Journal of Investigative Medicine最新文献

Background: Astrocytes regulate blood-brain barrier (BBB) integrity, whereas subarachnoid haemorrhage (SAH) results in astrocyte dysregulation and BBB disruption. Here, we explored the involvement of tissue inhibitor of matrix metalloprotease-1 (TIMP1) in astrocyte-mediated BBB protection during SAH, along with its underlying mechanisms.

Methods: C57BL/6J mice were used to establish a model of SAH. The effects of TIMP1 on SAH outcomes were analysed by intraperitoneal injection of recombinant mouse TIMP1 protein (rm-TIMP1; 250 µg/kg). The roles of TIMP1 and its effector β1-integrin on astrocytes were observed by in vivo transduction with astrocyte-targeted adeno-associated virus carrying TIMP1 overexpression plasmid or β1-integrin RNAi. The molecular mechanisms underlying TIMP1 and β1-integrin interactions were explored in primary cultured astrocytes stimulated with red blood cells (RBCs).

Results: TIMP1 was upregulated after SAH. Administration of rm-TIMP1 mitigated SAH-induced early brain injury (EBI) in male and female mice. TIMP1 was primarily expressed in astrocytes; its overexpression in astrocytes led to increased β1-integrin expression in astrocytes, along with the preservation of astrocytic endfoot attachment to the endothelium and subsequent recovery of endothelial tight junctions. All of these effects were reversed by the knockdown of β1-integrin in astrocytes. Molecular analysis showed that TIMP1 overexpression decreased the RBC-induced ubiquitination of β1-integrin; this effect was partially achieved by inhibiting the interaction between β1-integrin and the E3 ubiquitin ligase Trim21.

Conclusion: TIMP1 inhibits the interaction between β1-integrin and Trim21 in astrocytes, thereby rescuing the ubiquitination of astrocytic β1-integrin. It subsequently restores interactions between astrocytic endfeet and the endothelium, as well as BBB integrity, eventually mitigating SAH-induced EBI.

Background and purpose: Acute vestibular syndrome (AVS) typically manifests as isolated dizziness or vertigo with no apparent neurological impairments. However, distinguishing life-threatening stroke from innocuous peripheral vestibular lesions in the emergency room (ER) remains challenging. This study aimed to explore the ability of the head impulse-nystagmus-test of skew (HINTS) combined with truncal ataxia or ABCD² score to differentiate stroke from peripheral vestibular disease in patients with AVS in the ER.

Methods: We prospectively recruited 121 patients with AVS from December 2022 to June 2023, 69 of whom presented with vestibular neuritis (VN) and the remaining with posterior circulation stroke (PCS). We analysed the HINTS results, truncal ataxia and ABCD² score and compared the sensitivity and specificity among HINTS, truncal ataxia, ABCD² score and their combinations using the McNemar test for paired samples.

Results: HINTS combined with grade 2-3 truncal ataxia achieved significantly higher sensitivity than that of isolated HINTS in differentiating PCS from VN (100% vs 88.5%, p=0.031). The specificity of HINTS plus grade 2-3 truncal ataxia did not significantly differ from that of isolated HINTS (p=0.125); however, the combination of ABCD² score and HINTS did not improve the diagnostic accuracy. The sensitivity of ABCD² score ≥4 plus grade 2-3 truncal ataxia was significantly higher than those of isolated ABCD² score ≥4 or isolated grade 2-3 truncal ataxia (p=0.016 and p<0.001, respectively) and not significantly lower than that of isolated HINTS (p=0.508).

Conclusion: Compared with the ABCD² score, the truncal ataxia is of more valuable assistance to HINTS in differentiating PCS. Although the combination of ABCD² score and truncal ataxia has a significant implication, it is not a replacement for HINTS.

Background and objectives: Prior evidence suggests that atrial fibrillation detected after stroke (AFDAS) is distinct from known atrial fibrillation (KAF), with particular clinical characteristics and impacts on outcomes in ischaemic stroke. However, the results remained inconsistent in ischaemic stroke, and the role of AFDAS in haemorrhagic stroke remains unclear. Therefore, we aimed to estimate the prevalence, risk factors and prognostic value of AFDAS in haemorrhagic stroke in comparison with ischaemic stroke.

