Translational Stroke Research最新文献

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.

Animal models mimicking human transient ischemic attack (TIA) and cerebral microinfarcts are essential tools for studying their pathogenetic mechanisms and finding methods of their treatment. Despite its advantages, the model of single arteriole photothrombosis requires complex experimental equipment and highly invasive surgery, which may affect the results of further studies. Hence, to achieve high translational potential, we focused on developing a TIA model based on photothrombosis of arterioles to combine good reproducibility and low invasiveness. For the first time, noninvasive laser speckle contrast imaging (LSCI) was used to monitor blood flow in cerebral arterioles and reperfusion was achieved. We demonstrate that irradiation of mouse cerebral cortical arterioles using a 532-nm laser with a 1-mm-wide beam at 2.4 or 3.7 mW for 55 or 40 s, respectively, after 15 mg/kg intravenous Rose Bengal administration, induces similar ischemia-reperfusion lesions resulting in microinfarct formation. The model can be used to study the pathogenesis of spontaneously developing cerebral microinfarcts in neurodegeneration. Reducing the exposure times by 10 s while maintaining the same other parameters caused photothrombosis of the arteriole with reperfusion in less than 1 h. This mode of photodynamic exposure caused cellular and subcellular level ischemic changes in neurons and promoted the activation of astrocytes and microglia in the first day after irradiation, but not later, without the formation of microinfarcts. This mode of photodynamic exposure most accurately reproduced human TIA, characterized by the absence of microinfarcts.

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.

Chinese population have a high prevalence of unruptured intracranial aneurysm (UIA). Clinical and imaging risk factors predicting UIA growth or rupture are poorly understood in the Chinese population due to the lack of large-scale longitudinal studies, and the treatment decision for UIA patients was challenging. Develop a decision tree (DT) model for UIA instability, and validate its performance in multi-center studies. Single-UIA patients from two prospective, longitudinal multicenter cohort studies were analyzed, and set as the development cohort and validation cohort. The primary endpoint was UIA instability (rupture, growth, or morphological change). A DT was established within the development cohort and validated within the validation cohort. The performance of clinicians in identifying unstable UIAs before and after the help of the DT was compared using the area under curve (AUC). The development cohort included 1270 patients with 1270 UIAs and a follow-up duration of 47.2 ± 15.5 months. Aneurysm instability occurred in 187 (14.7%) patients. Multivariate Cox analysis revealed hypertension (hazard ratio [HR], 1.54; 95%CI, 1.14-2.09), aspect ratio (HR, 1.22; 95%CI, 1.17-1.28), size ratio (HR, 1.31; 95%CI, 1.23-1.41), bifurcation configuration (HR, 2.05; 95%CI, 1.52-2.78) and irregular shape (HR, 4.30; 95%CI, 3.19-5.80) as factors of instability. In the validation cohort (n = 106, 12 was unstable), the DT model incorporating these factors was highly predictive of UIA instability (AUC, 0.88 [95%CI, 0.79-0.97]), and superior to existing UIA risk scales such as PHASES and ELAPSS (AUC, 0.77 [95%CI, 0.67-0.86] and 0.76 [95%CI, 0.66-0.86], P < 0.001). Within all 1376 single-UIA patients, the use of the DT significantly improved the accuracy of junior neurosurgical clinicians to identify unstable UIAs (AUC from 0.63 to 0.82, P < 0.001). The DT incorporating hypertension, aspect ratio, size ratio, bifurcation configuration and irregular shape was able to predict UIA instability better than existing clinical scales in Chinese cohorts. CLINICAL TRIAL REGISTRATION: IARP-CP cohort were included (unique identifier: ChiCTR1900024547. Published July 15, 2019. Completed December 30, 2020), with 100-Project phase-I cohort (unique identifier: NCT04872842, Published May 5, 2021. Completed November 8, 2022) as the development cohort. The 100-Project phase-II cohort (unique identifier: NCT05608122. Published November 8, 2022) as the validation cohort.

Ischemic stroke can lead to systemic inflammation, which can activate peripheral immune cells, causing neuroinflammation and brain injury. Meningeal lymphatics play a crucial role in transporting solutes and immune cells out of the brain and draining them into cervical lymph nodes (CLNs). However, the role of meningeal lymphatics in regulating systemic inflammation during the reperfusion stage after ischemia is not well understood. In this study, we demonstrated that brain infarct size, neuronal loss, and the effector function of inflammatory macrophage subsets were reduced after ischemia-reperfusion and disruption of meningeal lymphatics. Spatial memory function was improved in the late stage of ischemic stroke following meningeal lymphatic disruption. Brain-infiltrating immune cells, including neutrophils, monocytes, and T and natural killer cells, were reduced after cerebral ischemia-reperfusion and meningeal lymphatic disruption. Single-cell RNA sequencing analysis revealed that meningeal lymphatic disruption reprogrammed the transcriptome profile related to chemotaxis and leukocyte migration in CLN lymphatic endothelial cells (LECs), and it also decreased chemotactic CCN1 expression in floor LECs. Replenishment of CCN1 through intraventricular injection increased brain infarct size and neuronal loss, while restoring numbers of macrophages/microglia in the brains of meningeal lymphatic-disrupted mice after ischemic stroke. Blocking CCN1 in cerebrospinal fluid reduced brain infarcts and improves spatial memory function after ischemia-reperfusion injury. In summary, this study indicates that CCN1-mediated detrimental inflammation was alleviated after cerebral ischemia-reperfusion injury and meningeal lymphatic disruption. CCN1 represents a novel therapeutic target for inhibiting systemic inflammation in the brain-CLN axis after ischemia-reperfusion injury.

