Translational Stroke Research最新文献

Unruptured intracranial aneurysms (IAs) are highly prevalent in the general population and there is an unmet need for radiological surrogates for the assessment of an increased risk of rupture. High turnover of type I collagen, i.e. abundant proportions of newly synthesized, immature collagen, has been linked to structural instability of the IA wall. This study aimed to test a newly synthesized positron emission tomography tracer that could selectively visualize immature type I collagen in human IAs as a marker for structural instability and thereby increased rupture risk. Following the synthesis of [⁶⁸Ga]Ga-NODA-GA-PEG₁-collagelin, in vitro and ex vivo analyses of collagen, nonhuman tissue and human IAs were performed. Patients undergoing microsurgical repair for unruptured and ruptured IAs were prospectively included in this cross-sectional, single-center study. After safe IA clipping and IA excision, cryosections of IAs were incubated with the tracer, and signal intensity was quantified via autoradiography. To differentiate immature from mature collagen, polarization microscopy was performed after picrosirius red staining. Our study showed that the synthesized tracer [⁶⁸Ga]Ga-NODA-GA-PEG₁-collagelin bound specifically to type I collagen in vitro and in rat tail tendon ex vivo. We included 25 patients with 25 IAs (12 unruptured, 13 ruptured). The tracer preferentially labeled immature type I collagen in human IAs ex vivo: Regions with high tracer uptake correlated with areas rich in immature collagen, as identified by polarization microscopy (r = 0.40, P = 0.002). [⁶⁸Ga]Ga-NODA-GA-PEG₁-collagelin could serve as a complementary, noninvasive molecular imaging tool for personalized assessment of IA instability, but animal studies are required before in vivo use of [⁶⁸Ga]Ga-NODA-GA-PEG₁-collagelin in humans.

To explore the association of lipid accumulation product (LAP) with 3-month functional outcome and etiologic subtypes in patients with acute ischemic stroke. Patients with acute ischemic stroke admitted from July 1, 2020, to June 30, 2022 were enrolled in this study. Initial neurological severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) at admission. Functional outcome was evaluated by the modified Rankin Scale (mRS) at 3 months after ischemic stroke onset. Etiologic subtypes were determined according to the method reported in the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. LAP was calculated by a well-established formula and analyzed by quartiles (Q1-Q4). Multivariate logistic regression analysis was conducted to evaluate the association of LAP quartiles with 3-month functional outcome and etiologic subtypes in patients with acute ischemic stroke. A total of 431 patients with acute ischemic stroke were included in this study. After adjusting for several confounding factors, compared with those in the LAP-Q1 group, patients in LAP-Q3 and LAP-Q4 group had a reduced association with poor 3-month functional outcome [odds ratio (OR): 0.038, 95% confidence interval (CI): 0.004-0.339; OR: 0.014, 95% CI: 0.001-0.158]. Furthermore, patients in LAP-Q3 and LAP-Q4 group showed an increased association with Small-artery occlusion (SAO) subtype (OR: 1.919, 95% CI: 1.075-3.425; OR: 2.322, 95% CI: 1.265-4.262). Elevated LAP levels were associated with favorable 3-month functional outcome in patients with acute ischemic stroke, supporting the concept of the "obesity-stroke paradox". Concurrently, patients with elevated LAP levels were more likely to experience SAO as the etiological subtype of their stroke.

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.