{"title":"Time-of-Day-Dependent Effects of Rehabilitation on Motor Recovery After Experimental Focal Cerebral Ischemia.","authors":"Linran Yuan, Yunlei Wang, Xueyan Hu, Yao Zuo, Tianyu Jin, Xudong Li, Xingzhu Li, Lingna Cheng, Haojie Zhang, Tong Zhang","doi":"10.1161/STROKEAHA.125.050084","DOIUrl":"10.1161/STROKEAHA.125.050084","url":null,"abstract":"<p><strong>Background: </strong>Rehabilitation is an efficacious method to improve poststroke motor dysfunction. Various rehabilitative techniques have become popular in this field of research. However, it has not been reported whether better outcomes can be achieved if rehabilitation training is conducted at the optimal time of the day.</p><p><strong>Methods: </strong>A model of photothrombotic ischemic stroke was used in C57BL/6 mice, and poststroke 24-hour activity cycles were evaluated. We found an activity peak around Zeitgeber time (ZT)13 (21:00) and a trough around ZT20 (04:00) during the dark phase. In addition, we selected ZT6 (14:00) as the daytime training group (corresponding to the ZT13 training group, ZT20 training group, and ZT6 training group, respectively). The 3 groups underwent treadmill training for 4 weeks. Functional and histological recovery levels were compared. In addition, bulk RNA sequencing analysis was used to explore the possible molecular mechanisms.</p><p><strong>Results: </strong>The results showed that stroke-induced mice maintained a regular nocturnal locomotor rhythm with reduced amplitude. Motor recovery was greater in the ZT13 training group than in the ZT6 group, with a trend toward better outcomes at ZT13 than ZT20. The ZT13 group also showed superior neuronal survival and neurogenesis compared with ZT6, while improvements between ZT13 and ZT20 were less pronounced. Bulk RNA sequencing suggested that synaptic plasticity, calcium signaling, cAMP signaling, and MAPK (mitogen-activated protein kinase) signaling pathways contributed to neural repair differences between ZT13 and ZT6. In addition, the results showed a similar pattern of motor recovery in female and aged mice trained at ZT13 compared with ZT6, reinforcing the benefits of time-of-day training.</p><p><strong>Conclusions: </strong>In conclusion, rehabilitative training during the most active phase is beneficial for enhanced recovery outcomes. Our study suggests that rehabilitation should be conducted when the body is in an optimal physiological state-that is, a time-of-day-dependent rehabilitation strategy.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"2277-2290"},"PeriodicalIF":8.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StrokePub Date : 2025-08-01Epub Date: 2025-04-24DOI: 10.1161/STROKEAHA.125.050560
Erik M Vos, Cacha M P C D Peeters-Scholte, Jelis Boiten, Hajo M Hund, Korné Jellema, Raoul P Kloppenborg, Elyas Ghariq, Adriaan C G M van Es, Esmee Venema, Hester F Lingsma, Annigje E S van der Hoeven, Peter W Vis, Diederik W J Dippel, Bob Roozenbeek, Ido R van den Wijngaard
{"title":"Safety, Tolerability, and Pharmacokinetics of the Neuroprotectant 2-Iminobiotin in Patients With Large-Vessel Occlusion Ischemic Stroke Treated With Endovascular Thrombectomy.","authors":"Erik M Vos, Cacha M P C D Peeters-Scholte, Jelis Boiten, Hajo M Hund, Korné Jellema, Raoul P Kloppenborg, Elyas Ghariq, Adriaan C G M van Es, Esmee Venema, Hester F Lingsma, Annigje E S van der Hoeven, Peter W Vis, Diederik W J Dippel, Bob Roozenbeek, Ido R van den Wijngaard","doi":"10.1161/STROKEAHA.125.050560","DOIUrl":"10.1161/STROKEAHA.125.050560","url":null,"abstract":"<p><strong>Background: </strong>2-Iminobiotin (2-IB) is a biotin analog with neuroprotective properties. It selectively inhibits neuronal and inducible nitric oxide synthase. The primary objective of this study was to assess the safety, tolerability, and pharmacokinetics of 2-IB in patients with ischemic stroke due to large-vessel occlusion treated with endovascular thrombectomy. The secondary objective was to investigate preliminary efficacy.