SFX-01 is a novel drug for clinical delivery of sulforaphane (SFN). SFN is a potent nuclear factor erythroid 2-related factor 2 activator that reduces inflammation and oxidation, improving outcomes after subarachnoid haemorrhage (SAH) in animal models. This was a multi-centre, double-blind, placebo-controlled, parallel-group randomised clinical trial to evaluate the safety, pharmacokinetics and efficacy of 28 days of SFX-01 300 mg BD in patients aged 18-80 with spontaneous SAH and high blood load on CT. Primary outcomes were (1) safety, (2) plasma and CSF SFN and metabolite levels and (3) vasospasm on transcranial doppler ultrasound. Secondary outcomes included CSF haptoglobin and malondialdehyde and clinical outcome on the modified Rankin Scale (mRS) and SAH outcome tool (SAHOT). A total of 105 patients were randomised (54 SFX-01, 51 placebo). There were no differences in adverse events other than nausea (9 SFX-01 (16.7%), 1 placebo (2.0%)). SFN, SFN-glutathione and SFN-N-acetyl-cysteine AUC_last were 16.2, 277 and 415 h × ng/ml. Plasma SFN was higher in GSTT1 null individuals (t = 2.40, p = 0.023). CSF levels were low with many samples below the lower limit of quantification and predicted by the CSF/serum albumin ratio (R² = 0.182, p = 0.039). There was no difference in CSF haptoglobin (1.981 95%CI 0.992-3.786, p = 0.052) or malondialdehyde (1.12 95%CI 0.7477-1.687, p = 0.572) or middle cerebral artery flow velocity (1.04 95%CI 0.903-1.211, p = 0.545) or functional outcome (mRS 1.647 95%CI 0.721-3.821, p = 0.237, SAHOT 1.082 95%CI 0.464-2.525, p = 0.855). SFX-01 is safe and effective for the delivery of SFN in acutely unwell patients. SFN penetrated CSF less than expected and did not reduce large vessel vasospasm or improve outcome. Trial registration: NCT02614742 clinicaltrials.gov.

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.

Cerebral cavernous malformation (CCM) is a hemorrhagic cerebrovascular disease where lesions develop in the setting of endothelial mutations of CCM genes, with many cases also harboring somatic PIK3CA gain of function (GOF) mutations. Rapamycin, an mTORC1 inhibitor, inhibited progression of murine CCM lesions driven by Ccm gene loss and Pik3ca GOF, but it remains unknown if rapamycin is beneficial in the absence of induction of Pik3ca GOF. We investigated the effect of rapamycin at three clinically relevant doses on lesion development in the Ccm3^-/-PDGFb-icreER^Positive murine model of familial CCM disease, without induction of Pik3ca GOF. Lesion burden, attrition, and acute and chronic hemorrhaging were compared between placebo and rapamycin-treated mice. Plasma miRNome was compared to identify potential biomarkers of rapamycin response. Outlier, exceptionally large CCM lesions (> 2 SD above the mean lesion burden) were exclusively observed in the placebo group. Rapamycin, across all dosages, may have prevented the emergence of large outlier lesions. Yet rapamycin also appeared to exacerbate mean lesion burden of surviving mice when outliers were excluded, increased attrition, and did not alter hemorrhage. miR-30c-2-3p, decreased in rapamycin-treated mouse plasma, has gene targets in PI3K/AKT and mTOR signaling. Progression of outlier lesions in a familial CCM model may have been halted by rapamycin treatment, at the potential expense of increased mean lesion burden and increased attrition. If confirmed, this can have implications for potential rapamycin treatment of familial CCM disease, where lesion development may not be driven by PIK3CA GOF. Further studies are necessary to determine specific pathways that mediate potential beneficial and detrimental effects of rapamycin treatment, and whether somatic PIK3CA mutations drive particularly aggressive lesions.

Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic telangiectasis (HHT). All available managements have limitations. We showed that intravenous (i.v.) delivery of soluble Feline McDonough Sarcoma (FMS)-related tyrosine kinase 1 using an adeno-associated viral vector (AAV9-sFLT1) reduced bAVM severity of endoglin deficient mice. However, minor liver inflammation and growth arrest in young mice were observed. To identify AAV variants and delivery methods that can best transduce brain and nasal tissue with an optimal transduction profile, we compared 3 engineered AAV capsids (AAV.cc47, AAV.cc84, and AAV1RX) with AAV9. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered i.v. or intranasally (i.n.) to wild-type mice. A CMV promoter driven Alk1 transgene was packaged into AAV.cc84 and delivered to PdgfbiCre;Alk1^f/f mice through i.v. followed by bAVM induction. Transduced cells in organs, vessel density, abnormal vessels in the bAVMs, and liver inflammation were analyzed histologically. Liver and kidney function were measured enzymatically. Compared to other viral vectors, AAV.cc84, after i.v. delivery, transduced a high percentage of brain endothelial cells (ECs) and few hepatocytes; whereas after i.n. delivery, AAV.cc84 transduced ECs and perivascular cells in the brain, and ECs, epithelial cells, and muscles in the nose with minimum hepatocyte transduction. No changes to liver or kidney function were detected. The delivery of AAV.cc84-Alk1 through i.v. to PdgfbiCre;Alk1^f/f mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.