Translational Stroke Research最新文献

The translation of the highly effective Environmental Enrichment (EE) paradigm from preclinical animal models to human clinical settings has been slow and showed inconsistent results. The primary translational challenge lies in defining what constitutes an EE for humans. To tackle this challenge, this study conducted a scoping review of preclinical EE protocols to explore what constitutes EE for animal models of stroke, laying the foundation for the translation of EE to human application. A systematic search was conducted in the MEDLINE, PsycINFO, and Web of Science databases to identify studies that conducted an EE intervention in the post-stroke animal model. A total of 116 studies were included in the review. A critical reflection of the characteristics of the included studies revealed that EE for post-stroke is a strategy that frequently modifies the animals' daily environment to create a richness of spatial, structural, and/or social opportunities to engage in a variety of daily life-related motor, cognitive, and social exploratory activities. These activities are relevant to the inhabiting individual and involve the activation of the body function(s) affected by the stroke. This review also identified six principles that underpinned the EE protocols: complexity (spatial and social), variety, novelty, targeting needs, scaffolding, and integration of rehabilitation tasks. These findings can be used as steppingstones to define what constitutes EE in human clinical applications and to develop a set of principles that can inform the design of EE protocols for patients after a stroke.

To explore the predictive value of dual-energy CT-based thrombus radiomics for the functional outcome of intravenous thrombolysis in patients with acute ischemic stroke (AIS). One hundred four AIS patients who received intravenous thrombolysis were enrolled and classified into favorable and unfavorable outcome based on their modified Rankin Scale (mRS) scores at 90 days. All patients underwent a one-stop-shop CT scan upon admission, including NCCT, dual-energy CTA, and CTP. The thrombus radiological and radiomics models were developed using NCCT, CTA, and iodine overlay map (IOM) images. The clinical model was developed using clinical information and other radiological data. The best-performing radiomics model was selected for the further development of a clinical-radiomics nomogram. The performance of these models was evaluated using receiver operating characteristic (ROC) curves, clinical decision curves, calibration curves, and DeLong's test. The AUCs of the model_Thrombus built using the thrombus characteristics were lower than those of most radiomics models (training, 0.77; test, 0.75). The AUCs of the model_IOM were higher than those of model_CTA (training, 0.84 vs. 0.71; test, 0.78 vs. 0.66) and were comparable to model_NCCT (training, 0.84 vs. 0.82; test, 0.78 vs. 0.78). The model_NCCT+IOM demonstrated improved predictive performance compared to either single-sequence model alone (training, 0.92; test, 0.83). Systolic blood pressure and baseline NIHSS score were independent predictors of favorable outcome. Among all models, the nomogram has the highest predictive value (training, 0.96; test, 0.91). The thrombus radiomics model based on dual-energy CT can effectively predict functional outcome of intravenous thrombolysis in patients with AIS. The addition of clinical data to the model can improve predictive performance.

