Pub Date : 2024-07-22DOI: 10.1007/s12975-024-01281-6
Isabel Fernández-Pérez, Joan Jiménez-Balado, Adrià Macias-Gómez, Antoni Suárez-Pérez, Marta Vallverdú-Prats, Alberto Pérez-Giraldo, Marc Viles-García, Julia Peris-Subiza, Sergio Vidal-Notari, Eva Giralt-Steinhauer, Daniel Guisado-Alonso, Manel Esteller, Ana Rodriguez-Campello, Jordi Jiménez-Conde, Angel Ois, Elisa Cuadrado-Godia
{"title":"Correction to: Blood DNA Methylation Analysis Reveals a Distinctive Epigenetic Signature of Vasospasm in Aneurysmal Subarachnoid Hemorrhage.","authors":"Isabel Fernández-Pérez, Joan Jiménez-Balado, Adrià Macias-Gómez, Antoni Suárez-Pérez, Marta Vallverdú-Prats, Alberto Pérez-Giraldo, Marc Viles-García, Julia Peris-Subiza, Sergio Vidal-Notari, Eva Giralt-Steinhauer, Daniel Guisado-Alonso, Manel Esteller, Ana Rodriguez-Campello, Jordi Jiménez-Conde, Angel Ois, Elisa Cuadrado-Godia","doi":"10.1007/s12975-024-01281-6","DOIUrl":"https://doi.org/10.1007/s12975-024-01281-6","url":null,"abstract":"","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735104","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}
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.
{"title":"CCN1 Is a Therapeutic Target for Reperfused Ischemic Brain Injury.","authors":"Gilbert Aaron Lee, Yu-Wei Chang, Jing-Huei Lai, Tzu-Hao Chang, Shiu-Wen Huang, Chih-Hao Yang, Ting-An Shen, Wan-Li Lin, Ying-Chieh Wu, Li-Wen Tseng, Sung-Hui Tseng, Yung-Chieh Chen, Yung-Hsiao Chiang, Cheng-Yu Chen","doi":"10.1007/s12975-024-01279-0","DOIUrl":"https://doi.org/10.1007/s12975-024-01279-0","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724579","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 : 2024-07-19DOI: 10.1007/s12975-024-01278-1
Ardalan Zolnourian, Patrick Garland, Patrick Holton, Mukul Arora, Jonathan Rhodes, Christopher Uff, Tony Birch, David Howat, Stephen Franklin, Ian Galea, Diederik Bulters
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 AUClast 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.
{"title":"A Randomised Controlled Trial of SFX-01 After Subarachnoid Haemorrhage - The SAS Study.","authors":"Ardalan Zolnourian, Patrick Garland, Patrick Holton, Mukul Arora, Jonathan Rhodes, Christopher Uff, Tony Birch, David Howat, Stephen Franklin, Ian Galea, Diederik Bulters","doi":"10.1007/s12975-024-01278-1","DOIUrl":"https://doi.org/10.1007/s12975-024-01278-1","url":null,"abstract":"<p><p>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<sub>last</sub> 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 (R<sup>2</sup> = 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.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724578","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 : 2024-07-13DOI: 10.1007/s12975-024-01271-8
Christopher R Andersen, Justin Presseau, Bev Shea, Maria Luisa Marti, Madeline McCoy, Gordon Fernie, Lauralyn McIntyre, Anthony Delaney, Michaël Chassé, Victoria Saigle, Shawn Marshall, Dean A Fergusson, Ian Graham, Jamie Brehaut, Alexis F Turgeon, François Lauzier, Peter Tugwell, Xiaohui Zha, Phil Talbot, John Muscedere, John C Marshall, Kednapa Thavorn, Donald Griesdale, Shane W English
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.
