicles per synapse is not influenced by age or sex. Methods: 80 healthy volunteers underwent 11C-UCB-J PET and structural T1 and T2 MR imaging. Grey matter changes with aging were firstly evaluated by voxel-based morphometry (VBM). Parametric 11C-UCB-J standardized uptake value ratio (SUVR) images were calculated using the centrum semiovale as reference tissue. To correct for atrophy-related partial volume effects, a region-based voxel-wise type partial volume correction (PVC) was applied in FreeSurfer. The correlations of 11C-UCB-J binding with age and with sex were investigated by a voxel-based and volume-of-interest (VOI)-based approach, and with and without PVC to assess the contribution of underlying morphology changes upon aging. Results: Full results were available for 78 participants (19–85y; 33 M/45 F). VBM grey matter concentration changes with aging were most predominant in the perisylvian and frontal regions. After PVC, no significantly decreased 11C-UCB-J SUVR with aging was found in the voxel-based analysis, whereas the VOI-based analysis showed a slight decrease in the caudate nucleus (−1.7% decrease per decade, p= 0.0025) only. There was no association between sex and 11C-UCB-J SUVR, nor an interaction between aging and sex for this parameter. Conclusion: In vivo, PET using 11C-UCB-J does not support a cortical decrease of synaptic density with aging, whereas subcortically a small effect with aging in the caudate nucleus was observed. In addition, no association between synaptic density and sex was detected, which allows pooling of datasets of both sexes.

Background and Aims: Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) on MRI are a radiological marker of vessel occlusion and indirect sign of collateral circulation. However, the clinical relevance is uncertain. We explored whether the extent of FHVs is associated with outcome and how FHVs modify treatment effect of thrombolysis in a subgroup of patients with confirmed unilateral vessel occlusion from the randomized controlled WAKE-UP trial.Methods: One hundred sixty-five patients were analyzed. Two blinded raters independently assessed the presence and extent of FHVs (defined as the number of slices with visible FHV multiplied by FLAIR slice thickness). Patients were then separated into two groups to distinguish between few and extensive FHVs (dichotomization at the median

Introduction: The modified Rankin Scale (mRS) after 90 days documents outcome in stroke patients, but focusses only on activities of daily living. Here we studied stroke outcome beyond these activities by the Dutch-Flemish version of the Patient Reported Outcomes Measurement Information System (PROMIS) questionnaire.Patients and Methods: We documented the mRS at day 90 in stroke patients who filled out a questionnaire on pain intensity and seven PROMIS domains: physical function, ability to participate in social roles, anxiety, fatigue, depression, sleep disturbance, pain interference. In a subgroup of patients this questionnaire was reduced to one overall question per PROMIS domain. We correlated these findings with the mRS.Results: We received 102 questionnaires and identified physical function as the most affected PROMIS domain. The strongest correlation with mRS was found for the health domains of physical function (ρs = 0.70, p < 0.001) and ability to participate in social roles (ρs = 0.61, p < 0.001). The other domains with substantial proportions of patients with worse scores compared to the general population (19–44%) correlated weakly with the mRS. We identified a strong correlation between the single question per health domain and the overall score per PROMIS domain.Discussion and Conclusion: PROMIS better reflects the overall health status of stroke patients beyond functional outcome as measured by the mRS. Simplification of the questionnaire with a single question per PROMIS domain could potentially replace the full questionnaire, but needs further validation.

