Pub Date : 2024-08-05DOI: 10.1007/s12975-024-01286-1
Lynn Bitar, Berta Puig, Thomas G Oertner, Ádám Dénes, Tim Magnus
The direct interplay between the immune and nervous systems is now well established. Within the brain, these interactions take place between neurons and resident glial cells, i.e., microglia and astrocytes, or infiltrating immune cells, influenced by systemic factors. A special form of physical cell-cell interactions is the so-called "neuroimmunological (NI) synapse." There is compelling evidence that the same signaling pathways that regulate inflammatory responses to injury or ischemia also play potent roles in brain development, plasticity, and function. Proper synaptic wiring is as important during development as it is during disease states, as it is necessary for activity-dependent refinement of neuronal circuits. Since the process of forming synaptic connections in the brain is highly dynamic, with constant changes in strength and connectivity, the immune component is perfectly suited for the regulatory task as it is in constant turnover. Many cellular and molecular players in this interaction remain to be uncovered, especially in pathological states. In this review, we discuss and propose possible communication hubs between components of the adaptive and innate immune systems and the synaptic element in ischemic stroke pathology.
{"title":"Changes in Neuroimmunological Synapses During Cerebral Ischemia.","authors":"Lynn Bitar, Berta Puig, Thomas G Oertner, Ádám Dénes, Tim Magnus","doi":"10.1007/s12975-024-01286-1","DOIUrl":"https://doi.org/10.1007/s12975-024-01286-1","url":null,"abstract":"<p><p>The direct interplay between the immune and nervous systems is now well established. Within the brain, these interactions take place between neurons and resident glial cells, i.e., microglia and astrocytes, or infiltrating immune cells, influenced by systemic factors. A special form of physical cell-cell interactions is the so-called \"neuroimmunological (NI) synapse.\" There is compelling evidence that the same signaling pathways that regulate inflammatory responses to injury or ischemia also play potent roles in brain development, plasticity, and function. Proper synaptic wiring is as important during development as it is during disease states, as it is necessary for activity-dependent refinement of neuronal circuits. Since the process of forming synaptic connections in the brain is highly dynamic, with constant changes in strength and connectivity, the immune component is perfectly suited for the regulatory task as it is in constant turnover. Many cellular and molecular players in this interaction remain to be uncovered, especially in pathological states. In this review, we discuss and propose possible communication hubs between components of the adaptive and innate immune systems and the synaptic element in ischemic stroke pathology.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Evidence demonstrating the involvement of apoptosis in the death of the potentially salvageable area (penumbra zone) in patients during stroke remains limited. Our aim was to investigate whether apoptotic processes occur in penumbral brain tissue by analyzing circulating neuron- and glia-derived apoptotic bodies (CNS-ApBs), which are vesicles released into the bloodstream during the late stage of apoptosis. We have also assessed the clinical utility of plasma neuronal and glial apoptotic bodies in predicting early neurological evolution and functional outcome. The study included a total of 71 patients with acute hemispheric ischemic stroke (73 ± 10 years; 30 women). Blood samples were collected from these patients immediately upon arrival at the hospital (within 9 h) and at 24 and 72 h after symptom onset. Subsequently, isolation, quantification, and phenotypic characterization of CNS-ApBs during the first 72 h post-stroke were performed using centrifugation and flow cytometry techniques. We found a correlation between infarct growth and final infarct size with the amount of plasma CNS-ApBs detected in the first 72 h after stroke. In addition, patients with neurological worsening (progressive ischemic stroke) had higher plasma levels of CNS-ApBs at 24 h after symptom onset than those with a stable or improving course. Circulating CNS-ApB concentration was further associated with patients' functional prognosis. In conclusion, apoptosis may play an important role in the growth of the cerebral infarct area and plasma CNS-ApB quantification could be used as a predictive marker of penumbra death, neurological deterioration, and functional outcome in patients with ischemic stroke.