Methods: This was a multicentre cohort study. Patients who had an ischaemic and haemorrhagic stroke hospitalised in the Chinese Stroke Center Alliance hospitals were enrolled and classified as AFDAS, KAF or sinus rhythm (SR) based on heart rhythm. Univariate and multivariate logistic regression analyses were used to assess the prevalence, characteristics, risk factors and outcomes of AFDAS, KAF and SR in different stroke subtypes.

Results: A total of 913 163 patients, including 818 799 with ischaemic stroke, 83 450 with intracerebral haemorrhage (ICH) and 10 914 with subarachnoid haemorrhage (SAH), were enrolled. AFDAS was the most common in ischaemic stroke. There were differences in the risk factor profile between stroke subtypes; older age is a common independent risk factor shared by ischaemic stroke (OR 1.06, 95% CI 1.06 to 1.06), ICH (OR 1.08, 95% CI 1.07 to 1.09) and SAH (OR 1.07, 95% CI 1.05 to 1.10). Similar to KAF, AFDAS was associated with an increased risk of in-hospital mortality compared with SR in both ischaemic stroke (OR 2.23, 95% CI 1.94 to 2.56) and ICH (OR 2.84, 95% CI 1.84 to 4.38).

Discussion: There are differences in the prevalence, characteristics and risk factors for AFDAS and KAF in different stroke subtypes. AFDAS was associated with an increased risk of mortality compared with SR in both ischaemic stroke and ICH. Rhythm monitoring and risk factor modification after both ischaemic and haemorrhagic stroke are essential in clinical practice. More emphasis and appropriate treatment should be given to AFDAS.

Background: We investigated outcomes in patients with intracerebral haemorrhage (ICH) according to prior anticoagulation treatment with Vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or no anticoagulation.

Methods: This is an individual patient data study combining two prospective national stroke registries from Switzerland and Norway (2013-2019). We included all consecutive patients with ICH from both registries. The main outcomes were favourable functional outcome (modified Rankin Scale 0-2) and mortality at 3 months.

Results: Among 11 349 patients with ICH (mean age 73.6 years; 47.6% women), 1491 (13.1%) were taking VKAs and 1205 (10.6%) DOACs (95.2% factor Xa inhibitors). The median percentage of patients on prior anticoagulation was 23.7 (IQR 22.6-25.1) with VKAs decreasing (from 18.3% to 7.6%) and DOACs increasing (from 3.0% to 18.0%) over time. Prior VKA therapy (n=209 (22.3%); adjusted ORs (aOR), 0.64; 95% CI, 0.49 to 0.84) and prior DOAC therapy (n=184 (25.7%); aOR, 0.64; 95% CI, 0.47 to 0.87) were independently associated with lower odds of favourable outcome compared with patients without anticoagulation (n=2037 (38.8%)). Prior VKA therapy (n=720 (49.4%); aOR, 1.71; 95% CI, 1.41 to 2.08) and prior DOAC therapy (n=460 (39.7%); aOR, 1.28; 95% CI, 1.02 to 1.60) were independently associated with higher odds of mortality compared with patients without anticoagulation (n=2512 (30.2%)).

Conclusions: The spectrum of anticoagulation-associated ICH changed over time. Compared with patients without prior anticoagulation, prior VKA treatment and prior DOAC treatment were independently associated with lower odds of favourable outcome and higher odds of mortality at 3 months. Specific reversal agents unavailable during the study period might improve outcomes of DOAC-associated ICH in the future.

Background: The benefit of intravenous alteplase in acute ischaemic stroke (AIS) is time-dependent. Tenecteplase is non-inferior to alteplase among patients with AIS. We aimed to delineate the association of the stroke onset to treatment time (OTT) with tenecteplase compared with alteplase on therapeutic benefit and clinical risks.

Methods: This is a post hoc analysis of the Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-2 an open-label, randomised, controlled, non-inferior trial. A total of 1430 AIS within 4.5 hours onset at 53 sites in China from 12 June 2021 to 29 May 2022 were randomly assigned (1:1) to receive either tenecteplase 0.25 mg/kg or alteplase 0.9 mg/kg. The primary efficacy outcome was the proportion of participants with a modified Rankin Scale score of 0-1 at 90 days. A post hoc subgroup analysis was conducted with the OTT divided into three intervals (0-90 min, 91-180 min and 181-270 min). The primary safety outcome was symptomatic intracranial haemorrhage within 36 hours post-thrombolytic treatment.

