Translational Stroke Research最新文献

The role of different imaging modalities-non-contrast CT (NCCT), CT perfusion (CTP), and diffusion-weighted imaging (DWI)-in selecting patients with large-core stroke for endovascular thrombectomy (EVT) is a subject of ongoing debate. This study aims to determine whether patients with large-core acute ischemic stroke (AIS) undergoing EVT triaged with CTP or DWI in addition to NCCT had different clinical outcomes compared to those only triaged with NCCT. We queried the Stroke Thrombectomy and Aneurysm Registry (STAR) for patients enrolled between 2014 and 2023 who presented with anterior-circulation AIS and large ischemic core (ASPECTS < 6) who underwent EVT in 41 stroke centers in the USA, Europe, Asia, and South America. Patients were stratified by the imaging used before EVT. Propensity score matching (PSM) was used to compare balanced cohorts of patients with NCCT vs CTP and NCCT vs DWI. The primary outcome was a favorable 90-day functional status (mRS 0-3). Secondary outcomes included intracerebral hemorrhage (ICH) rates, symptomatic ICH (sICH), and successful/complete recanalization, as determined by mTICI score. A total of 403 patients were included, 121 were selected with NCCT alone, 227 with CTP, and 55 with DWI. Before PSM, 90-day mRS 0-3, successful reperfusion mTICI ≥ 2B, and sICH rates were similar across the three imaging modalities. mTICI-2C or greater rates were highest in DWI (50.9%; p < 0.01), followed by NCCT (41.3%) and CTP (27.8%). Patients selected with CTP had the highest ICH incidence (44.1%; p < 0.01). After 1:1 PSM, 104 pairs of NCCT vs CTP and 36 pairs of NCCT vs DWI were compared. There were no significant differences in any procedural or functional outcome measure between the matched groups, including mTICI ≥ 2C recanalization, 90-day mRS 0-3, ICH rates, and sICH rates. In patients with anterior large-vessel occlusion AIS with low ASPECTS, we found that selecting patients for EVT based on NCCT or employing advanced imaging to elucidate collaterals, infarct volume, and ischemic penumbra does not alter procedural or patient outcomes. NCCT alone may be sufficient to select patients for EVT in this patient population, especially in settings with limited resources.

The implementation of artificial intelligence (AI), particularly Viz.ai software in stroke care, has emerged as a promising tool to enhance the detection of large vessel occlusion (LVO) and to improve stroke workflow metrics and patient outcomes. The aim of this systematic review and meta-analysis is to evaluate the impact of Viz.ai on stroke workflow efficiency in hospitals and on patients' outcomes. Following the PRISMA guidelines, we conducted a comprehensive search on electronic databases, including PubMed, Web of Science, and Scopus databases, to obtain relevant studies until 25 October 2024. Our primary outcomes were door-to-groin puncture (DTG) time, CT scan-to-start of endovascular treatment (EVT) time, CT scan-to-recanalization time, and door-in-door-out time. Secondary outcomes included symptomatic intracranial hemorrhage (ICH), any ICH, mortality, mRS score < 2 at 90 days, and length of hospital stay. A total of 12 studies involving 15,595 patients were included in our analysis. The pooled analysis demonstrated that the implementation of the Viz.ai algorithm was associated with lesser CT scan to EVT time (SMD -0.71, 95% CI [-0.98, -0.44], p < 0.001) and DTG time (SMD -0.50, 95% CI [-0.66, -0.35], p < 0.001) as well as CT to recanalization time (SMD -0.55, 95% CI [-0.76, -0.33], p < 0.001). Additionally, patients in the post-AI group had significantly lower door-in door-out time than the pre-AI group (SMD -0.49, 95% CI [-0.71, -0.28], p < 0.001). Despite the workflow metrics improvement, our analysis did not reveal statistically significant differences in patient clinical outcomes (p > 0.05). Our results suggest that the integration of the Viz.ai platform in stroke care holds significant potential for reducing EVT delays in patients with LVO and optimizing stroke flow metrics in comprehensive stroke centers. Further studies are required to validate its efficacy in improving clinical outcomes in patients with LVO.