{"title":"Plasma Levels of Neuron/Glia-Derived Apoptotic Bodies, an In Vivo Biomarker of Apoptosis, Predicts Infarct Growth and Functional Outcome in Patients with Ischemic Stroke.","authors":"Inmaculada Díaz-Maroto, Beatriz Castro-Robles, Miguel Villar, Jorge García-García, Óscar Ayo-Martín, Gemma Serrano-Heras, Tomás Segura","doi":"10.1007/s12975-024-01283-4","DOIUrl":"https://doi.org/10.1007/s12975-024-01283-4","url":null,"abstract":"<p><p>Evidence demonstrating the involvement of apoptosis in the death of the potentially salvageable area (penumbra zone) in patients during stroke remains limited. Our aim was to investigate whether apoptotic processes occur in penumbral brain tissue by analyzing circulating neuron- and glia-derived apoptotic bodies (CNS-ApBs), which are vesicles released into the bloodstream during the late stage of apoptosis. We have also assessed the clinical utility of plasma neuronal and glial apoptotic bodies in predicting early neurological evolution and functional outcome. The study included a total of 71 patients with acute hemispheric ischemic stroke (73 ± 10 years; 30 women). Blood samples were collected from these patients immediately upon arrival at the hospital (within 9 h) and at 24 and 72 h after symptom onset. Subsequently, isolation, quantification, and phenotypic characterization of CNS-ApBs during the first 72 h post-stroke were performed using centrifugation and flow cytometry techniques. We found a correlation between infarct growth and final infarct size with the amount of plasma CNS-ApBs detected in the first 72 h after stroke. In addition, patients with neurological worsening (progressive ischemic stroke) had higher plasma levels of CNS-ApBs at 24 h after symptom onset than those with a stable or improving course. Circulating CNS-ApB concentration was further associated with patients' functional prognosis. In conclusion, apoptosis may play an important role in the growth of the cerebral infarct area and plasma CNS-ApB quantification could be used as a predictive marker of penumbra death, neurological deterioration, and functional outcome in patients with ischemic stroke.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141876055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aimed to develop a machine learning model for predicting brain arteriovenous malformation (bAVM) rupture using a combination of traditional risk factors and radiomics features. This multicenter retrospective study enrolled 586 patients with unruptured bAVMs from 2010 to 2020. All patients were grouped into the hemorrhage (n = 368) and non-hemorrhage (n = 218) groups. The bAVM nidus were segmented on CT angiography images using Slicer software, and radiomic features were extracted using Pyradiomics. The dataset included a training set and an independent testing set. The machine learning model was developed on the training set and validated on the testing set by merging numerous base estimators and a final estimator based on the stacking method. The area under the receiver operating characteristic (ROC) curve, precision, and the f1 score were evaluated to determine the performance of the model. A total of 1790 radiomics features and 8 traditional risk factors were contained in the original dataset, and 241 features remained for model training after L1 regularization filtering. The base estimator of the ensemble model was Logistic Regression, whereas the final estimator was Random Forest. In the training set, the area under the ROC curve of the model was 0.982 (0.967-0.996) and 0.893 (0.826-0.960) in the testing set. This study indicated that radiomics features are a valuable addition to traditional risk factors for predicting bAVM rupture. In the meantime, ensemble learning can effectively improve the performance of a prediction model.
{"title":"CT Angiography Radiomics Combining Traditional Risk Factors to Predict Brain Arteriovenous Malformation Rupture: a Machine Learning, Multicenter Study.","authors":"Shaosen Zhang, Junjie Wang, Shengjun Sun, Qian Zhang, Yuanren Zhai, Xiaochen Wang, Peicong Ge, Zhiyong Shi, Dong Zhang","doi":"10.1007/s12975-023-01166-0","DOIUrl":"10.1007/s12975-023-01166-0","url":null,"abstract":"<p><p>This study aimed to develop a machine learning model for predicting brain arteriovenous malformation (bAVM) rupture using a combination of traditional risk factors and radiomics features. This multicenter retrospective study enrolled 586 patients with unruptured bAVMs from 2010 to 2020. All patients were grouped into the hemorrhage (n = 368) and non-hemorrhage (n = 218) groups. The bAVM nidus were segmented on CT angiography images using Slicer software, and radiomic features were extracted using Pyradiomics. The dataset included a training set and an independent testing set. The machine learning model was developed on the training set and validated on the testing set by merging numerous base estimators and a final estimator based on the stacking method. The area under the receiver operating characteristic (ROC) curve, precision, and the f1 score were evaluated to determine the performance of the model. A total of 1790 radiomics features and 8 traditional risk factors were contained in the original dataset, and 241 features remained for model training after L1 regularization filtering. The base estimator of the ensemble model was Logistic Regression, whereas the final estimator was Random Forest. In the training set, the area under the ROC curve of the model was 0.982 (0.967-0.996) and 0.893 (0.826-0.960) in the testing set. This study indicated that radiomics features are a valuable addition to traditional risk factors for predicting bAVM rupture. In the meantime, ensemble learning can effectively improve the performance of a prediction model.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9624615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2023-06-28DOI: 10.1007/s12975-023-01169-x
Carolina Buizza, Andreas Enström, Robert Carlsson, Gesine Paul
The current treatment options for ischemic stroke aim to achieve reperfusion but are time critical. Novel therapeutic approaches that can be given beyond the limited time window of 3-4.5 h are still an unmet need to be addressed to improve stroke outcomes. The lack of oxygen and glucose in the area of ischemic injury initiates a pathological cascade leading to blood-brain barrier (BBB) breakdown, inflammation, and neuronal cell death, a process that may be intercepted to limit stroke progression. Pericytes located at the blood/brain interface are one of the first responders to hypoxia in stroke and therefore a potential target cell for early stroke interventions. Using single-cell RNA sequencing in a mouse model of permanent middle cerebral artery occlusion, we investigated the temporal differences in transcriptomic signatures in pericytes at 1, 12, and 24 h after stroke. Our results reveal a stroke-specific subcluster of pericytes that is present at 12 and 24 h and characterized by the upregulation of genes mainly related to cytokine signaling and immune response. This study identifies temporal transcriptional changes in the acute phase of ischemic stroke that reflect the early response of pericytes to the ischemic insult and its secondary consequences and may constitute potential future therapeutic targets.