Results: Treatment was initiated within 270 min of stroke onset in 1412 patients who were randomly allocated to either tenecteplase (n=707) or alteplase (n=705). The OR of primary efficacy outcome was similar as OTT increased (p=0.84). Adjusted odds of an excellent functional outcome were 0.99 (95% CI 0.37 to 2.67) for 0-90 min, 1.23 (95% CI 0.88 to 1.71) for 91-180 min and 1.21 (95% CI 0.88 to 1.65) for 181-270 min. All were in favour of the tenecteplase group. Meta-analysis of 2949 patients yielded a pooled risk difference of 5.54 (95% CI -0.18 to 11.26; p=0.82) in favour of tenecteplase for more than 180 min and 1.77 (95% CI -2.66 to 6.20; p=0.58) for 0-180 min.

Conclusions: In AIS patients who were treated with either tenecteplase or alteplase within 4.5 hours onset, there was no difference observed in the efficacy and safety between the two groups at the three different OTT time intervals.

Introduction: To compare the perfusion volumes assessed by a new automated CT perfusion (CTP) software iStroke with the circular singular value decomposition software RAPID and determine its predictive value for functional outcome in patients with acute ischaemic stroke (AIS) who underwent endovascular treatment (EVT).

Methods: Data on patients with AIS were collected from four hospitals in China. All patients received CTP followed by EVT with complete recanalisation within 24 hours of symptom onset. We evaluated the agreement of CTP measures between the two softwares by Spearman's rank correlation tests and kappa tests. Bland-Altman plots were used to evaluate the agreement of infarct core volume (ICV) on CTP and ground truth on diffusion-weighted imaging (DWI). Logistic regression models were used to test the association between ICV on these two softwares and functional outcomes.

Results: Among 326 patients, 228 had DWI examinations and 40 of them had infarct volume >70 mL. In all patients, the infarct core and hypoperfusion volumes on iStroke had a strong correlation with those on RAPID (ρ=0.68 and 0.66, respectively). The agreement of large infarct core (volume >70 mL) was substantial (kappa=0.73, p<0.001) between these two softwares. The ICV measured by iStroke and RAPID was significantly correlated with independent functional outcome at 90 days (p=0.009 and p<0.001, respectively). In patients with DWI examinations and those with an ICV >70 mL, the ICV of iStroke and RAPID was comparable on individual agreement with ground truth.

Conclusion: The automatic CTP software iStroke is a reliable tool for assessing infarct core and mismatch volumes, making it clinically useful for selecting patients with AIS for acute reperfusion therapy in the extended time window.

Organised stroke care has become a keystone in delivering efficient and effective treatment to patients with stroke with improved outcomes. Delivering timely acute reperfusion therapy to those with acute ischaemic strokes is key to good recovery. Emergency stroke unit (ESU) is a novel organised stroke care system developed in China. It centralises all necessary procedures for the diagnosis and treatment of acute stroke into one unit that can perform clinical assessment, imaging examination and acute treatments. In ESU, artificial intelligence algorithms are used to aid in reading brain images and making clinical decisions. Therefore, ESU can significantly enhance the efficiency of emergent stroke care. In this guideline, we aim to clarify the concept, construction standards and personnel requirements of an ESU, standardise ESU-based acute stroke triage and treatment workflow, establish metrics of quality control, facilitate the construction and promotion of ESU and continue the improvement of the quality of stroke care.

Background and aims: Observational studies have implicated the involvement of gut microbiome in stroke development. Conversely, stroke may disrupt the gut microbiome balance, potentially causing systemic infections exacerbated brain infarction. However, the causal relationship remains controversial or unknown. To investigate bidirectional causality and potential ethnic differences, we conducted a bidirectional two-sample Mendelian randomisation (MR) study in both East Asian (EAS) and European (EU) populations.

Methods: Leveraging the hitherto largest genome-wide association study (GWAS) summary data from the MiBioGen Consortium (n=18 340, EU) and BGI (n=2524, EAS) for the gut microbiome, stroke GWAS data from the GIGASTROKE Consortium(264 655 EAS and 1 308 460 EU), we conducted bidirectional MR and sensitivity analyses separately for the EAS and EU population.