Background: Hemorrhagic transformation (HT) is an important complication of intravenous thrombolysis with alteplase. HT can show a wide range from petechiae to parenchymal hematoma with mass effect with varying clinical impact. We studied clinical and imaging characteristics of patients with HT and evaluated whether different types of HT are associated with functional outcome.Methods: We performed a post-hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in unknown onset stroke. HT was assessed on follow-up MRI or CT and diagnosed as hemorrhagic infarction type 1 and type 2 (HI1 and HI2, combined as HI), and parenchymal hemorrhage type 1 and type 2 (PH1 and PH2, combined as PH). Severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS) at baseline. Stroke lesion volume was measured on baseline diffusion weighted imaging (DWI). Primary endpoint was a favorable outcome defined as a modified Rankin Scale score 0–1 at 90 days.Results: Of 483 patients included in the analysis, 95 (19.7%) showed HI and 21 (4.4%) had PH. Multiple logistic regression analysis identified treatment with alteplase (OR, 2.08 [95% CI, 1.28–3.40]), baseline NIHSS score (OR, 1.11 [95% CI, 1.05–1.17]), DWI lesion volume (OR, 1.03 [95% CI, 1.01–1.05]), baseline glucose levels (OR, 1.01 [95% CI, 1.00–1.01]) and atrial fibrillation (OR, 3.02 [95% CI, 1.57–5.80]) as predictors of any HT. The same parameters predicted HI. Predictors of PH were baseline NIHSS score (OR, 1.11 [95% CI, 1.01–1.22]) and as a trend treatment with alteplase (OR, 2.40 [95% CI, 0.93–6.96]). PH was associated with lower odds of favorable outcome (OR 0.25, 95% [CI 0.05–0.86]), while HI was not.Conclusion: Our results indicate that HI is associated with stroke severity, cardiovascular risk factors and thrombolysis. PH is a rare complication, more frequent in severe stroke and with thrombolysis. In contrast to HI, PH is associated with worse functional outcome. The impact of HT after MRI-guided intravenous alteplase for unknown onset stroke on clinical outcome is similar as in the trials of stroke thrombolysis within a known early time-window.

Background: Magnetic resonance imaging (MRI) serves as a cornerstone in defining stroke phenotype and etiological subtype through examination of ischemic stroke lesion appearance and is therefore an essential tool in linking genetic traits and stroke. Building on baseline MRI examinations from the centralized and structured radiological assessments of ischemic stroke patients in the Stroke Genetics Network, the results of the MRI-Genetics Interface Exploration (MRI-GENIE) study are described in this work.Methods: The MRI-GENIE study included patients with symptoms caused by ischemic stroke (N = 3,301) from 12 international centers. We established and used a structured reporting protocol for all assessments. Two neuroradiologists, using a blinded evaluation protocol, independently reviewed the baseline diffusion-weighted images (DWIs) and magnetic resonance angiography images to determine acute lesion and vascular occlusion characteristics.Results: In this systematic multicenter radiological analysis of clinical MRI from 3,301 acute ischemic stroke patients according to a structured prespecified protocol, we identified that anterior circulation infarcts were most prevalent (67.4%), that infarcts in the middle cerebral artery (MCA) territory were the most common, and that the majority of large artery occlusions 0 to 48 h from ictus were in the MCA territory. Multiple acute lesions in one or several vascular territories were common (11%). Of 2,238 patients with unilateral DWI lesions, 52.6% had left-sided infarct lateralization (P = 0.013 for χ2 test).Conclusions: This large-scale analysis of a multicenter MRI-based cohort of AIS patients presents a unique imaging framework facilitating the relationship between imaging and genetics for advancing the knowledge of genetic traits linked to ischemic stroke.