{"title":"The Transcriptional Landscape of Pericytes in Acute Ischemic Stroke.","authors":"Carolina Buizza, Andreas Enström, Robert Carlsson, Gesine Paul","doi":"10.1007/s12975-023-01169-x","DOIUrl":"10.1007/s12975-023-01169-x","url":null,"abstract":"<p><p>The current treatment options for ischemic stroke aim to achieve reperfusion but are time critical. Novel therapeutic approaches that can be given beyond the limited time window of 3-4.5 h are still an unmet need to be addressed to improve stroke outcomes. The lack of oxygen and glucose in the area of ischemic injury initiates a pathological cascade leading to blood-brain barrier (BBB) breakdown, inflammation, and neuronal cell death, a process that may be intercepted to limit stroke progression. Pericytes located at the blood/brain interface are one of the first responders to hypoxia in stroke and therefore a potential target cell for early stroke interventions. Using single-cell RNA sequencing in a mouse model of permanent middle cerebral artery occlusion, we investigated the temporal differences in transcriptomic signatures in pericytes at 1, 12, and 24 h after stroke. Our results reveal a stroke-specific subcluster of pericytes that is present at 12 and 24 h and characterized by the upregulation of genes mainly related to cytokine signaling and immune response. This study identifies temporal transcriptional changes in the acute phase of ischemic stroke that reflect the early response of pericytes to the ischemic insult and its secondary consequences and may constitute potential future therapeutic targets.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11226519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9746586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2023-06-16DOI: 10.1007/s12975-023-01164-2
Peer B Jacobson, Andrea Mothe, Aharon Levy, Michael Krakovsky, Bradley A Hooker, Xiaomeng Zhang, Jennifer Mollon, Yulia Mordashova, Mathias Droescher, Sabine Weiss, Stefan Barghorn, Ingeborg Dreher, Khader Awwad, Volker Nimmrich, Lili Huang, Emma Fung, Wayne R Buck, Kimberly Pfleeger, Adam Ziemann, Elaine Smith, Gerard B Fox, Charles H Tator, Michael Gold
Repulsive guidance molecule A (RGMa) is an inhibitor of neuronal growth and survival which is upregulated in the damaged central nervous system following acute spinal cord injury (SCI), traumatic brain injury, acute ischemic stroke (AIS), and other neuropathological conditions. Neutralization of RGMa is neuroprotective and promotes neuroplasticity in several preclinical models of neurodegeneration and injury including multiple sclerosis, AIS, and SCI. Given the limitations of current treatments for AIS due to narrow time windows to intervention (TTI), and restrictive patient selection criteria, there is significant unmet need for therapeutic agents that enable tissue survival and repair following acute ischemic damage for a broader population of stroke patients. In this preclinical study, we evaluated whether elezanumab, a human anti-RGMa monoclonal antibody, could improve neuromotor function and modulate neuroinflammatory cell activation following AIS with delayed intervention times up to 24 h using a rabbit embolic permanent middle cerebral artery occlusion model (pMCAO). In two replicate 28-day pMCAO studies, weekly intravenous infusions of elezanumab, over a range of doses and TTIs of 6 and 24 h after stroke, significantly improved neuromotor function in both pMCAO studies when first administered 6 h after stroke. All elezanumab treatment groups, including the 24 h TTI group, had significantly less neuroinflammation as assessed by microglial and astrocyte activation. The novel mechanism of action and potential for expanding TTI in human AIS make elezanumab distinct from current acute reperfusion therapies, and support evaluation in clinical trials of acute CNS damage to determine optimal dose and TTI in humans.
