Translational Stroke Research最新文献

Background: In patients with symptomatic intracranial atherosclerotic stenosis (sICAS), recent evidence has suggested an association between artery-to-artery embolism (AAE) and cortical borderzone (CBZ) infarcts.

Methods: We recruited patients with 50-99% anterior-circulation sICAS in this cohort. Stroke mechanisms were categorized as isolated parent artery atherosclerosis occluding penetrating artery (PAO), isolated AAE, isolated hypoperfusion, and mixed mechanisms, using two classification systems. In Classification I, the probable stroke mechanisms of internal borderzone and CBZ infarcts were both hypoperfusion, which were respectively hypoperfusion and AAE in Classification II. Other classification criteria were the same. We investigated and compared the predictive values of the two systems in predicting 90-day and 1-year recurrent ischemic stroke in the same territory (SIT).

Results: Among 145 patients (median age 62 years), 101 (69.7%) were males. We found significant difference in the proportions of baseline stroke mechanisms between these two systems (p < 0.001). Eleven (7.6%) and 19 (13.1%) patients respectively had 90-day or 1-year recurrent SIT. Classification II better predicted the risk of 90-day recurrent SIT than Classification I, when patients were divided into 4 groups according to baseline stroke mechanisms (p = 0.029), or by the presence of hypoperfusion (p < 0.001). The two classification systems had comparable predictive values for 1-year recurrent SIT.

Conclusions: In medically treated sICAS patients, considering AAE rather than hypoperfusion as the stroke mechanism for CBZ infarcts could better predict early recurrent SITs.

To evaluate whether endovascular thrombectomy (EVT) combined with best medical management (BMM) is more effective than BMM alone in treating mild stroke patients (National Institutes of Health Stroke Scale score < 6) with large vessel occlusion (LVO). A multicentric retrospective cohort of patients with LVO and mild stroke within 24 h from symptom onset was included. Patients were divided into the primary EVT (EVT_pri) group and the primary BMM (BMM_pri) group according to the treatment strategy. Functional outcomes were compared after propensity score matching. Additionally, adjusted logistic regression analysis was used to assess the association between treatment strategy and functional outcomes. Finally, 419 patients were included, with 137 receiving EVT_pri and 282 receiving BMM_pri. After propensity score matching (EVT_pri, 126 vs. BMM_pri, 126), baseline characteristics were balanced between the two groups. No significant difference was observed in 3-month functional independence (modified Rankin Scale [mRS] 0-2, 78.6% vs. 76.2%. In the overall cohort, EVT_pri was not associated with functional independence (adjusted odds ratio [aOR], 0.87; 95% confidence interval [CI], 0.43-1.47). However, patients in the EVT_pri group were more likely to experience symptomatic intracranial hemorrhage (aOR, 1.27; 95% CI, 1.05-1.89). Subgroup analysis revealed that EVT_pri was significantly associated with functional independence in vertebrobasilar occlusion subgroup (aOR, 1.78; 95% CI, 1.20-3.90). Our findings did not support the systematic use of EVT for mild stroke with LVO, except in cases of vertebrobasilar occlusion, which may represent a subgroup where EVT_pri could provide significant benefits.

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 etiology and mechanisms of ischemic stroke are complex, encompassing a variety of pathological processes including atherosclerosis, energy failure, neuroinflammation, blood-brain barrier damage, abnormal glial cell activation, and neuronal edema and necrosis. Endothelial cell-derived extracellular vesicles have garnered significant attention in various diseases, including ischemic stroke, owing to their widespread distribution, rich content, diverse functional sites, low immunogenicity, and ability to cross the blood-brain barrier. This study reviewed the current status of research on endothelial cell-derived extracellular vesicles and their roles and potential mechanisms in ischemic stroke. It aimed to elucidate the potential of these extracellular vesicles for clinical translation related to ischemic stroke, thereby providing new strategies and directions for treating patients with stroke. The findings indicated that endothelial cell-derived extracellular vesicles reduce the occurrence of stroke and improve post-stroke ischemic injury and prognosis through various mechanisms. Although studies have demonstrated the significant potential of endothelial cell-derived extracellular vesicles in treating ischemic stroke, their clinical translation remains challenging. Further research is needed to elucidate the specific roles of endothelial cell-derived extracellular vesicles in ischemic stroke, using additional in vitro or animal models. This will enable a more comprehensive assessment of the benefits and risks of endothelial cell-derived extracellular vesicles, thereby facilitating their clinical translation.

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.

Ischemic stroke, the second leading cause of death worldwide and the leading cause of long-term disabilities, presents a significant global health challenge, particularly in aging populations where the risk and severity of cerebrovascular events are significantly increased. The aftermath of stroke involves neuronal loss in the infarct core and reactive astrocyte proliferation, disrupting the neurovascular unit, especially in aged brains. Restoring the balance between neurons and non-neuronal cells within the perilesional area is crucial for post-stroke recovery. The aged post-stroke brain mounts a fulminant proliferative astroglial response, leading to gliotic scarring that prevents neural regeneration. While countless therapeutic techniques have been attempted for decades with limited success, alternative strategies aim to transform inhibitory gliotic tissue into an environment conducive to neuronal regeneration and axonal growth through genetic conversion of astrocytes into neurons. This concept gained momentum following discoveries that in vivo direct lineage reprogramming in the adult mammalian brain is a feasible strategy for reprogramming non-neuronal cells into neurons, circumventing the need for cell transplantation. Recent advancements in glial cell reprogramming, including transcription factor-based methods with factors like NeuroD1, Ascl1, and Neurogenin2, as well as small molecule-induced reprogramming and chemical induction, show promise in converting glial cells into functional neurons. These approaches leverage the brain's intrinsic plasticity for neuronal replacement and circuit restoration. However, applying these genetic conversion therapies in the aged, post-stroke brain faces significant challenges, such as the hostile inflammatory environment and compromised regenerative capacity. There is a critical need for safe and efficient delivery methods, including viral and non-viral vectors, to ensure targeted and sustained expression of reprogramming factors. Moreover, addressing the translational gap between preclinical successes and clinical applications is essential, emphasizing the necessity for robust stroke models that replicate human pathophysiology. Ethical considerations and biosafety concerns are critically evaluated, particularly regarding the long-term effects and potential risks of genetic reprogramming. By integrating recent research findings, this comprehensive review provides an in-depth understanding of the current landscape and future prospects of genetic conversion therapy for ischemic stroke rehabilitation, highlighting the potential to enhance personalized stroke management and regenerative strategies through innovative approaches.