The blood-brain barrier (BBB) is a selectively permeable membrane that plays a crucial role in protecting the brain from harmful substances. Its disruption is associated with various central nervous system (CNS) disorders, including hemorrhagic stroke. Evans Blue (EB) dye, a protein-binding tracer, is commonly used to assess BBB permeability. However, the method of injection significantly influences the accuracy and reproducibility of experimental results in the C57/6 mice. In this study, we evaluated the effectiveness of jugular vein injection of EB dye for assessing BBB integrity in a mouse intracerebral hemorrhage (ICH) model. This study investigates the efficacy of jugular vein injection of EB dye for assessing BBB integrity in C57/6 mice with ICH. Neurological deficits were assessed using the Longa and Modified Garcia Scales (GS) on day 1 post-ICH to ensure baseline consistency. Mice were anesthetized and injected with a 2% EB solution via either the jugular or tail vein. Only mice with successful tail vein injections were included in the tail vein injection group. The jugular vein injection method was successfully applied to all animals in the respective group. Plasma and brain EB concentrations were quantified by spectrophotometry following the processing of plasma and brain homogenates. BBB permeability was assessed by measuring EB content in brain tissue after transcardial perfusion and homogenization. Neurological function was assessed 24 h post-modeling using the Longa score, with a score greater than 1 indicating successful modeling. No significant neurological deficits were observed in the sham group, while all animals in the ICH group showed significant deficits (P < 0.0001). No differences in deficits were observed among the experimental groups (P > 0.05). Plasma EB concentration decreased over time in both the sham and ICH groups (P < 0.0001), with the tail vein group showing no significant change between 30 min and 2 h (P > 0.05), but a significant decrease at 24 h (P < 0.0001). At 30 min and 2 h, no significant differences in plasma EB concentration were observed between the sham and ICH jugular vein groups (P > 0.05), though the plasma concentration was significantly higher in the sham group at 24 h (P < 0.05). No significant differences in EB content were noted between ICH jugular vein group and ICH tail vein group groups at 30 min, 2 h, and 24 h in brain tissues (P > 0.05), although the ICH jugular vein group showed higher EB content than the sham group (P < 0.05). No significant differences were found between the ICH tail and sham groups at 2 and 24 h, though the distribution is more dispersed in the tail vein group. Additionally, the hemorrhagic side of the brain showed significantly higher EB content than the non-hemorrhagic side after 2 h (P < 0.05), but no difference was observed at 24 h. Jugular vein injection of EB dye provides a precise, reliable, and reproducible method for evaluating BBB integrity in mouse mod

Although endovascular treatment (EVT) was the first-line therapeutic strategy for acute ischemic stroke (AIS), half of the patients could not achieve functional independence. Previous studies suggested arterial collateral was an important predictor of this phenomenon. However, cerebral collateral circulation was regulated by arteries, venous, and microcirculation, and its role remained unclear. Therefore, based on the integrated cerebral collateral cascade (CCC) system, this study aimed to explore the relationship and potential mechanisms between CCC and futile recanalization. This was a multicenter retrospective study for AIS patients receiving EVT. The CCC model was used to comprehensively assess the collateral circulation, which consisted of arterial collaterals, venous outflow, and tissue-level collaterals. Imaging outcomes included ischemic core, hypoperfusion volume, and penumbra volume. The clinical outcome was futile recanalization, defined as a 90-day modified Rankin Scale (mRS) 3-6 after successful recanalization. Multivariate regression and mediation analyses were used to assess the relationship between CCC, futile recanalization, and potential mediators. Among 513 patients with successful recanalization, 50.6% (260) experienced futile recanalization. In the multivariable regression analysis, favorable CCC (aOR 0.48, 95% CI 0.31-0.75; P = 0.001) was independently associated with unfavorable outcome despite successful recanalization. Furthermore, mediation analysis revealed that favorable CCC significantly reduced the ischemic core accounting for 27.62% (95% CI 9.69-66.00%) of its beneficial effect on futile recanalization. The benefit of favorable CCC on futile recanalization may be mediated by a reduction in ischemic core volume in AIS patients undergoing EVT. Our findings deepen the understanding of futile recanalization and microcirculation.