排斥性引导分子 A(RGMa)是神经元生长和存活的抑制剂,在急性脊髓损伤(SCI)、创伤性脑损伤、急性缺血性中风(AIS)和其他神经病理情况下,它会在受损的中枢神经系统中上调。在包括多发性硬化、急性缺血性中风和 SCI 在内的几种神经变性和损伤临床前模型中,中和 RGMa 具有神经保护和促进神经可塑性的作用。由于干预时间窗(TTI)狭窄和患者选择标准受限,目前治疗 AIS 的方法存在局限性,因此,对于能使更多中风患者在急性缺血性损伤后组织存活和修复的治疗药物,仍有大量需求未得到满足。在这项临床前研究中,我们利用兔栓塞性永久性大脑中动脉闭塞模型(pMCAO),评估了人抗RGMa单克隆抗体elezanumab是否能改善AIS后的神经运动功能并调节神经炎症细胞的活化,干预时间可延迟至24小时。在两项为期28天的重复pMCAO研究中,每周静脉注射elezanumab,剂量范围为脑卒中后6小时和24小时,在脑卒中后6小时首次给药的情况下,均能显著改善pMCAO研究中的神经运动功能。所有elezanumab治疗组,包括24 h TTI组,通过小胶质细胞和星形胶质细胞激活评估,神经炎症都明显减轻。elezanumab在人类AIS中的新作用机制和扩大TTI的潜力使其有别于目前的急性再灌注疗法,并支持在急性中枢神经系统损伤的临床试验中进行评估,以确定在人类中的最佳剂量和TTI。
{"title":"Neutralizing RGMa with Elezanumab Promotes Cerebroprotection and Recovery in Rabbit Middle Cerebral Artery Occlusion.","authors":"Peer B Jacobson, Andrea Mothe, Aharon Levy, Michael Krakovsky, Bradley A Hooker, Xiaomeng Zhang, Jennifer Mollon, Yulia Mordashova, Mathias Droescher, Sabine Weiss, Stefan Barghorn, Ingeborg Dreher, Khader Awwad, Volker Nimmrich, Lili Huang, Emma Fung, Wayne R Buck, Kimberly Pfleeger, Adam Ziemann, Elaine Smith, Gerard B Fox, Charles H Tator, Michael Gold","doi":"10.1007/s12975-023-01164-2","DOIUrl":"10.1007/s12975-023-01164-2","url":null,"abstract":"<p><p>Repulsive guidance molecule A (RGMa) is an inhibitor of neuronal growth and survival which is upregulated in the damaged central nervous system following acute spinal cord injury (SCI), traumatic brain injury, acute ischemic stroke (AIS), and other neuropathological conditions. Neutralization of RGMa is neuroprotective and promotes neuroplasticity in several preclinical models of neurodegeneration and injury including multiple sclerosis, AIS, and SCI. Given the limitations of current treatments for AIS due to narrow time windows to intervention (TTI), and restrictive patient selection criteria, there is significant unmet need for therapeutic agents that enable tissue survival and repair following acute ischemic damage for a broader population of stroke patients. In this preclinical study, we evaluated whether elezanumab, a human anti-RGMa monoclonal antibody, could improve neuromotor function and modulate neuroinflammatory cell activation following AIS with delayed intervention times up to 24 h using a rabbit embolic permanent middle cerebral artery occlusion model (pMCAO). In two replicate 28-day pMCAO studies, weekly intravenous infusions of elezanumab, over a range of doses and TTIs of 6 and 24 h after stroke, significantly improved neuromotor function in both pMCAO studies when first administered 6 h after stroke. All elezanumab treatment groups, including the 24 h TTI group, had significantly less neuroinflammation as assessed by microglial and astrocyte activation. The novel mechanism of action and potential for expanding TTI in human AIS make elezanumab distinct from current acute reperfusion therapies, and support evaluation in clinical trials of acute CNS damage to determine optimal dose and TTI in humans.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11226526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9637626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rheumatoid factor (RF), an established diagnostic biomarker for rheumatoid arthritis (RA), is associated with cardiovascular diseases, but its impact on clinical outcomes of ischemic stroke remains unclear. We aimed to investigate the observational associations between serum RF and prognosis of ischemic stroke, and further examined the genetic associations of RA and its therapeutic strategy, interleukin-6 (IL-6) inhibitor, with prognosis of ischemic stroke. We measured serum RF levels in 3474 Chinese ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset. Mendelian randomization (MR) analyses were performed to examine the associations of genetically predicted RA and IL-6 inhibition with prognosis of ischemic stroke. During 3 months of follow-up, 866 patients (25.43%) experienced death or major disability. After multivariate adjustment, RF-positive was significantly associated with a high risk of primary outcome (OR, 1.47; 95% CI, 1.08-2.00; P =0.016) compared with RF-negative. The two-sample MR analyses suggested that genetically predicted RA was associated with an increased risk of primary outcome (OR, 1.09; 95% CI, 1.01-1.18; P=0.021), while genetically predicted IL-6 inhibition was associated with a decreased risk of primary outcome (OR, 0.88; 95% CI, 0.77-0.99; P=0.041). We found that positive RF was associated with increased risks of adverse outcomes after atherosclerotic ischemic stroke, and genetically predicted RA and IL-6 inhibition increased and decreased the risks of adverse outcomes after ischemic stroke, respectively.