Background: The “smoking paradox” indicates that patients with acute ischemic stroke (AIS) who smoke at the time of their stroke may have a better prognosis after intravenous thrombolysis than non-smokers. However, findings are inconsistent and data analyzing the effect of smoking on treatment efficacy of intravenous thrombolysis are scarce.Methods: We performed a pre-specified post-hoc subgroup analysis of the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial that randomized AIS patients with unknown time of symptom onset who had diffusion-weighted imaging-fluid attenuation inversion recovery (DWI-FLAIR) mismatch to either alteplase or placebo. Patients were categorized as current smokers or non-smokers (including former smokers and never-smokers). Baseline demographic and clinical characteristics, as well as clinical and imaging follow-up data were analyzed according to smoking status.Results: Four hundred and eighty six patients were included in the analysis. Current smokers (133, 27.4%) were younger (60.1 ± 13.0 vs. 67.2 ± 10.3 years; p < 0.001) and less often had arterial hypertension (45.0% vs. 56.8%; p = 0.02) or atrial fibrillation (3.8% vs. 15.3%; p < 0.001). The acute stroke presentation was more often due to large vessel occlusion among current smokers (27.1 vs. 16.2%; p = 0.01), and smokers had a trend towards more severe strokes (National Institutes of Health Stroke Scale score>10 in 27.1% vs. 19.5%; p = 0.08). The treatment effect of alteplase, quantified as odds ratio for a favorable outcome (modified Rankin Scale [mRS] score at 90 days of 0 or 1), did not differ between current smokers and non-smokers (p-value for interaction: 0.59). After adjustment for age and stroke severity, neither the proportion of patients with favorable outcome, nor the median mRS score at 90 days differed between current smokers and non-smokers. When additional potential confounders were included in the model, the median mRS score was higher in current smokers than in non-smokers (cOR of better outcome for current smokers vs. non-smokers: 0.664 [0.451–0.978], p = 0.04).Conclusions: In patients with mild to moderate MRI-proven AIS and unknown time of symptom onset with DWI-FLAIR mismatch, current smokers had worse functional outcome as compared to non-smokers. Current smoking did not modify the treatment effect of alteplase.Clinical Trial registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered 02 February 2012.

EphA4 is a receptor of the Eph-ephrin system, which plays an important role in axon guidance during development. Previously, we identified EphA4 as a genetic modifier of amyotrophic lateral sclerosis (ALS) in both zebrafish and rodent models, via modulation of the intrinsic vulnerability, and re-sprouting capacity of motor neurons. Moreover, loss of EphA4 rescued the motor axon phenotype in a zebrafish model of spinal muscular atrophy (SMA). Similar to ALS, SMA is a neurodegenerative disorder affecting spinal motor neurons resulting in neuromuscular junction (NMJ) denervation, muscle atrophy and paralysis. In this study, we investigated the disease modifying potential of reduced EphA4 protein levels in the SMNΔ7 mouse model for severe SMA. Reduction of EphA4 did not improve motor function, survival, motor neuron survival or NMJ innervation. Our data suggest that either lowering EphA4 has limited therapeutic potential in SMA or that the clinical severity hampers the potential beneficial role of EphA4 reduction in this mouse model for SMA.

Introduction: In WAKE-UP (Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke), patients with an acute stroke of unknown onset time were randomized to treatment with intravenous alteplase or placebo, guided by MRI.Methods: In this exploratory post-hoc secondary analysis we compared clinical and imaging data, as well as treatment effects and safety of intravenous thrombolysis between patients with infra- vs. supratentorial stroke.Results: Forty-eight out of 503 randomized patients (9.5%) presented with a stroke involving the cerebellum or brainstem. Patients with infratentorial stroke were younger compared to patients with supratentorial stroke (mean age 60 vs. 66 years), more frequently male (85 vs. 62%), and less severely affected (median NIHSS 4.5 vs. 6.0). There was no heterogeneity for treatment effect between supratentorial (OR 1.67 95% CI 1.11–2.51) and infratentorial (OR 1.31 95% CI 0.41–4.22) sub-groups (test for interaction p = 0.70). In patients with infratentorial stroke, favorable outcome [a score of 0–1 on the modified Rankin scale (mRS) at 90 days] was observed in 12/22 patients (54.5%) in the alteplase group and in 13/25 patients (52.0%) in the placebo group (p = 0.59). The primary safety endpoint (death or mRS 4–6 at day 90) occurred in three patients of the alteplase group (13.6%) and three patients in the placebo group (12.0%); p = 0.74.Discussion: WAKE-UP was underpowered for demonstrating treatment effect in subgroup analyses however, based on our current results, there is no evidence to recommend withholding MRI-guided thrombolysis in patients with unknown onset stroke of infratentorial localization.

