Translational Stroke Research最新文献

Deep intracerebral hemorrhage (ICH) exerts a direct force on corticospinal tracts (CST) causing shape deformation. Using serial MRI, Generalized Procrustes Analysis (GPA), and Principal Components Analysis (PCA), we temporally evaluated the change in CST shape. Thirty-five deep ICH patients with ipsilesional-CST deformation were serially imaged on a 3T-MRI with a median imaging time of day-2 and 84 of onset. Anatomical and diffusion tensor images (DTI) were acquired. Using DTI color-coded maps, 15 landmarks were drawn on each CST and the centroids were computed in 3 dimensions. The contralesional-CST landmarks were used as a reference. The GPA outlined the shape coordinates and we superimposed the ipsilesional-CST shape at the two-time points. A multivariate PCA was applied to identify eigenvectors associated with the highest percentile of change. The first three principal components representing CST deformation along the left-right (PC1), anterior-posterior (PC2), and superior-inferior (PC3) respectively were responsible for 57.9% of shape variance. The PC1 (36.1%, p < 0.0001) and PC3 (9.58%, p < 0.01) showed a significant deformation between the two-time points. Compared to the contralesional-CST, the ipsilesional PC scores were significantly (p < 0.0001) different only at the first-timepoint. A significant positive association between the ipsilesional-CST deformation and hematoma volume was observed. We present a novel method to quantify CST deformation caused by ICH. Deformation most often occurs in left-right axis (PC1) and superior-inferior (PC3) directions. As compared to the reference, the significant temporal difference at the first time point suggests CST restoration over time.

Endovascular treatment (EVT) has been proven to be the standard treatment for acute vertebrobasilar artery occlusion (VBAO). This study aimed to analyze the effects of international normalized ratio (INR) indicators on outcomes in patients with acute VBAO treated with EVT. Dynamic data on INR in patients with VBAO who received endovascular treatment (EVT) at 65 stroke centers in China were retrospectively enrolled. Outcome measures included the modified Rankin Scale (mRS) score at 90 days and 1 year and symptomatic intracranial hemorrhage (sICH). The associations between elevated INR (INR > 1.1), INR variability (time-weighted variance of INR changes), and various clinical outcomes were analyzed in all patients and subgroups stratified by oral anticoagulation (OAC) by mixed logistic regression analysis. A total of 1825 patients met the study criteria, of which 1384 had normal INR and 441 had elevated INR. Multivariate analysis showed that elevated INR was significantly associated with poor functional outcomes (mRS 4-6) at 90 days (odds ratio [OR] 1.36, 95% confidence interval [CI] 1.08-1.72) and 1 year (OR 1.32, 95% CI 1.05-1.66), but was not associated with an increased risk of sICH (OR 1.00, 95% CI 0.83-1.20). Similar associations exist between INR variability and poor functional outcomes at 90 days (OR 2.17, 95% CI 1.09-4.30), 1 year (OR 2.28, 95% CI 1.16-4.46), and sICH (OR 1.11, 95% CI 0.93-1.33). Subgroup analyses further revealed that elevated INR and INR variability remained associated with poor functional outcomes in patients not receiving oral anticoagulation (OAC) therapy, while no significant associations were observed in OAC-treated patients, regardless of whether they were on warfarin or direct oral anticoagulants. Elevated INR and INR variability in VBAO patients treated with EVT were associated with poor functional outcomes. The mechanism underlying the association between elevated INR and poor functional outcomes might be attributed to the fact that elevated INR indirectly reflects the burden of comorbidities, which could independently worsen outcomes. These findings underscore the importance of a comprehensive and dynamic evaluation of INR levels in the management of VBAO patients receiving EVT, providing valuable insights for optimizing patient outcomes.

