Translational Stroke Research最新文献

Metabolomics reflects the body's metabolic state and holds substantial promise for identifying associated biomarkers and exploring pathological processes. This study used serum metabolomics to predict malignant brain edema (MBE) following endovascular therapy (EVT) for acute ischemic stroke (AIS) and investigate the underlying mechanisms. In this prospective observational study, we enrolled patients with anterior circulation large vessel occlusion who underwent successful recanalization post-EVT for AIS, including those with or without concomitant hemorrhagic transformation. Eligible patients were stratified into two groups according to the subsequent presence of MBE. Following propensity score matching to adjust for potential confounders, widely targeted metabolomic analysis was conducted on the serum samples. A prediction model, based on the identified differential metabolites, was then developed and validated in another independent cohort. Through widely targeted metabolomic analysis of serum samples from matched 46 patients, we identified 30 metabolites that were significantly altered between patients with and without MBE, including notable differences in acylcarnitine, lysophosphatidylcholine, riboflavin, and tyrosine. A prediction model incorporating 9 differential metabolites was constructed using 10-fold frame shift cross-validation, demonstrating prediction performance in the training set, test set, and external validation, with areas under the curve (AUC) of 0.842, 0.815, and 0.734, respectively. Dynamic change analysis based on multiple time points may suggest a potential role of diminished oxidative energy supply and sustained stress in MBE. The identified acylcarnitine and lysophosphatidylcholine might play influential roles in the pathogenesis of MBE. The prediction model derived from these differential metabolites holds promise as a noninvasive assay for the early detection of MBE and warrants additional refinement and validation.

Background: Prior clinical research demonstrated that rapid reduction in arterial carbon dioxide (PaCO₂) levels during extracorporeal membrane oxygenation (ECMO) is associated with acute brain injury (ABI), which may be due to sudden cerebral vasoconstriction and impaired cerebrovascular autoregulation (CVAR). However, the causal relationship between rapid PaCO₂ correction and its impact on ABI has not been firmly established due to the lack of high-quality evidence. We aimed to investigate whether rapid PaCO₂ correction following extracorporeal cardiopulmonary resuscitation (ECPR) causes CVAR impairment and neuronal injury in a porcine model.

Methods: In this prospective preclinical experimental study, six female pigs (mean weight: 50.75 ± 1.89 kg) were subjected to 15 min of ventricular fibrillation and were then supported by ECMO. The return of spontaneous circulation (ROSC) was attempted in animals at 20 min post-ECMO initiation. Arterial blood gas (ABG) was sampled at specific time points, while arterial blood pressure (ABP) and intracranial pressure (ICP) were continuously monitored. Sweep gas flow was set relative to each animal's ECMO flow rate: 100% in the control group, 200% in the rapid correction group, and 25% in the slow correction group. PRx was computed as the Pearson correlation coefficient between 10-s average mean arterial pressure (MAP) and ICP values using 1-min windows updated every 30 s. Experimental phases were defined for data analysis, including baseline, fibrillation, ECMO I (0-10 min after ECMO initiation), ECMO II (10-20 min), and POST-R (post-ROSC, 20-30 min). Linear mixed-effects models were used to assess group-wise differences in ΔPRx over time. Histopathological analysis was performed to quantify neuronal injury across cortical and subcortical regions. Brain tissues were harvested and histologically analyzed for neuronal injury ischemia vulnerable regions: the midbrain, cerebellum, striatum in the basal ganglia, temporal cortex, hypothalamus, and hippocampus.

Results: In the rapid group, PaCO₂ correction caused a steep drop in PaCO₂-from 60 to approximately 30 mmHg within 5 min-and was associated with impaired CVAR. Following ECMO initiation, the rapid group exhibited a significant rise in ΔPRx, indicating impaired CVAR. Group differences in ΔPRx were significant at ECMO I (F = 8.12, p = 0.001), ECMO II (F = 6.21, p = 0.003), and POST-R (F = 13.47, p < 0.001). At ECMO II, median PRx in the rapid group was 0.50 (IQR: 0.10, 0.78), significantly higher than the control (0.11, IQR: - 0.27, 0.42) and slow (0.38, IQR: - 0.06, 0.55). Histologically, the rapid correction group exhibited significantly increased ischemic neuronal injury in ischemia-prone regions: caudate (43.1% injured neurons vs. 10.6% in control, p = 0.041), putamen (66.6% vs. 23.9%, p = 0.003), temporal cortex (34.9% vs. 8.9%, p = 0.013), and hi