</p><p><strong>Methods: </strong>In this single-center, randomized, placebo-controlled phase 2a study, patients received continuous infusion of 2-IB or placebo for 24 hours. The primary outcome was safety and tolerability measured by vital parameters and pharmacokinetic parameters in the first 28 hours after treatment and serious adverse events up until 7 days. Secondary and additional outcomes included National Institutes of Health Stroke Scale score and infarct volume at 24 to 48 hours, mortality at 90 days, and (baseline-prognosis adjusted) modified Rankin Scale score at 90 days.</p><p><strong>Results: </strong>In the modified intention-to-treat population, 40 patients were randomized, 20 per treatment group. Median age was 76 (interquartile range [IQR], 66-82) years and 40% were female. Baseline characteristics were similar between groups. Vital parameters during treatment did not differ between groups. In total, 17 serious adverse events occurred, 6 (30%) in 2-IB and 11 (55%) in placebo. Median 2-IB exposure (AUC<sub>avg_4 h</sub>) was 320 (IQR, 243-395) ng h/mL. Median National Institutes of Health Stroke Scale score at 7 days was 3 (IQR, 1-11) in 2-IB and 3 (IQR, 0-16) in placebo. Median infarct volume at 24 to 48 hours was 12.5 (IQR, 8.4-60.5) mL versus 13.7 (IQR, 4.0-94.5) mL. Median modified Rankin Scale at 3 months was 3 (IQR, 1-3) in the 2-IB group versus 3 (2-6) in placebo-treated patients. Mortality was 15% (3/20) in 2-IB versus 40% (8/20) in placebo.</p><p><strong>Conclusions: </strong>In patients with ischemic stroke with large-vessel occlusion treated with endovascular thrombectomy, 2-IB is safe and well tolerated. Pharmacokinetic parameters could be predicted well. The efficacy of 2-IB needs to be investigated further in a phase 2b/3 clinical trial.</p><p><strong>Registration: </strong>URL: www.onderzoekmetmensen.nl; Unique identifier: NL-OMON51194.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"1991-1999"},"PeriodicalIF":8.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StrokePub Date : 2025-08-01Epub Date: 2025-05-21DOI: 10.1161/STROKEAHA.125.051230
Naëiri Pauillac, Dorothée Faille, Mialitiana Solo Nomenjanahary, Mélanie Souvanheuane, Nahida Brikci-Nigassa, Alain Ameri, Tristan Benoit, François Delvoye, Benjamin Maier, Benoit Ho-Tin-Noé, Mikael Mazighi, Jean-Philippe Desilles, Pierre Seners
{"title":"Fibrinogen Depletion Coagulopathy and Hemorrhagic Transformation in Acute Ischemic Stroke Treated With Bridging Therapy.","authors":"Naëiri Pauillac, Dorothée Faille, Mialitiana Solo Nomenjanahary, Mélanie Souvanheuane, Nahida Brikci-Nigassa, Alain Ameri, Tristan Benoit, François Delvoye, Benjamin Maier, Benoit Ho-Tin-Noé, Mikael Mazighi, Jean-Philippe Desilles, Pierre Seners","doi":"10.1161/STROKEAHA.125.051230","DOIUrl":"10.1161/STROKEAHA.125.051230","url":null,"abstract":"<p><strong>Background: </strong>Hemorrhagic transformation (HT) frequently occurs in acute ischemic stroke patients with a large vessel occlusion undergoing endovascular therapy (EVT), significantly impacting functional outcomes. We aimed to determine whether an early fibrinogen depletion coagulopathy (FDC) was associated with HT following bridging therapy (ie, intravenous thrombolysis [IVT] followed by EVT), and to identify its associated factors.</p><p><strong>Methods: </strong>We retrospectively analyzed prospectively collected data from 296 patients with acute ischemic stroke with a large vessel occlusion who underwent EVT alone or bridging therapy, with fibrinogen levels measured both before baseline imaging and at the start of the EVT procedure. FDC was defined as a fibrinogen level <2.0 g/L at the start of the EVT procedure, with an absolute decrease >1.0 g/L from baseline. The primary outcome was the occurrence of any HT at 24 to 36 hours. Secondary outcomes included symptomatic HT, parenchymal hematomas, and 3-month mortality. The relationships between FDC and outcomes were studied using multivariable logistic regression analyses, adjusting for relevant confounders. We also studied baseline characteristics associated with FDC occurrence.