{"title":"Associations of Rheumatoid Factor, Rheumatoid Arthritis, and Interleukin-6 Inhibitor with the Prognosis of Ischemic Stroke: a Prospective Multicenter Cohort Study and Mendelian Randomization Analysis.","authors":"Yiming Jia, Kaixin Zhang, Mengyao Shi, Daoxia Guo, Pinni Yang, Xiaoqing Bu, Jing Chen, Aili Wang, Tan Xu, Jiang He, Zhengbao Zhu, Yonghong Zhang","doi":"10.1007/s12975-023-01161-5","DOIUrl":"10.1007/s12975-023-01161-5","url":null,"abstract":"<p><p>Rheumatoid factor (RF), an established diagnostic biomarker for rheumatoid arthritis (RA), is associated with cardiovascular diseases, but its impact on clinical outcomes of ischemic stroke remains unclear. We aimed to investigate the observational associations between serum RF and prognosis of ischemic stroke, and further examined the genetic associations of RA and its therapeutic strategy, interleukin-6 (IL-6) inhibitor, with prognosis of ischemic stroke. We measured serum RF levels in 3474 Chinese ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset. Mendelian randomization (MR) analyses were performed to examine the associations of genetically predicted RA and IL-6 inhibition with prognosis of ischemic stroke. During 3 months of follow-up, 866 patients (25.43%) experienced death or major disability. After multivariate adjustment, RF-positive was significantly associated with a high risk of primary outcome (OR, 1.47; 95% CI, 1.08-2.00; P =0.016) compared with RF-negative. The two-sample MR analyses suggested that genetically predicted RA was associated with an increased risk of primary outcome (OR, 1.09; 95% CI, 1.01-1.18; P=0.021), while genetically predicted IL-6 inhibition was associated with a decreased risk of primary outcome (OR, 0.88; 95% CI, 0.77-0.99; P=0.041). We found that positive RF was associated with increased risks of adverse outcomes after atherosclerotic ischemic stroke, and genetically predicted RA and IL-6 inhibition increased and decreased the risks of adverse outcomes after ischemic stroke, respectively.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9548246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2023-07-07DOI: 10.1007/s12975-023-01163-3
Xiao Liu, Xiaofeng Jia
Neurological injuries can have numerous debilitating effects on functional status including sensorimotor deficits, cognitive impairment, and behavioral symptoms. Despite the disease burden, treatment options remain limited. Current pharmacological interventions are targeted at symptom management but are ineffective in reversing ischemic brain damage. Stem cell therapy for ischemic brain injury has shown promising preclinical and clinical results and has attracted attention as a potential therapeutic option. Various stem cell sources (embryonic, mesenchymal/bone marrow, and neural stem cells) have been investigated. This review provides an overview of the advances made in our understanding of the various types of stem cells and progress made in the use of these stem cells for the treatment of ischemic brain injuries. In particular, the use of stem cell therapy in global cerebral ischemia following cardiac arrest and in focal cerebral ischemia after ischemic stroke are discussed. The proposed mechanisms of stem cells' neuroprotective effects in animal models (rat/mice, pig/swine) and other clinical studies, different routes of administration (intravenous/intra-arterial/intracerebroventricular/intranasal/intraperitoneal/intracranial) and stem cell preconditioning are discussed. Much of the promising data on stem cell therapies after ischemic brain injury remains in the experimental stage and several limitations remain unsettled. Future investigation is needed to further assess the safety and efficacy and to overcome the remaining obstacles.