{"title":"What to Measure in Aneurysmal Subarachnoid Haemorrhage Research-An International Delphi Survey.","authors":"Christopher R Andersen, Justin Presseau, Bev Shea, Maria Luisa Marti, Madeline McCoy, Gordon Fernie, Lauralyn McIntyre, Anthony Delaney, Michaël Chassé, Victoria Saigle, Shawn Marshall, Dean A Fergusson, Ian Graham, Jamie Brehaut, Alexis F Turgeon, François Lauzier, Peter Tugwell, Xiaohui Zha, Phil Talbot, John Muscedere, John C Marshall, Kednapa Thavorn, Donald Griesdale, Shane W English","doi":"10.1007/s12975-024-01271-8","DOIUrl":"https://doi.org/10.1007/s12975-024-01271-8","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601807","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 : 2024-07-09DOI: 10.1007/s12975-024-01270-9
Roberto J Alcazar-Felix, Robert Shenkar, Christian R Benavides, Akash Bindal, Abhinav Srinath, Ying Li, Serena Kinkade, Tatiana Terranova, Evon DeBose-Scarlett, Rhonda Lightle, Dorothy DeBiasse, Hanadi Almazroue, Diana Vera Cruz, Sharbel Romanos, Aditya Jhaveri, Janne Koskimäki, Stephanie Hage, Carolyn Bennett, Romuald Girard, Douglas A Marchuk, Issam A Awad
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-icreERPositive 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.
{"title":"Except for Robust Outliers, Rapamycin Increases Lesion Burden in a Murine Model of Cerebral Cavernous Malformations.","authors":"Roberto J Alcazar-Felix, Robert Shenkar, Christian R Benavides, Akash Bindal, Abhinav Srinath, Ying Li, Serena Kinkade, Tatiana Terranova, Evon DeBose-Scarlett, Rhonda Lightle, Dorothy DeBiasse, Hanadi Almazroue, Diana Vera Cruz, Sharbel Romanos, Aditya Jhaveri, Janne Koskimäki, Stephanie Hage, Carolyn Bennett, Romuald Girard, Douglas A Marchuk, Issam A Awad","doi":"10.1007/s12975-024-01270-9","DOIUrl":"10.1007/s12975-024-01270-9","url":null,"abstract":"<p><p>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<sup>-/-</sup>PDGFb-icreER<sup>Positive</sup> 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.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559845","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 : 2024-07-08DOI: 10.1007/s12975-024-01275-4
Alka Yadav, Rich Liang, Kelly Press, Annika Schmidt, Zahra Shabani, Kun Leng, Calvin Wang, Abinav Sekhar, Joshua Shi, Garth W Devlin, Trevor J Gonzalez, Aravind Asokan, Hua Su
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;Alk1f/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;Alk1f/f mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.
{"title":"Evaluation of AAV Capsids and Delivery Approaches for Hereditary Hemorrhagic Telangiectasia Gene Therapy.","authors":"Alka Yadav, Rich Liang, Kelly Press, Annika Schmidt, Zahra Shabani, Kun Leng, Calvin Wang, Abinav Sekhar, Joshua Shi, Garth W Devlin, Trevor J Gonzalez, Aravind Asokan, Hua Su","doi":"10.1007/s12975-024-01275-4","DOIUrl":"10.1007/s12975-024-01275-4","url":null,"abstract":"<p><p>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<sup>f/f</sup> 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<sup>f/f</sup> mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559844","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}
Chronic cerebral ischemia (CCI) results in a prolonged insufficient blood supply to the brain tissue, leading to impaired neuronal function and subsequent impairment of cognitive and motor abilities. Our previous research showed that in mice with bilateral carotid artery stenosis, the collateral neovascularization post Encephalo-myo-synangiosis (EMS) treatment could be facilitated by bone marrow mesenchymal stem cells (MSCs) transplantation. Considering the advantages of biomaterials, we synthesized and modified a gelatin hydrogel for MSCs encapsulation. We then applied this hydrogel on the brain surface during EMS operation in rats with CCI, and evaluated its impact on cognitive performance and collateral circulation. Consequently, MSCs encapsulated in hydrogel significantly augment the therapeutic effects of EMS, potentially by promoting neovascularization, facilitating neuronal differentiation, and suppressing neuroinflammation. Furthermore, taking advantage of multi-RNA-sequencing and in silico analysis, we revealed that MSCs loaded in hydrogel regulate PDCD4 and CASP2 through the overexpression of miR-183-5p and miR-96-5p, thereby downregulating the expression of apoptosis-related proteins and inhibiting early apoptosis. In conclusion, a gelatin hydrogel to enhance the functionality of MSCs has been developed, and its combination with EMS treatment can improve the therapeutic effect in rats with CCI, suggesting its potential clinical benefit.