Subarachnoid haemorrhage (SAH) is a subtype of stroke that predominantly impacts younger individuals. It is associated with high mortality rates and can cause long-term disabilities. This review examines the contribution of the initial blood load and the dynamics of clot clearance to the pathophysiology of SAH and the risk of adverse outcomes. These outcomes include hydrocephalus and delayed cerebral ischaemia (DCI), with a particular focus on the impact of blood located in the cisternal spaces, as opposed to ventricular blood, in the development of DCI. The literature described underscores the prognostic value of haematoma characteristics, such as volume, density, and anatomical location. The limitations of traditional radiographic grading systems are discussed, compared with the more accurate volumetric quantification techniques for predicting patient prognosis. Further, the significance of red blood cells (RBCs) and their breakdown products in secondary brain injury after SAH is explored. The review presents novel interventions designed to accelerate clot clearance or mitigate the effects of toxic byproducts released from erythrolysis in the cerebrospinal fluid following SAH. In conclusion, this review offers deeper insights into the complex dynamics of SAH and discusses the potential pathways available for advancing its management.

The 2023 International Subarachnoid Hemorrhage Conference identified a need to provide an up-to-date review on prevention methods for delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage and highlight areas for future research. A PubMed search was conducted for key factors contributing to development of delayed cerebral ischemia: anesthetics, antithrombotics, cerebrospinal fluid (CSF) diversion, hemodynamic, endovascular, and medical management. It was found that there is still a need for prospective studies analyzing the best methods for anesthetics and antithrombotics, though inhaled anesthetics and antiplatelets were found to have some advantages. Lumbar drains should increasingly be considered the first line of CSF diversion when applicable. Finally, maintaining euvolemia before and during vasospasm is recommended as there is no evidence supporting prophylactic spasmolysis or angioplasty. There is accumulating observational evidence, however, that intra-arterial spasmolysis with refractory DCI might be beneficial in patients not responding to induced hypertension. Nimodipine remains the medical therapy with the most support for prevention.

Emerging evidence indicates that aneurysmal subarachnoid hemorrhage (aSAH) elicits a response from both innate and adaptive immune systems. An upregulation of CD8 + CD161 + cells has been observed in the cerebrospinal fluid (CSF) after aSAH, yet the precise role of these cells in the context of aSAH is unkown. CSF samples from patients with aSAH and non-aneurysmal SAH (naSAH) were analyzed. Single-cell RNA sequencing (scRNAseq) was performed on CD8 + CD161 + sorted samples from aSAH patients. Cell populations were identified using "clustering." Gene expression levels of ten previously described genes involved in inflammation were quantified from aSAH and naSAH samples using RT-qPCR. The study focused on the following genes: CCL5, CCL7, APOE, SPP1, CXCL8, CXCL10, HMOX1, LTB, MAL, and HLA-DRB1. Gene clustering analysis revealed that monocytes, NK cells, and T cells expressed CD8 + CD161 + in the CSF of patients with aSAH. In comparison to naSAH samples, aSAH samples exhibited higher mRNA levels of CXCL10 (median, IQR = 90, 16-149 vs. 0.5, 0-6.75, p = 0.02). A trend towards higher HMOX1 levels was also observed in aSAH (median, IQR = 12.6, 9-17.6 vs. 2.55, 1.68-5.7, p = 0.076). Specifically, CXCL10 and HMOX1 were expressed by the monocyte subpopulation. Monocytes, NK cells, and T cells can potentially express CD8 + CD161 + in patients with aSAH. Notably, monocytes show high levels of CXCL10. The elevated expression of CXCL10 in aSAH compared to naSAH indicates its potential significance as a target for future studies.

Intracranial aneurysms (IA) are a disease process with potentially devastating outcomes, particularly when rupture occurs leading to subarachnoid hemorrhage. While some candidates exist, there is currently no established pharmacological prevention of growth and rupture. The development of prophylactic treatments is a critical area of research, and preclinical models using animals play a pivotal role. These models, which utilize various species and induction methods, each possess unique characteristics that can be leveraged depending on the specific aim of the study. A comprehensive understanding of these models, including their historical development, is crucial for appreciating the advantages and limitations of aneurysm research in animal models.We summarize the significant roles of animal models in IA research, with a particular focus on rats, mice, and large animals. We discuss the pros and cons of each model, providing insights into their unique characteristics and contributions to our understanding of IA. These models have been instrumental in elucidating the pathophysiology of IA and in the development of potential therapeutic strategies.A deep understanding of these models is essential for advancing research on preventive treatments for IA. By leveraging the unique strengths of each model and acknowledging their limitations, researchers can conduct more effective and targeted studies. This, in turn, can accelerate the development of novel therapeutic strategies, bringing us closer to the goal of establishing an effective prophylactic treatment for IA. This review aims to provide a comprehensive view of the current state of animal models in IA research.