{"title":"Neuroprotection of Stem Cells Against Ischemic Brain Injury: From Bench to Clinic.","authors":"Xiao Liu, Xiaofeng Jia","doi":"10.1007/s12975-023-01163-3","DOIUrl":"10.1007/s12975-023-01163-3","url":null,"abstract":"<p><p>Neurological injuries can have numerous debilitating effects on functional status including sensorimotor deficits, cognitive impairment, and behavioral symptoms. Despite the disease burden, treatment options remain limited. Current pharmacological interventions are targeted at symptom management but are ineffective in reversing ischemic brain damage. Stem cell therapy for ischemic brain injury has shown promising preclinical and clinical results and has attracted attention as a potential therapeutic option. Various stem cell sources (embryonic, mesenchymal/bone marrow, and neural stem cells) have been investigated. This review provides an overview of the advances made in our understanding of the various types of stem cells and progress made in the use of these stem cells for the treatment of ischemic brain injuries. In particular, the use of stem cell therapy in global cerebral ischemia following cardiac arrest and in focal cerebral ischemia after ischemic stroke are discussed. The proposed mechanisms of stem cells' neuroprotective effects in animal models (rat/mice, pig/swine) and other clinical studies, different routes of administration (intravenous/intra-arterial/intracerebroventricular/intranasal/intraperitoneal/intracranial) and stem cell preconditioning are discussed. Much of the promising data on stem cell therapies after ischemic brain injury remains in the experimental stage and several limitations remain unsettled. Future investigation is needed to further assess the safety and efficacy and to overcome the remaining obstacles.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10771544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10135538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2023-07-18DOI: 10.1007/s12975-023-01173-1
Jasneet Parmar, Georg von Jonquieres, Nagarajesh Gorlamandala, Brandon Chung, Amanda J Craig, Jeremy L Pinyon, Lutz Birnbaumer, Matthias Klugmann, Andrew J Moorhouse, John M Power, Gary D Housley
Canonical transient receptor potential (TRPC) non-selective cation channels, particularly those assembled with TRPC3, TRPC6, and TRPC7 subunits, are coupled to Gαq-type G protein-coupled receptors for the major classes of excitatory neurotransmitters. Sustained activation of this TRPC channel-based pathophysiological signaling hub in neurons and glia likely contributes to prodigious excitotoxicity-driven secondary brain injury expansion. This was investigated in mouse models with selective Trpc gene knockout (KO). In adult cerebellar brain slices, application of glutamate and the class I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine to Purkinje neurons expressing the GCaMP5g Ca2+ reporter demonstrated that the majority of the Ca2+ loading in the molecular layer dendritic arbors was attributable to the TRPC3 effector channels (Trpc3KO compared with wildtype (WT)). This Ca2+ dysregulation was associated with glutamate excitotoxicity causing progressive disruption of the Purkinje cell dendrites (significantly abated in a GAD67-GFP-Trpc3KO reporter brain slice model). Contribution of the Gαq-coupled TRPC channels to secondary brain injury was evaluated in a dual photothrombotic focal ischemic injury model targeting cerebellar and cerebral cortex regions, comparing day 4 post-injury in WT mice, Trpc3KO, and Trpc1/3/6/7 quadruple knockout (TrpcQKO), with immediate 2-h (primary) brain injury. Neuroprotection to secondary brain injury was afforded in both brain regions by Trpc3KO and TrpcQKO models, with the TrpcQKO showing greatest neuroprotection. These findings demonstrate the contribution of the Gαq-coupled TRPC effector mechanism to excitotoxicity-based secondary brain injury expansion, which is a primary driver for mortality and morbidity in stroke, traumatic brain injury, and epilepsy.
{"title":"TRPC Channels Activated by G Protein-Coupled Receptors Drive Ca<sup>2+</sup> Dysregulation Leading to Secondary Brain Injury in the Mouse Model.","authors":"Jasneet Parmar, Georg von Jonquieres, Nagarajesh Gorlamandala, Brandon Chung, Amanda J Craig, Jeremy L Pinyon, Lutz Birnbaumer, Matthias Klugmann, Andrew J Moorhouse, John M Power, Gary D Housley","doi":"10.1007/s12975-023-01173-1","DOIUrl":"10.1007/s12975-023-01173-1","url":null,"abstract":"<p><p>Canonical transient receptor potential (TRPC) non-selective cation channels, particularly those assembled with TRPC3, TRPC6, and TRPC7 subunits, are coupled to G<sub>αq</sub>-type G protein-coupled receptors for the major classes of excitatory neurotransmitters. Sustained activation of this TRPC channel-based pathophysiological signaling hub in neurons and glia likely contributes to prodigious excitotoxicity-driven secondary brain injury expansion. This was investigated in mouse models with selective Trpc gene knockout (KO). In adult cerebellar brain slices, application of