{"title":"Mesenchymal Stem Cell-Loaded Hydrogel Improves Surgical Treatment for Chronic Cerebral Ischemia.","authors":"Huayu Kang, Yimin Huang, Huan Peng, Xincheng Zhang, Yuan Liu, Yanchao Liu, Yuze Xia, Shengwen Liu, Yaqi Wu, Sheng Wang, Ting Lei, Huaqiu Zhang","doi":"10.1007/s12975-024-01274-5","DOIUrl":"https://doi.org/10.1007/s12975-024-01274-5","url":null,"abstract":"<p><p>Chronic cerebral ischemia (CCI) results in a prolonged insufficient blood supply to the brain tissue, leading to impaired neuronal function and subsequent impairment of cognitive and motor abilities. Our previous research showed that in mice with bilateral carotid artery stenosis, the collateral neovascularization post Encephalo-myo-synangiosis (EMS) treatment could be facilitated by bone marrow mesenchymal stem cells (MSCs) transplantation. Considering the advantages of biomaterials, we synthesized and modified a gelatin hydrogel for MSCs encapsulation. We then applied this hydrogel on the brain surface during EMS operation in rats with CCI, and evaluated its impact on cognitive performance and collateral circulation. Consequently, MSCs encapsulated in hydrogel significantly augment the therapeutic effects of EMS, potentially by promoting neovascularization, facilitating neuronal differentiation, and suppressing neuroinflammation. Furthermore, taking advantage of multi-RNA-sequencing and in silico analysis, we revealed that MSCs loaded in hydrogel regulate PDCD4 and CASP2 through the overexpression of miR-183-5p and miR-96-5p, thereby downregulating the expression of apoptosis-related proteins and inhibiting early apoptosis. In conclusion, a gelatin hydrogel to enhance the functionality of MSCs has been developed, and its combination with EMS treatment can improve the therapeutic effect in rats with CCI, suggesting its potential clinical benefit.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559853","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 : 2024-07-04DOI: 10.1007/s12975-024-01277-2
Francesco Arba, Simone Ferretti, Richard Leigh, Andreia Fara, Steven J Warach, Marie Luby, Kennedy R Lees, Jesse Dawson
We investigated relations between cerebral small vessel disease (cSVD) markers and evolution of the ischemic tissue from ischemic core to final infarct in people with acute ischemic stroke treated with intravenous thrombolysis. Data from the Stroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA) were used. Any pre-existing lacunar infarcts and white matter hyperintensities (WMH) were assessed on magnetic resonance (MR) before thrombolytic therapy. Acute ischemic core and final infarct volume were then assessed by two independent radiologists. The relationship among baseline markers of cSVD, acute ischemic core volume, final infarct volume, infarct growth (IG = final infarct - ischemic core), and infarct growth ratio (IGR = final infarct/ischemic core) was then assessed using linear and ordinal regression adjusted for age, sex, onset-to-treatment time, and stroke severity. We included 165 patients, mean (± SD) age 69.5 (± 15.7) years, 74 (45%) males, mean (± SD) ischemic core volume 25.48 (± 42.22) ml, final infarct volume 52.06 (± 72.88) ml, IG 26.58 (± 51.02) ml, IGR 8.23 (± 38.12). Seventy (42%) patients had large vessel occlusion, 20 (12%) acute small subcortical infarct. WMHs were present in 131 (79%) and lacunar infarcts in 61 (37%) patients. Final infarct volumes were 53.8 ml and 45.2 ml (WMHs/no WMHs), p = 0.139, and 24.6 ml and 25.9 ml (lacunar infarcts/no lacunar infarcts), p = 0.842. In linear and ordinal regression analyses, presence of lacunar infarcts was associated with smaller IG (β = - 0.17; p = 0.024; cOR = 0.52; 95%CI = 0.28-0.96, respectively) and WMHs were associated with smaller IGR (β = - 0.30; p = 0.004; cOR = 0.27; 95%CI = 0.11-0.69, respectively). In people with acute ischemic stroke treated with intravenous thrombolysis, cSVD features were associated with smaller growth of the acute ischemic area, suggesting less salvageable tissue at time of reperfusion therapy.