Developing cost-effective, noninvasive biomarker-based tests could transform moyamoya disease (MMD) management. This study aimed to identify clinically relevant cerebrospinal fluid (CSF) biomarkers through comprehensive proteomic screening in a large MMD cohort. CSF protein profiles from 104 MMD patients and 14 non-tumorous hydrocephalus patients were analyzed via liquid chromatography-tandem mass spectrometry. Enrichment analysis was conducted on canonical pathways and differentially expressed proteins (DEPs). The protein-protein interaction network data included all proteins involved in canonical pathways. Potential markers were validated via ELISA. Weighted gene coexpression network analysis (WGCNA) revealed clinical factor-related modules. We identified 2463 proteins, and 2307 were quantified in at least one sample. A total of 321 significant DEPs were identified, with 8 proteins upregulated and 11 proteins downregulated in MMD samples. ELISA confirmed the increased expression of ALB and SLITRK1. WGCNA revealed seven modules correlated with clinical factors, linking preoperative cerebral infarction to the module eigengene (ME) red module and favorable modified Rankin scale scores to the MEblack module. BASP1 and LDHA were significantly upregulated in MEred, whereas CD9 and EMILIN1 were upregulated in MEblack. Our findings shed light on the proteomics of CSF from MMD patients, identifying potential novel biomarkers such as SLITRK1 and markers of preoperative cerebral infarction (BASP1, LDHA) and clinical outcome (CD9, EMILIN1). These markers have potential as new diagnostic and therapeutic targets for MMD.

Objective: To determine the temporal profiles of glial fibrillary acidic protein (GFAP), neurofilament light (NFL), total tau (t-tau), and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) in plasma the first week after acute ischemic stroke, and identify the optimal time points for assessing infarct volume by these biomarkers.

Patients & methods: In this cohort study, biomarker plasma concentrations were determined daily over the first week and at 90 days after symptom onset in patients with acute ischemic stroke. A brain MRI was performed on day three. Temporal variations in biomarker levels were analyzed using linear mixed-effects models, and optimal time points for infarct volume correlation were identified with continuous Pearson analysis.

Results: 38 patients with a median age of 78 (IQR 72-86) and mean infarct volume of 5.5 (IQR 1.6-17) cm³ were included. We identified three distinct temporal patterns: (1) a parabolic trajectory of GFAP, reaching zenith after three days, (2) a consistent increase in NFL throughout the week, and (3) an initial surge in t-tau and UCHL1 levels, stabilizing by day three. The optimal time point for infarct volume correlation occurred at 119 h for GFAP (r = 0.94, 95% CI: [0.84-0.98]), 144 h for NFL (r = 0.78, [0.47, 0.92]), 122 h for t-tau (r = 0.82, [0.56, 0.93]) and 113 h for UCHL1 (r = 0.83, [0.60, 0.93]).

Interpretation: This high-resolution serial sampling of plasma GFAP, NFL, t-tau, and UCHL1 the first week after acute ischemic stroke identified three distinct temporal profiles. These biomarkers provided the most accurate infarct volume assessment 4-6 days after symptom onset.

Clinicaltrials: gov NCT03812666 (registration date 2019-01-23).

Ischemic stroke contributes substantially to global death and disability, yet effective molecular targets remain scarce. This study integrates real-world pharmacovigilance data, molecular databases, and genetic evidence to support the discovery and validation of novel therapeutic targets. A stepwise analytic pipeline combined adverse event signals from the FDA Adverse Event Reporting System (FAERS), drug-target data from DrugBank, and Mendelian randomization (MR) using proteomic instruments from the UK Biobank Pharma Proteomics Project (UKB PPP). Disproportionality analyses identified drugs with signals for ischemic stroke. The top 30 drugs were cross-referenced in DrugBank to identify molecular targets, which were subjected to protein interaction and pathway enrichment analyses. MR analysis assessed the causal effects of plasma proteins on ischemic stroke using GWAS data from GIGASTROKE (discovery) and FinnGen (validation). Among 88,313 ischemic stroke-related reports in FAERS, 701 drugs showed consistent signals, with the top 30 prioritized for target identification. FLT1 was the only overlapping protein between MR-significant proteins and FAERS-associated drug targets. MR analysis showed a significant inverse causal relationship between plasma FLT1 levels and ischemic stroke in both the discovery (OR, 0.864; 95% CI, 0.774-0.965) and validation (OR, 0.829; 95% CI, 0.788-0.871) datasets. FLT1 was enriched in pathways such as MAPK and PI3K-Akt, implicated in stroke-related molecular processes. FLT1 was identified as a potential protective factor against ischemic stroke through a triangulated approach combining pharmacovigilance, target bioinformatics, and MR analysis. These findings offer mechanistic insights and a promising direction for targeted intervention.