glutamate and the class I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine to Purkinje neurons expressing the GCaMP5g Ca<sup>2+</sup> reporter demonstrated that the majority of the Ca<sup>2+</sup> loading in the molecular layer dendritic arbors was attributable to the TRPC3 effector channels (Trpc3<sup>KO</sup> compared with wildtype (WT)). This Ca<sup>2+</sup> dysregulation was associated with glutamate excitotoxicity causing progressive disruption of the Purkinje cell dendrites (significantly abated in a GAD67-GFP-Trpc3<sup>KO</sup> reporter brain slice model). Contribution of the G<sub>αq</sub>-coupled TRPC channels to secondary brain injury was evaluated in a dual photothrombotic focal ischemic injury model targeting cerebellar and cerebral cortex regions, comparing day 4 post-injury in WT mice, Trpc3<sup>KO</sup>, and Trpc1/3/6/7 quadruple knockout (Trpc<sup>QKO</sup>), with immediate 2-h (primary) brain injury. Neuroprotection to secondary brain injury was afforded in both brain regions by Trpc3<sup>KO</sup> and Trpc<sup>QKO</sup> models, with the Trpc<sup>QKO</sup> showing greatest neuroprotection. These findings demonstrate the contribution of the G<sub>αq</sub>-coupled TRPC effector mechanism to excitotoxicity-based secondary brain injury expansion, which is a primary driver for mortality and morbidity in stroke, traumatic brain injury, and epilepsy.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11226524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10186358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2023-05-30DOI: 10.1007/s12975-023-01160-6
Florian Welle, Kristin Stoll, Christina Gillmann, Jeanette Henkelmann, Gordian Prasse, Daniel P O Kaiser, Elias Kellner, Marco Reisert, Hans R Schneider, Julian Klingbeil, Anika Stockert, Donald Lobsien, Karl-Titus Hoffmann, Dorothee Saur, Max Wawrzyniak
Perfusion CT is established to aid selection of patients with proximal intracranial vessel occlusion for thrombectomy in the extended time window. Selection is mostly based on simple thresholding of perfusion parameter maps, which, however, does not exploit the full information hidden in the high-dimensional perfusion data. We implemented a multiparametric mass-univariate logistic model to predict tissue outcome based on data from 405 stroke patients with acute proximal vessel occlusion in the anterior circulation who underwent mechanical thrombectomy. Input parameters were acute multimodal CT imaging (perfusion, angiography, and non-contrast) as well as basic demographic and clinical parameters. The model was trained with the knowledge of recanalization status and final infarct localization. We found that perfusion parameter maps (CBF, CBV, and Tmax) were sufficient for tissue outcome prediction. Compared with single-parameter thresholding-based models, our logistic model had comparable volumetric accuracy, but was superior with respect to topographical accuracy (AUC of receiver operating characteristic). We also found higher spatial accuracy (Dice index) in an independent internal but not external cross-validation. Our results highlight the value of perfusion data compared with non-contrast CT, CT angiography and clinical information for tissue outcome-prediction. Multiparametric logistic prediction has high potential to outperform the single-parameter thresholding-based approach. In the future, the combination of tissue and functional outcome prediction might provide an individual biomarker for the benefit from mechanical thrombectomy in acute stroke care.
{"title":"Tissue Outcome Prediction in Patients with Proximal Vessel Occlusion and Mechanical Thrombectomy Using Logistic Models.","authors":"Florian Welle, Kristin Stoll, Christina Gillmann, Jeanette Henkelmann, Gordian Prasse, Daniel P O Kaiser, Elias Kellner, Marco Reisert, Hans R Schneider, Julian Klingbeil, Anika Stockert, Donald Lobsien, Karl-Titus Hoffmann, Dorothee Saur, Max Wawrzyniak","doi":"10.1007/s12975-023-01160-6","DOIUrl":"10.1007/s12975-023-01160-6","url":null,"abstract":"<p><p>Perfusion CT is established to aid selection of patients with proximal intracranial vessel occlusion for thrombectomy in the extended time window. Selection is mostly based on simple thresholding of perfusion parameter maps, which, however, does not exploit the full information hidden in the high-dimensional perfusion data. We implemented a multiparametric mass-univariate logistic model to predict tissue outcome based on data from 405 stroke patients with acute proximal vessel occlusion in the anterior circulation who underwent mechanical thrombectomy. Input parameters were acute multimodal CT imaging (perfusion, angiography, and non-contrast) as well as basic demographic and clinical parameters. The model was trained with the knowledge of recanalization status and final infarct localization. We found that perfusion parameter maps (CBF, CBV, and T<sub>max</sub>) were sufficient for tissue outcome prediction. Compared with single-parameter thresholding-based models, our logistic model had comparable volumetric accuracy, but was superior with respect to topographical accuracy (AUC of receiver operating characteristic). We also found higher spatial accuracy (Dice index) in an independent internal but not external cross-validation. Our results highlight the value of perfusion data compared with non-contrast CT, CT angiography and clinical information for tissue outcome-prediction. Multiparametric logistic prediction has high potential to outperform the single-parameter thresholding-based approach. In the future, the combination of tissue and functional outcome prediction might provide an individual biomarker for the benefit from mechanical thrombectomy in acute stroke care.