{"title":"Cerebral Small Vessel Disease and Infarct Growth in Acute Ischemic Stroke Treated with Intravenous Thrombolysis.","authors":"Francesco Arba, Simone Ferretti, Richard Leigh, Andreia Fara, Steven J Warach, Marie Luby, Kennedy R Lees, Jesse Dawson","doi":"10.1007/s12975-024-01277-2","DOIUrl":"https://doi.org/10.1007/s12975-024-01277-2","url":null,"abstract":"<p><p>We investigated relations between cerebral small vessel disease (cSVD) markers and evolution of the ischemic tissue from ischemic core to final infarct in people with acute ischemic stroke treated with intravenous thrombolysis. Data from the Stroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA) were used. Any pre-existing lacunar infarcts and white matter hyperintensities (WMH) were assessed on magnetic resonance (MR) before thrombolytic therapy. Acute ischemic core and final infarct volume were then assessed by two independent radiologists. The relationship among baseline markers of cSVD, acute ischemic core volume, final infarct volume, infarct growth (IG = final infarct - ischemic core), and infarct growth ratio (IGR = final infarct/ischemic core) was then assessed using linear and ordinal regression adjusted for age, sex, onset-to-treatment time, and stroke severity. We included 165 patients, mean (± SD) age 69.5 (± 15.7) years, 74 (45%) males, mean (± SD) ischemic core volume 25.48 (± 42.22) ml, final infarct volume 52.06 (± 72.88) ml, IG 26.58 (± 51.02) ml, IGR 8.23 (± 38.12). Seventy (42%) patients had large vessel occlusion, 20 (12%) acute small subcortical infarct. WMHs were present in 131 (79%) and lacunar infarcts in 61 (37%) patients. Final infarct volumes were 53.8 ml and 45.2 ml (WMHs/no WMHs), p = 0.139, and 24.6 ml and 25.9 ml (lacunar infarcts/no lacunar infarcts), p = 0.842. In linear and ordinal regression analyses, presence of lacunar infarcts was associated with smaller IG (β = - 0.17; p = 0.024; cOR = 0.52; 95%CI = 0.28-0.96, respectively) and WMHs were associated with smaller IGR (β = - 0.30; p = 0.004; cOR = 0.27; 95%CI = 0.11-0.69, respectively). In people with acute ischemic stroke treated with intravenous thrombolysis, cSVD features were associated with smaller growth of the acute ischemic area, suggesting less salvageable tissue at time of reperfusion therapy.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499100","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 : 2024-07-02DOI: 10.1007/s12975-024-01268-3
Sricharan S Veeturi, Arshaq Saleem, Diego J Ojeda, Elena Sagues, Sebastian Sanchez, Andres Gudino, Elad I Levy, David Hasan, Adnan H Siddiqui, Vincent M Tutino, Edgar A Samaniego
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.