Indirect bypass surgery is an effective treatment for moyamoya disease (MMD), but the success of the surgery depends on the formation of spontaneous collateral vessels, which cannot be accurately predicted before surgery. Developing a prediction nomogram model for neoangiogenesis in patients after indirect revascularization surgery can aid surgeons in identifying suitable candidates for indirect revascularization surgery. This retrospective observational study enrolled patients with MMD who underwent indirect bypass surgery from a multicenter cohort between December 2010 and December 2018. Data including potential clinical and radiological predictors were obtained from hospital records. A nomogram was generated based on a multivariate logistic regression analysis identifying potential predictors of good neoangiogenesis. A total of 263 hemispheres of 241 patients (mean ± SD age 24.38 ± 15.78 years, range 1-61 years) were reviewed, including 168 (63.9%) hemispheres with good postoperative collateral formation and 95 (36.1%) with poor postoperative collateral formation. Based on multivariate analysis, a nomogram was formulated incorporating four predictors, including age at operation, abundance of ICA moyamoya vessels, onset type, and Suzuki stage. The C-index for this nomogram was 0.80. Calibration curve and decision-making analysis validated the fitness and clinical application value of this nomogram. The nomogram developed in this study exhibits high accuracy in predicting good neoangiogenesis after indirect revascularization surgery in MMD patients. This model can be very helpful for clinicians when making decisions about surgical strategies for MMD patients in clinical practice.

Nanozymes are a new kind of material which has been applied since the beginning of this century, and its birth has promoted the development of chemistry, materials science, and biology. Nanozymes can be used as a substitute for natural enzyme and has a wide range of applications; therefore, it has attracted extensive attention from all sectors of the community, and the number of studies has constantly increasing. In this paper, we introduced the outstanding achievements in the field of nanozymes in recent years from the main function, the construction of nanozyme-based biosensors, and the treatment of ischemic stroke, and we also illustrated the internal mechanism and the catalytic principle. In the end, the obstacles and challenges in the future development of nanozymes were proposed.

Intracranial aneurysm (IA) has the potential to rupture. Despite scientific advances, we are still not in a position to screen patients for IA and identify those at risk of rupture. It is critical to comprehend the molecular basis of disease to facilitate the development of novel diagnostic strategies. We used transcriptomics to identify the dysregulated genes and understand their role in the disease biology. In particular, RNA-Seq was performed in tissue samples of controls, unruptured IA, and ruptured IA. Dysregulated genes (DGs) were identified and analyzed to understand the functional aspects of molecules. Subsequently, candidate genes were validated at both transcript and protein level. There were 314 DGs in patients with unruptured IA when compared to control samples. Out of these, SPARC and OSM were validated as candidate molecules in unruptured IA. PI3K-AKT signaling pathway was found to be an important pathway for the formation of IA. Similarly, 301 DGs were identified in the samples of ruptured IA when compared with unruptured IAs. CTSL was found to be a key candidate molecule which along with Hippo signaling pathway may be involved in the rupture of IA. We conclude that activation of PI3K-AKT signaling pathway by OSM along with up-regulation of SPARC is important for the formation of IA. Further, regulation of Hippo pathway through PI3K-AKT signaling results in the down-regulation of YAP1 gene. This along with up-regulation of CTSL leads to further weakening of aneurysm wall and its subsequent rupture.

p53 expression and acetylation are crucial for the survival and death of neurons in penumbra. At the same time, the outcome of ischemia for penumbra cells depends largely on the histone acetylation status, but the effect of histone acetyltransferases and deacetylases on non-histone proteins like p53 is largely understudied. With combined in silico and in vitro approach, we have identified enzymes capable of acetylation/deacetylation, distribution, stability, and pro-apoptotic activity of p53 in ischemic penumbra in the course of post-stroke recovery, and also detected involved loci of acetylation in p53. The dynamic regulation of the acetylation of p53 at lysine 320 is controlled by acetyltransferase PCAF and histone deacetylases HDAC1 and HDAC6. The in silico simulation have made it possible to suggest the acetylation of p53 at lysine 320 acetylation may facilitate the shuttling of p53 between the nucleus and cytoplasm in penumbra neurons. Acetylation of p53 at lysine 320 is more preferable than acetylation at lysine 373 and probably promotes survival and repair of penumbra neurons after stroke. Strategies to increase p53 acetylation at lysine 320 via increasing PCAF activity, inhibiting HDAC1 or HDAC6, inhibiting p53, or a combination of these interventions may have therapeutic benefits for stroke recovery and would be promising for neuroprotective therapy of stroke.