In 2014, the definition of embolic strokes of undetermined source (ESUS) emerged as a new clinical construct to characterize cryptogenic stroke (CS) patients with complete vascular workup to determine nonlacunar, nonatherosclerotic strokes of presumable embolic origin. NAVIGATE ESUS, the first phase III randomized-controlled, clinical trial (RCT) comparing rivaroxaban (15 mg daily) with aspirin (100 mg daily), was prematurely terminated for lack of efficacy after enrollment of 7213 patients. Except for the lack of efficacy in the primary outcome, rivaroxaban was associated with increased risk of major bleeding and hemorrhagic stroke compared with aspirin. RE-SPECT ESUS was the second phase III RCT that compared the efficacy and safety of dabigatran (110 or 150 mg, twice daily) to aspirin (100 mg daily). The results of this trial have been recently presented and showed similar efficacy and safety outcomes between dabigatran and aspirin. Indirect analyses of these trials suggest similar efficacy on the risk of ischemic stroke (IS) prevention, but higher intracranial hemorrhage risk in ESUS patients receiving rivaroxaban compared to those receiving dabigatran (indirect HR = 6.63, 95% CI: 1.38–31.76). ESUS constitute a heterogeneous group of patients with embolic cerebral infarction. Occult AF represents the underlying mechanism of cerebral ischemia in the minority of ESUS patients. Other embolic mechanisms (paradoxical embolism via patent foramen ovale, aortic plaque, nonstenosing unstable carotid plaque, etc.) may represent alternative mechanisms of cerebral embolism in ESUS, and may mandate different management than oral anticoagulation. The potential clinical utility of ESUS may be challenged since the concept failed to identify patients who would benefit from anticoagulation therapy. Compared with the former diagnosis of CS, ESUS patients required thorough investigations; more comprehensive diagnostic work-up than is requested in current ESUS diagnostic criteria may assist clinicians in uncovering the source of brain embolism in CS patients and individualize treatment approaches.

White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery.In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94–0.95; p

IntroductionStroke severity measured by the baseline National Institutes of Health Stroke Scale (NIHSS) is a strong predictor of stroke outcome. Early change of baseline severity may be a better predictor of outcome. Here, we hypothesized that the change in NIHSS in the first 24 h after stroke improved stroke outcome prediction.Materials and methodsPatients from the Leuven Stroke Genetics Study were included when the baseline NIHSS (B-NIHSS) was determined on admission in the hospital and NIHSS after 24 h could be obtained from patient files. The delta NIHSS, relative reduction NIHSS, and major neurological improvement (NIHSS of 0–1 or ≥8-point improvement at 24 h) were calculated. Good functional outcome (GFO) at 90 days was defined as a modified Rankin Scale of 0–2. Independent predictors of outcome were identified by multivariate logistic regression. We performed a secondary analysis after excluding patients presenting with a minor stroke (NIHSS 0–5) since the assessment of change in NIHSS might be more reliable in patients presenting with a moderate to severe deficit.ResultsWe analyzed the outcome in 369 patients. B-NIHSS was associated with GFO (odds ratio: 0.82; 95% CI 0.77–0.86). In a multivariate model with B-NIHSS and age as predictors, the accuracy [area under the curve (AUC): 0.82] improved by including the delta NIHSS (AUC: 0.86; p