</p><p><strong>Results: </strong>Of the 296 patients enrolled, 102 (34.5%) experienced HT, and 54 (18.2%) developed FDC. FDC was strongly associated with IVT use (53/161 [32.9%] versus 1/135 [0.7%] in IVT-treated and non-IVT-treated patients, respectively; <i>P</i><0.01). In patients receiving bridging therapy, FDC occurrence was independently associated with any HT (adjusted odds ratio, 2.33 [95% CI, 1.11-4.91]), symptomatic HT (adjusted odds ratio, 3.35 [95% CI, 1.20-9.40]), parenchymal hematomas (adjusted odds ratio, 2.87 [95% CI, 1.14-7.24]), and 3-month mortality (adjusted odds ratio, 3.82 [95% CI, 1.47-9.93]). None of the 26 patients who received tenecteplase experienced FDC, compared with 53 of 135 (39.3%) patients treated with alteplase (<i>P</i><0.01).</p><p><strong>Conclusions: </strong>Following bridging therapy, FDC is a frequent event associated with increased risks of any HT, symptomatic HT, parenchymal hematomas, and 3-month mortality. FDC did not occur following IVT with tenecteplase in our cohort, suggesting that the fibrin specificity of thrombolytic agents may play a pivotal role in its development.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"2009-2020"},"PeriodicalIF":8.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StrokePub Date : 2025-08-01Epub Date: 2025-07-28DOI: 10.1161/STROKEAHA.125.051498
Lorenzo Barba, Lucio D'Anna, Samir Abu-Rumeileh, Matteo Foschi, Felipe A Montellano, Hermann Neugebauer, Markus Otto
{"title":"Implementing Blood Biomarkers in Stroke Research and Clinical Practice.","authors":"Lorenzo Barba, Lucio D'Anna, Samir Abu-Rumeileh, Matteo Foschi, Felipe A Montellano, Hermann Neugebauer, Markus Otto","doi":"10.1161/STROKEAHA.125.051498","DOIUrl":"10.1161/STROKEAHA.125.051498","url":null,"abstract":"<p><p>Blood-based biomarkers reflecting the severity of brain injury showed manifold promising applications in the management of patients with stroke. To date, NfL (neurofilament light chain) and GFAP (glial fibrillary acidic protein) represent the markers with the most support from the literature, but novel biomarker candidates are emerging. In this commentary, we discuss the potential benefits that blood biomarkers would have as additional tools for physicians and stroke specialists in the assessment of stroke risk in the general population, in the acute and postacute phase of stroke management as well as during the longitudinal monitoring of patients during rehabilitation. Moreover, we present an overview of the current applications of blood biomarkers in ongoing clinical trials and debate the still unmet needs of biomarker research in stroke that future studies should target to ease their implementation in the routine care of patients.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":"56 8","pages":"2380-2384"},"PeriodicalIF":8.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StrokePub Date : 2025-08-01Epub Date: 2025-07-28DOI: 10.1161/STROKEAHA.125.052000
Shegaw Zeleke, Peta Drury, Sabine M Allida, Caleb Ferguson