The role of chromatin biology and epigenetics in disease progression is gaining increasing recognition. Genes that escape X chromosome inactivation (XCI) can impact neuroinflammation through epigenetic mechanisms. Our previous study has suggested that the X escapee genes Kdm6a and Kdm5c are involved in microglial activation after stroke in aged mice. However, the underlying mechanisms remain unclear. We hypothesized that Kdm6a/5c demethylate H3K27Me3/H3K4Me3 in microglia, respectively, and mediate the transcription of interferon regulatory factor 5 (IRF5) and IRF4, leading to microglial pro-inflammatory responses and exacerbated stroke injury. Aged (17-20 months) Kdm6a/5c microglial conditional knockout (CKO) female mice (one allele of the gene) were subjected to a 60-min middle cerebral artery occlusion (MCAO). Gene floxed females (two alleles) and males (one allele) were included as controls. Infarct volume and behavioral deficits were quantified 3 days after stroke. Immune responses including microglial activation and infiltration of peripheral leukocytes in the ischemic brain were assessed by flow cytometry. Epigenetic modification of IRF5/4 by Kdm6a/5c was analyzed by CUT&RUN assay. The demethylation of H3K27Me3 by kdm6a increased IRF5 transcription; meanwhile, Kdm5c demethylated H3K4Me3 to repress IRF5. Both Kdm6a^fl/fl and Kdm5c^fl/fl mice had worse stroke outcomes compared to fl/y and CKO mice. Gene floxed females showed more robust expression of CD68 in microglia and elevated brain and plasma levels of IL-1β or TNF-α, after stroke. We concluded that IRF5 signaling plays a critical role in mediating the deleterious effect of Kdm6a, whereas Kdm5c's effect is independent of IRF5.

Our study aimed to investigate the factors associated with residual cavernous sinus extra-axial cavernous hemangiomas (ECHs) progression after surgery. This retrospective study consecutively included patients of cavernous sinus ECHs with incomplete lesion resection from February 2012 to January 2024. The progression of the lesions was defined as new lesions or a growth of residual lesion (≥ 10% increase in volume). Cox regression analysis was used to determine factors associated with residual lesion progression. Kaplan-Meier analysis was conducted to estimate the cumulative incidence of residual lesion progression. Sixty patients were included in this study. During the follow-up, there were 31 (51.7%) residual lesions underwent progression, whereas 29 (48.3%) patients were nonprogressive. Multivariate Cox analysis showed that the homogeneous enhancement lesion was correlated with the residual lesion progression (HR, 8.17 [95% CI, 1.03-64.58]; p = 0.046). Kaplan-Meier survival analysis indicated that the rate of homogeneous enhancement lesion progression (3.7 per 10 person-years) was significantly higher than that of the heterogeneous enhancement group (0.5 per 10 person-years; p = 0.019). Fourteen of the 31 patients with lesion progression underwent radiotherapy, and all of them experienced control over the progression of their lesions. This study found that end-of-treatment residual lesions are not rare in patients with cavernous sinus ECHs and the MRI feature is helpful to predict the progression of residual lesions.

Little is known about the association between periprocedural hemodynamics and in-stent restenosis (ISR) following stent implantation in patients with symptomatic intracranial atherosclerotic stenosis (ICAS). This study aims to identify periprocedural hemodynamics that may be associated with ISR. Subjects were selected from the NOVA trial (The First-in-man Trial Evaluating the Safety and Efficacy of the NOVA Intracranial Stent Trial). ISR was defined as greater than 50% stenosis of the luminal diameter within or immediately adjacent to (within 5 mm) the implanted stent. Periprocedural hemodynamics, including cerebral blood flow, cerebral blood volume, mean transit time, and time to peak (TTP), were derived from the time-density curve generated from digital subtraction angiography using the fast Fourier transform algorithm. Of the 263 patients enrolled in the NOVA trial, 176 with symptomatic high-grade ICAS who underwent stent implantation were included in this study. Of these, 35 (19.9%) were diagnosed with ISR at the one-year follow-up. No significant differences in pre-procedure hemodynamics were observed between stent groups and between the ISR groups and the non-ISR group. Higher post-procedure TTP (OR, 1.95; 95% CI, 1.26-3.02), the use of bare-metal stents (OR, 5.40; 95% CI, 2.21-13.19), and higher post-procedure residual stenosis (OR, 1.08; 95% CI, 1.03-1.13) were independent factors associated with ISR. Higher post-procedure TTP, the use of bare-metal stents, and higher post-procedure residual stenosis were independent factors associated with ISR. The combined use of periprocedural hemodynamics and clinical factors may help predict ISR in patients with symptomatic high-grade ICAS.

