Translational Stroke Research最新文献

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.

While subarachnoid hemorrhage is the second most common hemorrhagic stroke in epidemiologic studies, the recent DISCHARGE-1 trial has shown that in reality, three-quarters of focal brain damage after subarachnoid hemorrhage is ischemic. Two-fifths of these ischemic infarctions occur early and three-fifths are delayed. The vast majority are cortical infarcts whose pathomorphology corresponds to anemic infarcts. Therefore, we propose in this review that subarachnoid hemorrhage as an ischemic-hemorrhagic stroke is rather a third, separate entity in addition to purely ischemic or hemorrhagic strokes. Cumulative focal brain damage, determined by neuroimaging after the first 2 weeks, is the strongest known predictor of patient outcome half a year after the initial hemorrhage. Because of the unique ability to implant neuromonitoring probes at the brain surface before stroke onset and to perform longitudinal MRI scans before and after stroke, delayed cerebral ischemia is currently the stroke variant in humans whose pathophysiological details are by far the best characterized. Optoelectrodes located directly over newly developing delayed infarcts have shown that, as mechanistic correlates of infarct development, spreading depolarizations trigger (1) spreading ischemia, (2) severe hypoxia, (3) persistent activity depression, and (4) transition from clustered spreading depolarizations to a negative ultraslow potential. Furthermore, traumatic brain injury and subarachnoid hemorrhage are the second and third most common etiologies of brain death during continued systemic circulation. Here, we use examples to illustrate that although the pathophysiological cascades associated with brain death are global, they closely resemble the local cascades associated with the development of delayed cerebral infarcts.

Specific inflammatory pathways are important in the development of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Understanding the specific pathways of inflammation may be critical for finding new treatments. Evidence is accumulating that innate inflammatory cells and proteins play a more important role than cells of the adaptive inflammatory system. In this work, we review the evidence from clinical and preclinical data regarding which cells of the immune system play a role in DCI with particular emphasis on the bone-marrow-derived cells monocytes and neutrophils and the brain parenchymal microglia. In addition, we will review the evidence that complement proteins, a non-cellular part of the innate immune system, play a role in the development of DCI.

Despite advancements in acute management, morbidity rates for subarachnoid hemorrhage (SAH) remain high. Therefore, it is imperative to utilize standardized outcome scales in SAH research for evaluating new therapies effectively. This review offers a comprehensive overview of prevalent scales and clinical outcomes used in SAH assessment, accompanied by recommendations for their application and prognostic accuracy. Standardized terminology and diagnostic criteria should be employed when reporting pathophysiological outcomes such as symptomatic vasospasm and delayed cerebral ischemia. Furthermore, integrating clinical severity scales like the World Federation of Neurosurgical Societies scale and modified Fisher score into clinical trials is advised to evaluate their prognostic significance, despite their limited correlation with outcomes. The modified Rankin score is widely used for assessing functional outcomes, while the Glasgow outcome scale-extended version is suitable for broader social and behavioral evaluations. Avoiding score dichotomization is crucial to retain valuable information. Cognitive and behavioral outcomes, though frequently affected in patients with favorable neurological outcomes, are often overlooked during follow-up outpatient visits, despite their significant impact on quality of life. Comprehensive neuropsychological evaluations conducted by trained professionals are recommended for characterizing cognitive function, with the Montreal Cognitive Assessment serving as a viable screening tool. Additionally, integrating psychological inventories like the Beck Depression and Anxiety Inventory, along with quality-of-life scales such as the Stroke-Specific Quality of Life Scale, can effectively assess behavioral and quality of life outcomes in SAH studies.

Aneurysm wall enhancement (AWE) has the potential to be used as an imaging biomarker for the risk stratification of intracranial aneurysms (IAs). Radiomics provides a refined approach to quantify and further characterize AWE's textural features. This study examines the performance of AWE quantification combined with clinical information in detecting symptomatic IAs. Ninety patients harboring 104 IAs (29 symptomatic and 75 asymptomatic) underwent high-resolution magnetic resonance imaging (HR-MRI). The assessment of AWE was performed using two different methods: 3D-AWE mapping and composite radiomics-based score (RadScore). The dataset was split into training and testing subsets. The testing set was used to build two different nomograms using each modality of AWE assessment combined with patients' clinical information and aneurysm morphological data. Finally, each nomogram was evaluated on an independent testing set. A total of 22 radiomic features were significantly different between symptomatic and asymptomatic IAs. The 3D-AWE mapping nomogram achieved an area under the curve (AUC) of 0.77 (63% accuracy, 78% sensitivity, and 58% specificity). The RadScore nomogram exhibited a better performance, achieving an AUC of 0.83 (77% accuracy, 89% sensitivity, and 73% specificity). The comprehensive analysis of IAs with the quantification of AWE data through radiomic analysis, patient clinical information, and morphological aneurysm metrics achieves a high accuracy in detecting symptomatic IA status.

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating condition with high mortality and morbidity. The outcome measures used in aSAH clinical research vary making it challenging to compare and combine different studies. Additionally, there may be a mismatch between the outcomes prioritized by patients, caregivers, and health care providers and those selected by researchers. We conducted an international, online, multiple round Delphi study to develop consensus on domains (where a domain is a health concept or aspect) prioritized by key stakeholders including those with lived experience of aSAH, health care providers, and researchers, funders, or industry professionals. One hundred seventy-five people participated in the survey, 59% of whom had lived experience of aSAH. Over three rounds, 32 domains reached the consensus threshold pre-defined as 70% of participants rating the domain as being critically important. During the fourth round, participants ranked the importance of each of these 32 domains. The top ten domains ranked highest to lowest were (1) Cognition and executive function, (2) Aneurysm obliteration, (3) Cerebral infarction, (4) Functional outcomes including ability to walk, (5) Delayed cerebral ischemia, (6) The overall quality of life as reported by the SAH survivor, (7) Changes to emotions or mood (including depression), (8) The basic activities of daily living, (9) Vasospasm, and (10) ICU complications. Our findings confirm that there is a mismatch between domains prioritized by stakeholders and outcomes used in clinical research. Our future work aims to address this mismatch through the development of a core outcome set in aSAH research.