Recurrence of thrombotic events during aspirin therapy is known as aspirin resistance (AR). This study aimed to investigate the rate of AR, the factors influencing AR in patients with acute ischemic stroke under regular aspirin use, and the relationship between AR and ABCB1 (MDR-1) C3435T (rs1045642) polymorphism. Throughout this multicenter prospective study, 174 patients with acute ischemic stroke who had been prescribed aspirin for at least one month due to the risk of vascular disease, along with 106 healthy volunteers, were included as part of the study group. The results of our study indicate that AR was detected in 21.3% of the patient group. According to the results of an analysis of the polymorphism of the ABCB1 C3435T in patients with AR compared to those with aspirin sensitivity, patients with AR possessed more heterozygous (CT) and homozygous genotypes (TT) than those with aspirin sensitivity (p = 0.001). Based on multivariate logistic regression analysis of factors affecting AR in acute ischemic stroke patients, hypertension (OR: 5.679; 95% CI: 1.144-28.19; p = 0.034), heterozygous (CT) genotype (OR: 2.557; 95% CI: 1.126-5.807; p = 0.025), increased platelet values (OR: 1.005; 95% CI: 1.001-1.009; p = 0.029), and CRP/albumin values (OR: 1.547; 95% CI: 1.005-2.382; p = 0.047) were found to be associated with a greater risk of AR. The presence of heterozygous (CT) genotype in the ABCB1 C3435T gene region in the Turkish population is associated with an increased risk of AR. When planning aspirin therapy, it is crucial to consider the ABCB1 (MDR-1) C3435T polymorphism.

Approximately one-quarter of strokes occur in individuals with prior stroke. Despite the advancement in secondary stroke prevention, the long-term risk of recurrent stroke has remained unchanged. The objective of this study was to identify metabolite risk markers that are associated with recurrent stroke. We performed targeted metabolomic profiling of 162 metabolites by liquid chromatography-tandem mass spectrometry in baseline plasma in a stroke case-cohort study nested within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, an observational cohort study of 30,239 individuals aged 45 and older enrolled in 2003-2007. Weighted Cox proportional hazard models were used to identify metabolites that had a differential effect on first-time versus recurrent stroke using an interaction term between metabolite and prior stroke at baseline (yes or no). The study included 1391 incident stroke cases identified during 7.1 ± 4.5 years of follow-up and 1050 participants in the random cohort sample. Among 162 metabolites, 13 candidates had a metabolite-by-prior stroke interaction at a p-value <0.05, with one metabolite, acetylglutamine, surpassing the Bonferroni adjusted p-value threshold (p for interaction = 5.78 × 10^-5). In an adjusted model that included traditional stroke risk factors, acetylglutamine was associated with recurrent stroke (HR = 2.27 per SD increment, 95% CI = 1.60-3.20, p = 3.52 × 10^-6) but not with first-time stroke (HR = 0.96 per SD increment, 95% CI = 0.87-1.06, p = 0.44). Acetylglutamine was associated with recurrent stroke but not first-time stroke, independent of traditional stroke risk factors. Future studies are warranted to elucidate the pathogenesis of acetylglutamine and recurrent stroke risk.

The contraction and subsequent death of brain pericytes may play a role in microvascular no-reflow following the reopening of an occluded artery during ischemic stroke. Mammalian target of rapamycin (mTOR) inhibition has been shown to reduce motility/contractility of various cancer cell lines and reduce neuronal cell death in stroke. However, the effects of mTOR inhibition on brain pericyte contraction and death during ischemia have not yet been investigated. Cultured pericytes exposed to simulated ischemia for 12 h in vitro contracted after less than 1 h, which was about 7 h prior to cell death. Rapamycin significantly reduced the rate of pericyte contraction during ischemia; however, it did not have a significant effect on pericyte viability at any time point. Rapamycin appeared to reduce pericyte contraction through a mechanism that is independent of changes in intracellular calcium. Using a mouse model of middle cerebral artery occlusion, we showed that rapamycin significantly increased the diameter of capillaries underneath pericytes and increased the number of open capillaries 30 min following recanalisation. Our findings suggest that rapamycin may be a useful adjuvant therapeutic to reduce pericyte contraction and improve cerebral reperfusion post-stroke.