Results: We identified nominally significant associations between 85 gut microbiomes taxa in EAS and 64 gut microbiomes taxa in EU with stroke or its subtypes. Following multiple testing, we observed that genetically determined 1 SD increase in the relative abundance of species Bacteroides pectinophilus decreased the risk of cardioembolic stroke onset by 28% (OR 0.72 (95% CI 0.62 to 0.84); p=4.22e-5), and that genetically determined 1 SD increase in class Negativicutes resulted in a 0.76% risk increase in small vessel stroke in EAS. No significant causal association was identified in the EU population and the reverse MR analysis.

Conclusion: Our study revealed subtype-specific and population-specific causal associations between gut microbiome and stroke risk among EAS and EU populations. The identified causality holds promise for developing a new stroke prevention strategy, warrants further mechanistic validation and necessitates clinical trial studies.

Background: The relationship between anterior cerebral artery (ACA) occlusion and moyamoya disease (MMD) has rarely been studied. In this study, we focused on a special type of MMD: isolated ACA-occlusive MMD. We investigated clinical attributes, genotypes and progression risk factors in patients with ACA-occlusive MMD, providing initial insights into the relationship between ACA occlusion and MMD.

Methods: We retrospectively analysed digital subtraction angiography (DSA) from 2486 patients and diagnosed 139 patients with ACA-occlusive MMD. RNF213 p.R4810K (rs112735431) mutation analysis was performed. Patients were categorised into progression and non-progression groups based on whether they progressed to typical MMD. Differences in clinical characteristics, neuropsychological assessment, radiological findings and genotypes were evaluated. Logistic regression analyses identified risk factors for ACA-occlusive MMD progression.

Results: The median age of patients with ACA-occlusive MMD was 36 years, and the primary symptom was transient ischaemic attack (TIA). 72.3% of ACA-occlusive MMD patients had cognitive decline. Of 116 patients who underwent RNF213 gene mutation analysis, 90 patients (77.6%) carried the RNF213 p.R4810K GG allele and 26 (22.4%) carried the GA allele. Of 102 patients with follow-up DSA data, 40 patients (39.2%) progressed. Kaplan-Meier curve estimates indicated a higher incidence of ischaemic stroke in the progression group during follow-up (p=0.035). Younger age (p=0.041), RNF213 p.R4810K GA genotype (p=0.037) and poor collateral compensation from the middle cerebral artery (MCA) to ACA (p<0.001) were risk factors of ACA-occlusive MMD progression to typical MMD.

Conclusions: Cognitive decline and TIA might be the main manifestations of ACA-occlusive MMD. Isolated ACA occlusion may be an early signal of MMD. The initial lesion site of MMD is not strictly confined to the terminal portion of the internal carotid artery. Younger patients, patients with RNF213 p.R4810K GA genotype or those with inadequate MCA-to-ACA compensation are more likely to develop typical MMD.

Background and purpose: Tenecteplase (TNK) has demonstrated non-inferiority to alteplase in patients who had an acute ischaemic stroke presenting within 4.5 hours from symptom onset. The trial is aimed to explore the efficacy and safety of TNK in Chinese patients who had an acute ischaemic stroke with large/medium vessel occlusion in an extended time window.

Methods and design: Chinese Acute Tissue-Based Imaging Selection for Lysis In Stroke Tenecteplase II (CHABLIS-T II) is a multicentre, prospective, block-randomised, open-label, blinded-endpoint, phase IIb study. Eligible patients are 1:1 randomised into two groups: 0.25 mg/kg TNK versus best medical management (excluding TNK). The safety and efficacy of 0.25 mg/kg TNK are assessed through reperfusion status and presence of symptomatic intracranial haemorrhage (sICH).

Study outcomes: The primary outcome is major reperfusion without sICH at 24-48 hours after randomisation. Major reperfusion is defined as restoration of blood flow to greater than 50% of the involved ischaemic territory assessed by catheter angiography or repeated perfusion imaging. Secondary outcomes include post-thrombolytic recanalisation, neurological improvements, change in the National Institutes of Health Stroke Scale score, haemorrhagic transformation at 24-48 hours, systematic bleeding at discharge, modified Rankin Scale (mRS) 0-1, mRS 0-2, mRS 5-6, mRS distribution and Barthel index at 90 days.

Discussion: CHABLIS-T II will provide important evidence of intravenous thrombolysis with TNK for patients who had an acute stroke in an extended time window.