{"title":"Multicultural Recommendations to Guide Stroke Care: A Document Review of International Stroke Guidelines.","authors":"Shegaw Zeleke, Peta Drury, Sabine M Allida, Caleb Ferguson","doi":"10.1161/STROKEAHA.125.052000","DOIUrl":"10.1161/STROKEAHA.125.052000","url":null,"abstract":"<p><p>Stroke disproportionately affects individuals from culturally and linguistically diverse backgrounds, often leading to poorer outcomes. Although stroke guidelines are essential for ensuring evidence-based care, the extent to which they incorporate cultural considerations remains unclear. This document review aims to systematically review international stroke guidelines for the inclusion of culture-related recommendations that support equitable stroke care. We conducted a document review of English-language international stroke guidelines published between June 2019 and May 2024, using a structured search strategy. Paired reviewers independently screened and extracted cultural recommendations, with a third reviewer resolving discrepancies. Guideline quality was appraised using the Appraisal of Guidelines for Research and Evaluation II instrument. Among 24 included guidelines, only 3 (12%) contained culture-related recommendations. Of 2991 total recommendations, 6 (0.2%) addressed cultural considerations, spanning prehospital care, acute care, rehabilitation, and palliative care. Most were supported by low-to-moderate quality evidence. The majority (88%) of international stroke guidelines lack cultural recommendations. Incorporating cultural considerations is critical for promoting culturally safe and equitable stroke care. Future research should explore barriers and facilitators to integrating cultural recommendations into stroke guidelines.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":"56 8","pages":"2375-2379"},"PeriodicalIF":8.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StrokePub Date : 2025-08-01Epub Date: 2025-04-24DOI: 10.1161/STROKEAHA.124.050159
Alexandra Maury, Joseph Benzakoun, Alexandre Bani-Sadr, Adrien Ter Schiphorst, Peggy Reiner, Hassan Hosseini, Pierre Seners, Johan Pallud, Catherine Oppenheim, David Calvet, Andreas Charidimou, Pascale Varlet, Guillaume Turc, Jean-Claude Baron
{"title":"Diagnostic Accuracy of Finger-Like Projections and Subarachnoid Hemorrhage for Cerebral Amyloid Angiopathy: Pathological Validation From Lobar Hematoma Evacuation or Brain Biopsy.","authors":"Alexandra Maury, Joseph Benzakoun, Alexandre Bani-Sadr, Adrien Ter Schiphorst, Peggy Reiner, Hassan Hosseini, Pierre Seners, Johan Pallud, Catherine Oppenheim, David Calvet, Andreas Charidimou, Pascale Varlet, Guillaume Turc, Jean-Claude Baron","doi":"10.1161/STROKEAHA.124.050159","DOIUrl":"10.1161/STROKEAHA.124.050159","url":null,"abstract":"<p><strong>Background: </strong>Diagnosing cerebral amyloid angiopathy (CAA) after spontaneous lobar intracerebral hemorrhage has significant clinical implications. A previous postmortem study found that the presence of both subarachnoid hemorrhage (SAH) and hematoma finger-like projections (FLP) on acute-stage computed tomography strongly rules in CAA. In the present study, we assessed the diagnostic value of these imaging markers against histopathologic diagnosis in less severe presentations.</p><p><strong>Methods: </strong>This retrospective (2002-2022) multicenter study included patients aged ≥45 years with lobar intracerebral hemorrhage of unknown cause, for whom acute-stage computed tomography or magnetic resonance imaging and neuropathological samples from hematoma evacuation or biopsy were available. Centralized consensus reading (2 raters) of imaging and neuropathological data (including Aβ immunohistochemistry) were performed. Analysis was restricted to samples containing at least 10 vessels. The diagnostic performance was evaluated against the neuropathological reference, that is, CAA/no CAA.</p><p><strong>Results: </strong>We analyzed data from 66 patients (age, 65±9 years; men, 33%; hematoma volume, 45±26 mL; death within 1 year, 14%) from 6 French centers. Neuropathological material included samples from hematoma evacuation (n=48) and biopsy (n=18). CAA was present in 38 (58%) patients, and FLP and SAH were observed in 29 (44%) and 50 (76%) patients, respectively. FLP had a sensitivity of 0.58 (95% CI, 0.41-0.74) and a specificity of 0.74 (95% CI, 0.54-0.89) for the diagnosis of CAA. SAH demonstrated a high sensitivity of 0.92 (95% CI, 0.78-0.98; negative predictive value=0.80 [0.52-0.96]) but moderate specificity of 0.43 (95% CI, 0.24-0.63). The combined presence of FLP and SAH had a specificity of 0.54 (95% CI, 0.37-0.71) and a sensitivity of 0.79 (95% CI, 0.59-0.92).