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11226467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9542237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Clinical implications of RNF213 genetic variants, other than p.Arg4810Lys, in moyamoya disease (MMD), remain unclear. This study aimed to investigate the association of RNF213 variants with clinical phenotypes in MMD. This retrospective cohort study collected data regarding the clinical characteristics of 139 patients with MMD and evaluated the angioarchitectures of 253 hemispheres using digital subtraction angiography at diagnosis. All RNF213 exons were sequenced, and the associations of clinical characteristics and angiographical findings with p.Arg4810Lys, p.Ala4399Thr, and other rare variants (RVs) were examined. Among 139 patients, 100 (71.9%) had p.Arg4810Lys heterozygote (GA) and 39 (28.1%) had the wild type (GG). Fourteen RVs were identified and detetcted in 15/139 (10.8%) patients, and p.Ala4399Thr was detected in 17/139 (12.2%) patients. Hemispheres with GG and p.Ala4399Thr presented with significantly less ischemic events and more hemorrhagic events at diagnosis (p = 0.001 and p = 0.028, respectively). In asymptomatic hemispheres, those with GG were more susceptible to de novo hemorrhage than those with GA (adjusted hazard ratio [aHR] 5.36) with an increased risk when accompanied by p.Ala4399Thr or RVs (aHR 15.22 and 16.60, respectively). Within the choroidal anastomosis-positive hemispheres, GG exhibited a higher incidence of de novo hemorrhage than GA (p = 0.004). The GG of p. Arg4810Lys was a risk factor for de novo hemorrhage in asymptomatic MMD hemispheres. This risk increased with certain other variants and is observed in choroidal anastomosis-positive hemispheres. A comprehensive evaluation of RNF213 variants and angioarchitectures is essential for predicting the phenotype of asymptomatic hemispheres in MMD.
{"title":"RNF213 p.Arg4810Lys Wild Type is Associated with De Novo Hemorrhage in Asymptomatic Hemispheres with Moyamoya Disease.","authors":"Seiei Torazawa, Satoru Miyawaki, Hideaki Imai, Hiroki Hongo, Daiichiro Ishigami, Masahiro Shimizu, Hideaki Ono, Yuki Shinya, Daisuke Sato, Yu Sakai, Motoyuki Umekawa, Satoshi Kiyofuji, Daisuke Shimada, Satoshi Koizumi, Daisuke Komura, Hiroto Katoh, Shumpei Ishikawa, Hirofumi Nakatomi, Akira Teraoka, Nobuhito Saito","doi":"10.1007/s12975-023-01159-z","DOIUrl":"10.1007/s12975-023-01159-z","url":null,"abstract":"<p><p>Clinical implications of RNF213 genetic variants, other than p.Arg4810Lys, in moyamoya disease (MMD), remain unclear. This study aimed to investigate the association of RNF213 variants with clinical phenotypes in MMD. This retrospective cohort study collected data regarding the clinical characteristics of 139 patients with MMD and evaluated the angioarchitectures of 253 hemispheres using digital subtraction angiography at diagnosis. All RNF213 exons were sequenced, and the associations of clinical characteristics and angiographical findings with p.Arg4810Lys, p.Ala4399Thr, and other rare variants (RVs) were examined. Among 139 patients, 100 (71.9%) had p.Arg4810Lys heterozygote (GA) and 39 (28.1%) had the wild type (GG). Fourteen RVs were identified and detetcted in 15/139 (10.8%) patients, and p.Ala4399Thr was detected in 17/139 (12.2%) patients. Hemispheres with GG and p.Ala4399Thr presented with significantly less ischemic events and more hemorrhagic events at diagnosis (p = 0.001 and p = 0.028, respectively). In asymptomatic hemispheres, those with GG were more susceptible to de novo hemorrhage than those with GA (adjusted hazard ratio [aHR] 5.36) with an increased risk when accompanied by p.Ala4399Thr or RVs (aHR 15.22 and 16.60, respectively). Within the choroidal anastomosis-positive hemispheres, GG exhibited a higher incidence of de novo hemorrhage than GA (p = 0.004). The GG of p. Arg4810Lys was a risk factor for de novo hemorrhage in asymptomatic MMD hemispheres. This risk increased with certain other variants and is observed in choroidal anastomosis-positive hemispheres. A comprehensive evaluation of RNF213 variants and angioarchitectures is essential for predicting the phenotype of asymptomatic hemispheres in MMD.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11226534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9560218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}