Translational Stroke Research最新文献

The prognostic implications of Alberta Stroke Program Early CT Score (ASPECTS) subscores in patients with large-core ischemic stroke undergoing endovascular thrombectomy (EVT) remain uncertain. We hypothesized that specific ASPECTS regions substantially influence functional outcomes after EVT and therefore sought to identify which individual subscores are associated with outcome and whether any of them account for the association between total ASPECTS and functional outcomes. We retrospectively analyzed patients with large-core ischemic stroke (ASPECTS ≤ 5) who underwent EVT. Multivariate logistic regression identified factors associated with functional outcomes, and mediation analysis assessed whether specific ASPECTS subscores explains the effect of total ASPECTS on outcomes. Among 295 patients (median ASPECTS 4), 49.2% had a median mRS score of 3 at 3 months. Internal capsule (IC) involvement was the only subscore significantly associated with worse outcomes, including ordinal mRS shift (Odds ratio 2.03 [ 95% confidence interval 1.19‒3.46], P = 0.009), mRS ≥ 4 (3.01 [1.45‒6.24], P = 0.003), and mRS ≥ 3 (2.24 [1.03‒4.87], P = 0.042). Mediation analysis showed that IC involvement explained 50.6% of the total ASPECTS effect on outcomes. Patients with IC lesions showing reversal on follow-up imaging had a significantly lower risk of poor outcomes (0.28 [0.09-0.80], P = 0.018). IC involvement independently predicts poor outcomes after EVT for large-core stroke and substantially explains the effect of total ASPECTS on prognosis.

Intracerebral hemorrhage (ICH) is associated with high mortality and disability, and current treatments offer limited benefits for functional recovery. Human umbilical cord-derived mesenchymal stromal cell (hUCMSC) have strong proliferative, neuroprotective, and immunomodulatory properties, making them attractive for clinical translation. We evaluated the therapeutic effects of intravenously administered hUCMSCs in a collagenase-induced ICH model using male mice. Mice received low or high doses of hUCMSC once or twice within 72 h after ICH. Repeated high-dose administration significantly improved motor, cognitive, and affective behaviors. Although repeated administration of high-dose hUCMSCs produced the most pronounced behavioral recovery, most subsequent analyses were performed using the single-dose groups. Histological analysis showed reduced neuronal apoptosis and microglial activation, consistent with neuroprotection. In vitro assays demonstrated suppression of inflammatory gene expression and promotion of an anti-inflammatory phenotype in immune cells. Flow cytometry revealed selective reduction of pro-inflammatory macrophages and microglia, increased reparative subsets, and systemic modulation of myeloid dynamics. Our results suggest that intravenous hUCMSC administration at a higher dose confers robust neuroprotection through coordinated local and systemic immunomodulation, providing translational insights for clinical MSC therapy in ICH.

Despite advances in reperfusion therapies following cerebral ischemic stroke, effective treatment options remain limited, and achieving optimal outcomes post-revascularization continues to be a significant challenge. Increasing evidences have highlighted the crucial role of DNA damage and its associated downstream inflammatory and apoptotic pathways in the pathophysiology of stroke (collectively known as the DNA damage response, DDR). Enhancing DNA repair has emerged as a promising therapeutic approach to mitigate neural injury and promote function recovery after stroke. This review summarizes recent strategies aimed at neuroprotection through the modulation of DNA damage and repair pathways, focusing on both clinical patients with ischemic stroke and experimental stroke models. Additionally, we explore potential future directions.

Autonomic dysfunction leads to hemodynamic instability and immunosuppression after ischaemic stroke, and is independently associated with worse outcomes. We hypothesized that non-invasive peripheral neuromodulation, using transcutaneous auricular vagal nerve stimulation (tVNS), may reduce blood pressure variability and/or reverse immunosuppression early after ischaemic stroke requiring mechanical thrombectomy (MT). In this pre-registered phase 2 study (NCT05417009), we randomized 36 patients >18 years referred for emergent MT following an acute ischaemic stroke. Patients were randomized to receive bilateral auricular active-tVNS or sham-tVNS, for the entire MT and the morning after admission. Participants, clinicians and investigators were masked to treatment allocations. The primary outcome was systolic blood pressure variability (coefficient of variation) over the entire first 24h after mechanical thrombectomy, analysed by intention-to-treat. Secondary outcomes were whole blood RNA sequencing. Explanatory measures were time/frequency-domain measures of heart rate variability. Active-tVNS was safe in this hyperacute stroke setting, with no serious adverse events recorded. The systolic blood pressure coefficient of variability over the first 24h was 0.106±0.029 after active-tVNS, compared to 0.107±0.027 after sham-tVNS (p=0.93). Active-tVNS increased the relative expression of genes coordinating tumor-necrosis factor and toll-like receptor signaling, in parallel with alterations in heart rate variability over the first 24h after MT. This phase 2 study established thatearly tVNS is safe and feasible in the hyperacute phase of acute ischaemic stroke requiring MT, but did not alter systolic blood pressure variability. Trial registration number: NCT05417009, registered 8^TH June 2022.