Mendelian randomization studies have identified that apolipoprotein B (ApoB) is the primary genetic determinant of ischemic stroke, rather than other lipid markers. However, its association with recurrent non-cardioembolic acute ischemic stroke (NCAIS) remains unclear. This study aimed to investigate this association. This study recruited 578 patients with acute ischemic stroke, excluding those with cardiogenic embolism. After a 3-year follow-up, a total of 428 patients completed the prospective cohort study. A Cox regression model was used to evaluate the association between ApoB levels at admission and the recurrence rate. Additionally, a nested case-control study was conducted by comparing blood samples collected at the time of recurrence from recurrent patients with those from non-recurrent patients. Binary logistic regression and ROC analysis were used to assess the association between serum ApoB, low-density lipoprotein cholesterol (LDL-C), and recurrent stroke at the time of recurrence. The Cox regression model demonstrated that ApoB levels at admission were independently associated with an increased risk of recurrent NCAIS (HR=6.697; 95%CI 2.581-17.374, P < 0.001). Recurrent stroke patients had significantly higher serum ApoB levels at admission than non-recurrent ones [0.85 g/L (IQR 0.21) vs. 0.63 g/L (IQR 0.15)]. In ROC analysis, ApoB (AUC = 0.732) showed a greater discriminatory ability for recurrent stroke than LDL-C (AUC = 0.685). Higher serum ApoB levels increased the risk of recurrence in patients with NCAIS, and ApoB demonstrated better discriminatory ability than LDL-C after therapy. These findings suggest that routine ApoB measurement may help improve secondary stroke risk assessment.

Sarcosine has been reported to improve ischemic tolerance in animal models of brain ischemia, but population-based evidence from patients with ischemic stroke is lacking. We conducted a multicenter prospective study to investigate the associations between plasma sarcosine levels and adverse outcomes among patients with ischemic stroke. We measured plasma sarcosine levels among 3473 patients with ischemic stroke from 26 hospitals across China. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale [mRS] score, 3-6) at 3 months after ischemic stroke. Secondary outcomes were major disability (mRS score, 3-5), death (mRS score, 6), and cardiovascular events. During 3 months of follow-up, 853 participants experienced the primary outcome. Compared with the lowest quartile of sarcosine, the multivariable-adjusted odds ratios or hazard ratios of the highest quartile were 0.59 (P_trend < 0.001) for primary outcome, 0.70 (P_trend = 0.002) for major disability, 0.20 (P_trend < 0.001) for death, and 0.43 (P_trend = 0.017) for cardiovascular events. Multivariable-adjusted spline regression model showed linear associations of sarcosine with adverse outcomes (all P_linearity < 0.05). Adding sarcosine to conventional prognostic factors modestly improved the risk reclassification of adverse outcomes after ischemic stroke, as evidenced by net reclassification improvement and integrated discrimination improvement (all P < 0.05). Additionally, there was a strong combined effect of sarcosine and glycine on the risks of adverse outcomes after ischemic stroke. High plasma sarcosine levels were associated with low risks of adverse outcomes after ischemic stroke, suggesting that sarcosine might serve as a valuable prognostic biomarker for ischemic stroke.

Large vessel occlusion (LVO) acute ischemic stroke represents a leading cause of disability despite successful endovascular treatment (EVT). Venous outflow has recently emerged as a potential predictor of functional outcome in ischemic stroke. We aimed to investigate whether a comprehensive venous drainage evaluation is associated with stroke evolution and functional outcome. Prospective study on acute stroke patients with anterior LVO who underwent optimal recanalization from February 2023 to February 2024. Opacification and drainage time of superficial and deep veins were evaluated on digital subtraction angiography sequences. Clinical outcome was functional recovery at 90 days, whereas neuroradiological outcomes were ischemic lesion growth (ILG) and hemorrhagic transformation (HT). Multivariate logistic and linear regression models were performed. 24/50 patients (48%) displayed an unfavorable outcome, 14/50 (28%) a HT, and 28/50 (56%) an ILG. Longer median washout times of the superficial venous system were independently associated with a higher risk of poor functional outcome (aOR = 1.32; 95% CI 1.02-1.79; p = 0.049), ILG (aB = 3.06; SE 1.26; p = 0.020) and HT (aOR = 1.65; 95% CI 1.21-2.47; p = 0.005), and cortical frontal veins were the best predictor within veins' group. Opacification of Labbè and superficial middle cerebral veins predicted only HT (aOR = 0.178; 95% CI 0.026-0.766, p = 0.041) and ILG (aB = 9.78; SE 2.75; p = 0.003), respectively. In this cohort of LVO acute ischemic stroke patients with an optimal recanalization after EVT, qualitative and quantitative aspects of venous outflow were independent predictors of stroke evolution and functional outcome. A comprehensive venous outflow evaluation represents a potential target for a tailored management of patients after EVT.