Background and purposeThe perfusion-weighted imaging (PWI)/diffusion-weighted imaging (DWI) mismatch profile is used to select patients for endovascular treatment. A PWI map of Tmax is commonly used to identify tissue with critical hypoperfusion. A time to peak (TTP) map reflects similar hemodynamic properties with the added benefit that it does not require arterial input function (AIF) selection and deconvolution. We aimed to determine if TTP could substitute Tmax for mismatch categorization.MethodsImaging data of the DEFUSE 2 trial were reprocessed to generate relative TTP (rTTP) maps. We identified the rTTP threshold that yielded lesion volumes comparable to Tmax > 6 s and assessed the effect of reperfusion according to mismatch status, determined based on Tmax and rTTP volumes.ResultsAmong 102 included cases, the Tmax > 6 s lesion volumes corresponded most closely with rTTP > 4.5 s lesion volumes: median absolute difference 6.9 mL (IQR: 2.3–13.0). There was 94% agreement in mismatch classification between Tmax and rTTP-based criteria. When mismatch was assessed by Tmax criteria, the odds ratio (OR) for favorable clinical response associated with reperfusion was 7.4 (95% CI 2.3–24.1) in patients with mismatch vs. 0.4 (95% CI 0.1–2.6) in patients without mismatch. When mismatch was assessed with rTTP criteria, these ORs were 7.2 (95% CI 2.3–22.2) and 0.3 (95% CI 0.1–2.2), respectively.ConclusionrTTP yields lesion volumes that are comparable to Tmax and reliably identifies the PWI/DWI mismatch profile. Since rTTP is void of the problems associated with AIF selection, it is a suitable substitute for Tmax that could improve the robustness and reproducibility of mismatch classification in acute stroke.

Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease, resulting in selective motor neuron degeneration and paralysis. Patients die approximately 3–5 years after diagnosis. Disease pathophysiology is multifactorial, including excitotoxicity, but is not yet fully understood. Genetic analysis has proven fruitful in the past to further understand genes modulating the disease and increase knowledge of disease mechanisms. Here, we revisit a previously performed microsatellite analysis in ALS and focus on another hit, PLCD1, encoding phospholipase C delta 1 (PLCδ1), to investigate its role in ALS. PLCδ1 may contribute to excitotoxicity as it increases inositol 1,4,5-trisphosphate (IP3) formation, which releases calcium from the endoplasmic reticulum through IP3 receptors. We find that expression of PLCδ1 is increased in ALS mouse spinal cord and in neurons from ALS mice. Furthermore, genetic ablation of this protein in ALS mice significantly increases survival, but does not affect astrogliosis, microgliosis, aggregation or the amount of motor neurons at end stage compared to ALS mice with PLCδ1. Interestingly, genetic ablation of PLCδ1 prevents nuclear shrinkage of motor neurons in ALS mice at end stage. These results indicate that PLCD1 contributes to ALS and that PLCδ1 may be a new target for future studies.

Background Recent trials have demonstrated that extended cardiac monitoring increases the yield of paroxysmal atrial fibrillation (AF) detection in patients with cryptogenic stroke. The utility of extended cardiac monitoring is uncertain among patients with stroke caused by small and large vessel disease. We conducted a meta‐analysis to estimate the yield of AF detection in this population. Methods and Results We searched PubMed, Cochrane, and SCOPUS databases for studies on AF detection in stroke patients and excluded studies restricted to patients with cryptogenic stroke or transient ischemic attack. We abstracted AF detection rates for 3 populations grouped by stroke etiology: large vessel stroke, small vessel stroke, and stroke of undefined etiology (a mixture of cryptogenic, small vessel, large vessel, and other stroke etiologies). Our search yielded 30 studies (n=5687). AF detection rates were similar in patients with large vessel (2.2%, 95% CI 0.3–5.5; n=830) and small vessel stroke (2.4%, 95% CI 0.4–6.1; n=520). No studies had a monitoring duration longer than 7 days. The yield of AF detection in the undefined stroke population was higher (9.2%; 95% CI 7.1–11.5) compared to small vessel stroke (P=0.02) and large vessel stroke (P=0.02) populations. Conclusions AF detection rate is similar in patients with small and large vessel strokes (2.2–2.4%). Because no studies reported on extended monitoring (>7 days) in these stroke populations, we could not estimate the yield of AF detection with long‐term cardiac monitoring. Randomized controlled trials are needed to examine the utility of AF detection with long‐term cardiac monitoring (>7 days) in this patient population.

Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10⁻⁷), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6×10⁻⁸). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10⁻¹⁵; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p