This study compares the clinical efficacy and outcomes of three surgical techniques-robot-assisted stereotactic assistance (ROSA), neuroendoscopy, and craniotomy-in the removal of intracranial hematomas in patients with cerebral hemorrhage affecting the basal ganglia. This retrospective study included 110 patients, who were grouped based on the surgical method used: 40 patients in the ROSA group, 50 in the craniotomy group, and 20 in the endoscopy group. We then compared the outcomes of the ROSA group with those of the craniotomy and endoscopy groups. Compared with the craniotomy group, the ROSA group had a significantly shorter operation time, higher hematoma clearance rate, lesser intraoperative blood loss, fewer postoperative pulmonary infections, and lower modified Rankin Scale (mRS) score at discharge and > 3 months after discharge. Compared with the endoscopy group, the ROSA group had a shorter operation time, lesser intraoperative blood loss, and fewer intraoperative blood transfusions. The ROSA robot provided superior surgical outcomes and patient prognoses compared to craniotomy and neuroendoscopy for the removal of intracranial hematomas in patients with basal ganglia cerebral hemorrhage.

Cerebral small vessel disease (CSVD) is a global brain disorder that is characterized by a series of clinical, neuroimaging, and neuropathological manifestations. However, the molecular pathophysiological mechanisms of CSVD have not been thoroughly investigated. Liquid chromatography-tandem mass spectrometry-based proteomics has broad application prospects in biomedicine. It is used to elucidate disease-related molecular processes and pathophysiological pathways, thus providing an important opportunity to explore the pathophysiological mechanisms of CSVD. Serum samples were obtained from 96 participants (58 with CSVD and 38 controls) consecutively recruited from The First Affiliated Hospital of Zhengzhou University. After removing high-abundance proteins, the serum samples were analyzed using high-resolution mass spectrometry. Bioinformatics methods were used for in-depth analysis of the obtained proteomic data, and the results were verified experimentally. Compared with the control group, 52 proteins were differentially expressed in the sera of the CSVD group. Furthermore, analyses indicated the involvement of these differentially expressed proteins in CSVD through participation in the overactivation of complement and coagulation cascades and dysregulation of insulin-like growth factor-binding proteins. The proteomic biomarker panel identified by the machine learning model combined with clinical features is expected to facilitate the diagnosis of CSVD (AUC = 0.947, 95% CI = 0.895-0.978). The study is the most in-depth study on CSVD proteomics to date and suggests that the overactivation of the complement cascade and the dysregulation of IGFBP on- IGF may be closely correlated with the occurrence and progression of CSVD, offering the potential to develop peripheral blood biomarkers and providing new insights into the biological basis of CSVD.

The objective of this study is to investigate the protein components of acute ischemic stroke (AIS) thrombi using four-dimensional independent data acquisition (4D-DIA) proteomics and reveal the correlations between thrombotic protein components and AIS etiology. From April to September 2023, we enrolled a total of 30 patients who underwent endovascular thrombectomy at our institute and were diagnosed in accordance with large artery atherosclerosis (LAA; n = 15) or cardioembolism (CE; n = 15). Thromboembolic material was collected for 4D-DIA proteomic detection. We then analyzed it for differentially expressed proteins (DEPs; fold change [FC] ≥ 1.5 or ≤ 0.67), performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, and mapped protein-protein interactions (PPIs). In the 30 retrieved clots, 5115 proteins were expressed. Of these, we screened 246 DEPs between the LAA and CE groups, such as histone H4, collagen α1, and differentially expressed in neoplastic versus normal cells domain-containing protein 6A. GO analysis revealed that the DEPs' most important biological process was cellular process, the most important Cell Component was cell part, the molecular function was binding, and the most significantly enriched pathway was thiamine metabolism. PPI results revealed complicated interactions among these DEPs, of which superoxide dismutase, catalase, and γ-enolase might play important roles. This study outlines a promising molecular approach to differentiating the etiology of AIS between CE and LAA through the proteomics of retrieved thrombi, which might also inform future research into thrombotic biology.