Acute ischemic stroke (AIS) is a major cause of disability and mortality worldwide. While antiplatelet therapy is standard for secondary prevention, many patients still experience early neurological deterioration (END). Argatroban, a direct thrombin inhibitor, can potentially limit thrombus progression and improve AIS's functional outcomes. This meta-analysis assessed the efficacy and safety of argatroban in combination with single (SAPT) or dual antiplatelet therapy (DAPT) compared to antiplatelets alone. Following PRISMA guidelines, a systematic search of PubMed, Scopus, and Web of Science was conducted until January 2025. Randomized controlled trials (RCTs) and cohort studies evaluating argatroban plus antiplatelets versus antiplatelets alone in AIS patients were included. The primary outcome was a 90-day modified Rankin Score (mRS) of 0-2. Secondary outcomes included mRS 0-1 and mRS 3-5 at 90 days, END, and National Institutes of Health Stroke Scale (NIHSS) improvement, stroke recurrence, intracranial hemorrhage (ICH), symptomatic intracranial hemorrhage (sICH), and mortality. We used the mean difference (MD) for continuous variables and odds ratio (OR) for dichotomous ones at 95% confidence intervals (CI) and a P-value of 0.05. A total of 14 studies (four RCTs and 10 cohort studies) were included. Compared to antiplatelets alone, argatroban significantly improved functional outcomes, increasing the incidence of mRS 0-2 (OR = 1.36 [95%CI: 1.05, 1.76, P = 0.02]) and mRS 0-1 (OR = 1.54 [95%CI: 1.08, 2.2, P = 0.02]) while reducing END (OR = 0.42 [95%CI: 0.21, 0.85, P = 0.02]). Argatroban was also associated with greater NIHSS score improvement (MD =  - 0.52 [95%CI: - 0.89, - 0.15, P = 0.005]). No significant differences were observed in mRS 3-5, stroke recurrence, ICH, sICH, or mortality. Subgroup analysis indicated that argatroban combined with DAPT showed the greatest benefits. Argatroban combined with antiplatelet therapy improves functional recovery and reduces END without increasing bleeding risks. These findings support its use, particularly with DAPT, in mild to moderate AIS management. Further large-scale RCTs are needed to optimize dosing strategies and patient selection.

Intracranial aneurysms (IAs) are a major cause of spontaneous subarachnoid hemorrhage (SAH) and are associated with high morbidity and mortality. Current IA rodent models often exhibit low rupture rates and limited imaging capabilities, restricting their translational utility. This study introduces a modified elastase-based rat model that incorporates angiographic imaging to overcome these challenges. IAs were induced in 7-week-old female Sprague-Dawley rats using a combination of surgical and pharmacological interventions, including carotid artery and renal artery ligation, bilateral ovariectomy, high-salt diet, and two elastase injections into the basal cistern. Digital subtraction angiography (DSA) was employed to assess aneurysm formation and rupture rate. Histological and immunohistochemical analyses were conducted to characterize aneurysm morphology and the inflammatory response. The modified model achieved a high rate of IA formation (85%) and rupture (60%) within 28 days. DSA enabled visualization of vessel tortuosity and flow dynamics, features relevant to human IA development, which often occurs in areas subjected to hemodynamic stress, and the tortuosity of intracranial vessels affects their rupture ^[1]. Histological analysis indicated structural degradation of the aneurysm wall, while immunohistochemistry showed neutrophil infiltration, potentially implicating inflammation in IA rupture. This improved IA model offers a reliable method for inducing and visualizing IAs with a high rupture rate, making it a valuable tool for studying the pathophysiology and therapeutic interventions of IAs. Enhanced by DSA, this model has the potential to advance therapeutic research by enabling the real-time monitoring of aneurysm development and rupture.

Stroke is a prevalent age-related disease globally, contributing significantly to neurological dysfunction, disability, and mortality rates. Despite its substantial healthcare burden, effective therapies remain limited. Na/K-ATPase (NKA), beyond its canonical role in ion homeostasis, emerges as a pivotal player in oxidative stress induction, implicating its potential as a therapeutic target. Here, we investigate the efficacy of the semi-synthetic cardiotonic steroid gamma-benzylidene digoxin-15 (BD-15) in ameliorating brain ischemia-induced damage. A total of 44 male Wistar albino rats were randomly assigned to four groups (n = 11/group). The animals were subjected to experimental brain ischemia induction and treated with BD-15. Behavioral assessments revealed a significant improvement in mobility and exploration in BD-15-treated rats compared to brain ischemia alone (P < 0.05). Histological analysis suggested a reduction in brain damage in BD-15-treated rats. Moreover, BD-15 administration attenuated oxidative stress, evidenced by decreased thiobarbituric acid reactive substances levels (TBARS) in the hippocampus and sensory-motor cortex in brain ischemia rats (P < 0.05). Additionally, BD-15 treatment mitigated changes in lipid composition, possibly via modulation of membrane integrity. BD-15 also significantly restored ionic homeostasis in brain ischemia rats, improving the activities of NKA, Ca²⁺-ATPase, Sarcoendoplasmic Reticulum Calcium ATPase, and Mg²⁺-ATPase activities in the hippocampus and sensory-motor cortex (P < 0.05). Notably, acetylcholinesterase activity in brain ischemia rats was improved after BD-15 treatment (P < 0.05), suggesting additional benefits in maintaining neurotransmission following ischemic injury. These findings suggest a multifaceted neuroprotective mechanism of BD-15 in brain ischemia pathology. Our results propose BD-15 as a promising therapeutic strategy for mitigating ischemia-induced neurotoxicity. Further clinical studies are necessary to validate these findings and explore the translational potential of BD-15 in human stroke management.