</p><p><strong>Conclusions: </strong>This study is the first to evaluate the diagnostic performance of FLP and SAH with histopathologic reference in nonautopsied patients. The results suggest these markers have lower diagnostic performance than previously reported in severe hematomas leading to early death. However, the high sensitivity of SAH suggests its potential clinical utility in ruling out CAA when absent.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"2190-2197"},"PeriodicalIF":8.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Exposure to Multiple Metals and Cerebral White Matter Hyperintensity in Chinese Population: A Cross-Sectional Study.","authors":"Jianing Wang, Hao-Long Zeng, Ying Hui, Feipeng Cui, Yudiyang Ma, Linxi Tang, Meiqi Xing, Lei Zheng, Ning Chen, Xinru Zhao, Dankang Li, Run Liu, Shuohua Chen, Liming Cheng, Shouling Wu, Zhenchang Wang, Yaohua Tian","doi":"10.1161/STROKEAHA.124.050048","DOIUrl":"10.1161/STROKEAHA.124.050048","url":null,"abstract":"<p><strong>Background: </strong>Evidence about the impact of multiple metal exposure on brain neuroimaging metrics remains limited. We aim to investigate the effects of single and mixed metal exposure on white matter hyperintensities (WMHs).</p><p><strong>Methods: </strong>This cross-sectional study included 1183 subjects without stroke history from the META-KLS (Multi-modality Medical Imaging Study Based on Kailuan Study), which is an existing prospective cohort in Tangshan, China. Plasma metal levels, including Mg, Ca, V, Mn, Co, Ni, Cu, Zn, As, Se, Rb, Cs, Tl, Pb, and Cd, were measured using an inductively coupled plasma mass spectrometer. Ordinal and binary logistic regression models were used to examine the effects of metal exposure on the WMH burden, deep white matter hyperintensity, and periventricular white matter hyperintensity. All metal concentrations were naturally log-transformed to reduce skewness and were analyzed as both continuous and tertile forms. Weighted quantile sum regression, quantile-based g-computation model, and Bayesian Kernel Machine Regression were used in the metal mixture analysis.</p><p><strong>Results: </strong>Compared with the first tertile, the adjusted odds ratios and 95% CIs for the WMH burden in the third tertile were 1.57 (1.05-2.34) for As, 2.01 (1.28-3.18) for Cu, 1.68 (1.14-2.50) for V, 1.61 (1.07-2.44) for Cs, and 1.56 (1.04-2.34) for Tl (all <i>P</i> for trend<0.05). Additionally, Pb, Se, and Mg showed significant positive associations with WMH burden exclusively in continuous analysis, with odds ratios of 1.27 (1.02-1.56) for Pb, 1.32 (1.07-1.61) for Se, and 1.27 (1.04-1.55) for Mg for per interquartile range increase in Ln-transformed metal concentrations. The weighted quantile sum index revealed a significant positive correlation with WMH burden risk (each interquartile range increment in the weighted quantile sum index was associated with 60% higher odds for WMH burden [95% CI, 1.09-2.34]). The primary contributors to the weighted quantile sum index were As (39.4%), followed by Pb (12.5%) and Cu (11.3%). The bivariate exposure-response relationships suggested potential interactions between As and Cu, as well as As and Co.</p><p><strong>Conclusions: </strong>There were positive associations between individual exposures to As, Pb, Cu, V, Se, Cs, Tl, and Mg, and mixed metal exposure with WMH burden among the Chinese population, strengthening the evidence of detrimental effects of specific metals on brain health.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"2138-2146"},"PeriodicalIF":8.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}