Cerebral arteriovenous malformation (AVM) is a cerebrovascular disease associated with a risk of intracranial hemorrhage. Currently, most risk prediction models for AVM rupture are based on demographic characteristics and lesion morphology, while quantitative hemodynamics-based models remain scarce. This study aims to identify potential biomarkers associated with hemorrhagic risk through quantitative analysis of hemodynamic parameters within AVM lesions, and to develop a predictive model for AVM rupture risk. This study was based on a nationwide, multicenter registry (the MATCH study), enrolling untreated patients who underwent digital subtraction angiography (DSA) between January 2018 and December 2021. The model was trained using an internally derived cohort and validated with both internal and external center cohorts, as well as with follow-up data from patients who received conservative management. Quantitative hemodynamic parameters were extracted using quantitative angiography. Model performance was evaluated using confusion matrix-related metrics. A total of 857 patients with AVM were included in this study and were allocated into an internal cohort (n = 523; 418 for training and 105 for internal validation), an external validation cohort (n = 140), and a longitudinal validation cohort (n = 194). For each patient, 63 quantitative hemodynamic features were extracted. Based on variable importance ranking, the 10 most significant hemodynamic features were selected for model development. Thirteen individual machine learning models were constructed and evaluated. The best models achieved an area under the curve (AUC) of 0.754 in the training set (out-of-fold cross-validation), 0.750 in the internal validation cohort, 0.748 in the external validation cohort, demonstrating robust predictive performance. Furthermore, the SHapley Additive exPlanations (SHAP) framework was employed to interpret the contribution of individual variables within the model, providing insights into the underlying decision-making process. In the conservative treatment cohort, the prediction model results were used to divide patients into high-risk and low-risk groups for rupture, and there was a significant difference in actual risk between the two groups (P = 0.028). This comprehensive approach highlights the potential of quantitative hemodynamic analysis combined with advanced machine learning techniques for individualized risk prediction in AVM patients. This study demonstrates that quantitative hemodynamic features, when integrated with advanced machine learning algorithms, can effectively predict the risk of AVM rupture. The developed model exhibited robust performance across internal, external, and longitudinal validation cohorts. These findings suggest that quantitative hemodynamic analysis holds significant promise for improving individualized risk stratification and clinical decision-making in patients with cerebral arteriovenous malformations.

To assess the association of anticoagulation in patients with cardioembolic acute ischemic stroke (CES) who develop hemorrhagic transformation (HT) and its impact on neuroimaging and functional outcomes. This retrospective study enrolled patients presenting with CES within 48 h at a tertiary stroke center between January 2011 and August 2023. Patients who developed HT during hospitalization and underwent follow-up imaging within 1 week were included, focusing on those with hemorrhagic infarction or parenchymal hematoma type 1. Primary outcomes were HT exacerbation on follow-up imaging and 3-month modified Rankin Scale (mRS) distribution shift, comparing anticoagulation therapy (AC), antiplatelet therapy (APT), and drug discontinuation (DDDD). The safety outcome was the occurrence of symptomatic intracerebral hemorrhage (sICH), which was defined as a hemorrhage concomitant with neurological deterioration. Among 763 patients with HT (age 74.6 ± 8.9 years, 48.1% male), AC was associated with a higher incidence of HT exacerbation compared to APT (adjusted OR 0.48, 95% CI 0.29-0.80, p-value = 0.005). AC associated with a better 3-month mRS compared to both APT (adjusted OR 0.63, 95% CI 0.43-0.92, p-value = 0.017) and DD (adjusted OR 0.38, 95% CI 0.26-0.55, p-value < 0.001). sICH occurred in 5%, with rates of 1.5%, 2.1%, and 11.7% in the AC, APT, and DD groups, respectively (adjusted OR for DD vs. AC: 3.93, 95% CI 1.18-13.16, p-value = 0.026). Anticoagulation in CES patients with HT was associated with a better functional outcome and radiological exacerbation, without a significant increase in sICH risk. These findings suggest that the presence of HT should not necessarily preclude the use of anticoagulation therapy in this patient population. However, our study should be interpreted as hypothesis-generating, and confirmation from future prospective studies is warranted.