Aneurysmal subarachnoid hemorrhage (aSAH) often leads to cerebral vasospasm, a serious complication associated with delayed cerebral ischemia (DCI) and increased morbidity. For vasospasm management, both balloon angioplasty (BA) and intra-arterial (IA) calcium channel blockers (CCBs) are commonly used, although their combined efficacy and safety compared to monotherapy remain unclear. We conducted a systematic review and meta-analysis in accordance with Cochrane and PRISMA guidelines. Studies were included if they investigated patients with vasospasm post-aSAH treated with both BA and IA CCBs. Eight studies met inclusion criteria, comprising patients treated with BA, IA nimodipine, or IA verapamil. Combined BA with IA nimodipine significantly improved clinical outcomes compared to BA alone (OR: 0.07, 95% CI: 0.01-0.68, p = 0.02) without increasing hemorrhagic or ischemic risks. However, ischemic complications were higher with combined therapy than IA nimodipine alone (OR: 0.04, 95% CI: 0.01-0.40, p < 0.01). Combined therapy reduced retreatment rates compared to IA verapamil monotherapy (OR: 3.18, 95% CI: 1.15-8.79, p = 0.03). Our analysis indicates that combined BA and IA CCBs may improve clinical outcomes for aSAH patients with vasospasm without increasing complications compared to BA alone. However, combined therapy was associated with a significant increase in ischemic complications compared to CCB monotherapy. These findings highlight the potential role of combined therapy in select patients unresponsive to single-agent approaches and emphasize the importance of careful patient selection. Further randomized studies are necessary to confirm these findings and establish standardized guidelines for combined therapy use.

Spontaneous intracerebral hemorrhage (ICH) is a severe cerebrovascular condition with limited therapeutic options. One of the major contributors to ICH pathophysiology and secondary brain injury is the toxicity of blood products. As a result, removing parenchymal blood has emerged as a potential strategy to reduce mortality and improve patient outcomes. While minimally invasive surgical techniques have shown promising results, their broader application is limited by stringent patient selection criteria and technical challenges. Consequently, a pharmacological approach aiming at modulating the endogenous clearance of blood is of particular interest. Recent advances, from experimental models to human studies, have enhanced our understanding of the mechanisms involved in spontaneous hematoma resorption, leading to the identification of several biomarkers and potential therapeutic targets. This narrative review takes a translational approach to provide an update on the current knowledge of hematoma resorption, including its natural history, underlying mechanisms, and associated imaging and biological biomarkers. Special focus will be given to the most promising pharmacomodulatory strategies.