Inflammation exacerbates brain injury following acute ischemic stroke (AIS). Transcutaneous auricular vagus nerve stimulation (taVNS) reduces systemic inflammation, but its efficacy in AIS remains unexplored. We examined the safety and anti-inflammatory effect of taVNS in AIS patients. Prospective Randomized Open-label blinded endpoint design, sham-controlled trial. Anterior circulation large vessel occlusion (LVO) AIS patients were assigned to twice-daily taVNS or sham stimulation for five days or until discharge. Inclusion criteria: age≥18 years, NIHSS≥6, anterior circulation LVO, and enrollment within 36-hours of last known normal (LKN). Primary endpoints were changes in inflammatory biomarkers (interleukins (IL)-1β, 6, 10, 17α, and tumor necrosis factor alpha (TNFα) on Days 0, 1, 3, 5, and 7). TaVNS safety endpoints included bradycardia, hypotension, infection, and death. Thirty-five patients (17 taVNS, 18 sham) were enrolled and taVNS/sham treatment started a mean of 0.99 days (SD 0.26 days) from LKN. Mean stimulations received were 8.24 (SD 2.77) and 7.33 (SD 3.20), for treatment vs. sham respectively. The rate of protocol adherence was 77%. TaVNS treatment significantly changed IL-6 levels compared to sham treatment (overall p=0.0001). Although overall trajectories of other cytokines did not significantly differ between groups, a post-hoc analysis found significant differences on day 3 cytokine levels between groups for: IL-1β (p=0.024), IL-6 (p=0.045), and IL-17α (p=0.044). No significant difference between treatment groups in safety endpoints were found. taVNS safely reduced post-AIS inflammation in anterior circulation LVO patients. These findings warrant further investigation in larger clinical trials.ClinicalTrials.gov ID: NCT05390580, https://clinicaltrials.gov/study/NCT05390580 -Study started/registered: September 26, 2022.

Kynurenine pathway has been linked to several cardiovascular diseases, but their specific associations with stroke risk remain elusive. This study aimed to explore the associations between kynurenine pathway metabolites and the subsequent risk of stroke. A case-control study nested in a community-based cohort (n = 16,113) was performed between 2013 and 2018. A total of 412 incident stroke cases and 412 controls matched by age and sex were included. Plasma levels of kynurenine pathway metabolites, including tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (3-HK), 3-hydroxy anthranilic acid (3-HAA), anthranilic acid (AA), and xanthurenic acid (XA), were measured by ultrahigh performance liquid chromatography-tandem mass spectrometry. Conditional logistic regression analyses were used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs) between these biomarkers and stroke risk. After adjustment for body mass index, current smoking, marital status, estimated glomerular filtration rate, and physical activity, the corresponding OR for the highest versus lowest quintile of XA was 0.56 (95% CI: 0.36-0.89, P trend = 0.018) for total stroke risk and 0.48 (95% CI:0.28-0.81, P trend = 0.015) for ischemic stroke risk, respectively. No significant association was observed between plasma tryptophan, kynurenine, KA, 3-HK, 3-HAA, or AA and stroke risk. Our novel findings indicate an inverse association of plasma XA with the risk of total stroke and ischemic stroke in the general population. These findings highlight the potential of plasma XA as a valuable biomarker for assessing stroke risk and developing targeted prevention strategies.

Circadian organization of blood pressure (BP) is increasingly recognized as a determinant of vascular risk, but its role in acute ischemic stroke (AIS) remains undefined. We investigated whether early circadian BP phenotypes derived from high-frequency monitoring predict short- and long-term outcomes after AIS. In a prospective cohort of 529 patients with AIS, BP was recorded-noninvasively or via arterial line-during the first 72 h. Circadian parameters were extracted using cosinor analysis, and exploratory clustering was applied to identify recurrent BP patterns. Associations with early neurological deterioration (END), symptomatic intracerebral hemorrhage (sICH), 90-day functional outcome, mortality, and 1-year major adverse cardiovascular events (MACE) were assessed using multivariable logistic and Cox regression. Three distinct circadian BP phenotypes emerged: Steady-High (sustained elevation with blunted nocturnal decline), Disrupted-Rhythmicity (loss of amplitude and irregular oscillation), and Partial-Recovery (initial disorganization with progressive re-entrainment). Subtype-specific vulnerabilities were observed. In embolic stroke of undetermined source (ESUS), disrupted rhythmicity was associated with higher risk of END (adjusted OR 2.8, 95% CI 1.2-6.4). In cardioembolic stroke, circadian disorganization was linked to greater risk of sICH after reperfusion (adjusted OR 3.1, 95% CI 1.1-8.7). In large-artery atherosclerosis, the Steady-High phenotype predicted poor 90-day outcome (adjusted OR 2.2, 95% CI 1.0-4.6). Lacunar stroke showed relative preservation of circadian organization, with the lowest prevalence of adverse phenotypes. Across the cohort, Partial-Recovery was associated with the most favorable outcomes. High-frequency 72-hour BP monitoring combined with exploratory, data-driven clustering revealed reproducible circadian BP patterns with subtype-specific prognostic relevance in AIS. These findings suggest that circadian BP profiling may help inform individualized hemodynamic management in acute stroke.