This study hypothesized that Cerebrolysin, a multimodal neuroprotective agent, enhances the efficacy and safety of mechanical thrombectomy (MT) in both acute ischemic stroke (AIS) and recovery stroke phases in selected patients with good collateral status (CTA-CS 2-3) and effective recanalization (mTICI 2b-3). A single-center, prospective, open-label, single-arm study with blinded outcome assessment of 50 consecutive patients with moderate-to-severe AIS treated with MT ≤ 6 h of stroke onset followed by Cerebrolysin (30 ml iv within 8 h of onset and continued to day 21, first cycle) and in a recovery phase (between 69-90 days, second cycle) compared to 50 historical controls matched by propensity scores. Key outcomes included functional independence (mRS 0-2 at 90 days), safety endpoints, and neurological recovery (NIHSS at 24 h and 7 day post MT). Patients receiving Cerebrolysin achieved higher rates of mRS 0-2 at 90 days (68% vs. 44%, p = 0.016, OR 2.7, 95% CI 1.2-6.1; NNT: 4.2), had reduced risk of secondary ICH (14% vs. 40%, p = 0.02; RR 0.37, 95% CI 0.14-0.95), and had lower NIHSS on day 7 (median [IQR]: 3 [4] vs. 6 [9], p = 0.01). There was a significant difference in Barthel Index scores between the Cerebrolysin group and the control group at 30 days (median [IQR]: 77 [32] vs. 63 [50], p = 0.03) and at 3 months (86 [22] vs. 75 [29], p = 0.01) primarily driven by the increase in the mobility and transfer components. Multivariate analysis identified Cerebrolysin as an independent predictor of favorable outcomes at 3 months (OR 7.5, 95% CI 1.8-30.9), particularly in patients with diabetes (interaction OR 9.6, 95% CI 1.01-92). The overall mortality rates at 30 and 90 days were similar in both groups (2% vs 6% and 8% vs 12%, p > 0.1). Cerebrolysin improved functional outcomes at 90 days, accelerated neurological recovery, and reduced complications post-MT in patients with small ischemic core, good collateral circulation, and effective recanalization at baseline. These findings warrant further randomized trials to validate its efficacy and explore its long-term benefits.Registration: URL: https://www.clinicaltrials.gov ; unique identifier: NCT04904341.

Somatic PIK3CA and MAP3K3 mutations in cerebral and spinal cavernous malformations (CMs) have been identified in recent studies. However, their significance in the clinical presentation and risk of hemorrhage in CMs remains poorly understood. We aimed to analyze the association between these mutations and the clinical characteristics of CMs. Among patients with CMs who underwent surgical resection of lesions between July 2002 and March 2022, those with complete clinical and radiological data at the time of initial surgery were included. Somatic PIK3CA and MAP3K3 mutations were detected using droplet digital polymerase chain reaction. Subsequently, the clinical and radiological characteristics correlated with these mutations were assessed. Furthermore, the effect of these mutations on the first symptomatic intraparenchymal hemorrhage during follow-up was evaluated. In total, 72 patients were included; among them, 50 had sufficient mutation data. PIK3CA E542K, E545K, and H1047R mutations were identified in 7 (14%), 7 (14%), and 15 (30%) patients, respectively. MAP3K3 I441M was identified in 10 (20%) patients (8 [16%] had both PIK3CA and MAP3K3 mutations). MAP3K3 I441M was more common in patients with Zabramski classification type II lesions than in those with CMs of other types (p = 0.024). Multivariate Cox regression analyses identified the presence of a PIK3CA mutation as a risk factor for early (re)hemorrhage. The results suggest that PIK3CA and MAP3K3 mutations are associated with clinical and radiological characteristics in patients with CMs and that the presence of a somatic PIK3CA mutation increases susceptibility to hemorrhage. These findings may help guide future therapeutic strategies.

Patients presenting with stroke symptoms suffer from either ischemic stroke, hemorrhagic stroke, transient ischemic attacks (TIA), or "stroke mimics," which include benign headaches, epilepsy, and vestibular disorders. As ischemic and hemorrhagic stroke patients require different medical treatments, early identification of the underlying cause of symptoms is essential for tailored and urgent medical intervention. This study investigates whether extracellular vesicles (EVs), present in peripheral blood of patients presenting with stroke symptoms, can be used to identify patients with ischemic stroke. Blood was collected from 155 patients presenting with stroke symptoms in the emergency room and analyzed for EVs by flow cytometry (ethics approval number NL72929.018.20). The primary endpoint was to compare platelet EV concentrations between patients with (n = 66) and without (n = 89) ischemic stroke. Concentrations of EVs from both activated platelets and leukocytes were lower in patients presenting with ischemic stroke compared to other patients (p = 0.038 and p = 0.015, respectively). No significant differences in other EV types were observed. In addition, ischemic stroke patients were older and had a higher diastolic blood pressure compared to patients with other diagnoses. In a multivariable analysis, leukocyte EVs and diastolic blood pressure were independent indicators of ischemic stroke. To conclude, this study demonstrates that the plasma concentration of leukocyte EVs can be useful to identify ischemic stroke patients in an emergency setting.