{"title":"Radiomics-Based Predictive Nomogram for Assessing the Risk of Intracranial Aneurysms.","authors":"Sricharan S Veeturi, Arshaq Saleem, Diego J Ojeda, Elena Sagues, Sebastian Sanchez, Andres Gudino, Elad I Levy, David Hasan, Adnan H Siddiqui, Vincent M Tutino, Edgar A Samaniego","doi":"10.1007/s12975-024-01268-3","DOIUrl":"10.1007/s12975-024-01268-3","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141493536","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 : 2024-06-28DOI: 10.1007/s12975-024-01273-6
Tianjie Zhang, Fan Xia, Yingfeng Wan, Guohua Xi, Hua Ya, Richard F Keep
Blood components released by erythrolysis play an important role in secondary brain injury and posthemorrhagic hydrocephalus (PHH) after intraventricular hemorrhage (IVH). The current study examined the impact of N-acetylheparin (NAH), a complement inhibitor, on early erythrolysis, PHH and iron accumulation in aged rats following IVH. This study, on 18-months-old male Fischer 344 rats, was in 3 parts. First, rats had an intracerebroventricular injection of autologous blood (IVH) mixed with NAH or saline, or saline alone. After MRI at four hours, Western blot and immunohistochemistry examined complement activation and electron microscopy choroid plexus and periventricular damage. Second, rats had an IVH with NAH or vehicle, or saline. Rats underwent serial MRI at 4 h and 1 day to assess ventricular volume and erythrolysis. Immunohistochemistry and H&E staining examined secondary brain injury. Third, rats had an IVH with NAH or vehicle. Serial MRIs on day 1 and 28 assessed ventricular volume and iron accumulation. H&E staining and immunofluorescence evaluated choroid plexus phagocytes. Complement activation was found 4 h after IVH, and co-injection of NAH inhibited that activation. NAH administration attenuated erythrolysis, reduced ventricular volume, alleviated periventricular and choroid plexus injury at 4 h and 1 day after IVH. NAH decreased iron accumulation, the number of choroid plexus phagocytes, and attenuated hydrocephalus at 28 days after IVH. Inhibiting complement can reduce early erythrolysis, attenuates hydrocephalus and iron accumulation after IVH in aged animals.
红细胞溶解释放的血液成分在脑室内出血(IVH)后的继发性脑损伤和出血性脑积水(PHH)中起着重要作用。本研究探讨了补体抑制剂 N-乙酰肝素(NAH)对 IVH 后老龄大鼠早期红细胞溶解、出血性脑积水和铁积累的影响。这项研究以 18 个月大的雄性 Fischer 344 大鼠为对象,分为三个部分。首先,大鼠脑室内注射自体血液(IVH),混合 NAH 或生理盐水,或仅注射生理盐水。4小时后进行核磁共振成像,Western印迹和免疫组化检查补体激活情况,电镜检查脉络丛和脑室周围损伤情况。其次,用 NAH 或载体或生理盐水对大鼠进行 IVH。大鼠在4小时和1天后接受连续核磁共振成像,以评估心室容积和红细胞溶解。免疫组化和 H&E 染色检查继发性脑损伤。第三,用 NAH 或药物对大鼠进行 IVH 治疗。第1天和第28天的连续核磁共振成像可评估脑室容积和铁积累情况。H&E染色和免疫荧光评估了脉络丛吞噬细胞。IVH后4小时发现补体激活,同时注射NAH可抑制补体激活。在IVH后4小时和1天,注射NAH可减轻红细胞溶解,缩小心室容积,减轻脑室周围和脉络丛损伤。在 IVH 后 28 天,NAH 可减少铁的积累、脉络丛吞噬细胞的数量,并减轻脑积水。抑制补体可减少早期红细胞溶解,减轻老年动物IVH后的脑积水和铁积累。
{"title":"Complement Inhibition Reduces Early Erythrolysis, Attenuates Brain Injury, Hydrocephalus, and Iron Accumulation after Intraventricular Hemorrhage in Aged Rats.","authors":"Tianjie Zhang, Fan Xia, Yingfeng Wan, Guohua Xi, Hua Ya, Richard F Keep","doi":"10.1007/s12975-024-01273-6","DOIUrl":"https://doi.org/10.1007/s12975-024-01273-6","url":null,"abstract":"<p><p>Blood components released by erythrolysis play an important role in secondary brain injury and posthemorrhagic hydrocephalus (PHH) after intraventricular hemorrhage (IVH). The current study examined the impact of N-acetylheparin (NAH), a complement inhibitor, on early erythrolysis, PHH and iron accumulation in aged rats following IVH. This study, on 18-months-old male Fischer 344 rats, was in 3 parts. First, rats had an intracerebroventricular injection of autologous blood (IVH) mixed with NAH or saline, or saline alone. After MRI at four hours, Western blot and immunohistochemistry examined complement activation and electron microscopy choroid plexus and periventricular damage. Second, rats had an IVH with NAH or vehicle, or saline. Rats underwent serial MRI at 4 h and 1 day to assess ventricular volume and erythrolysis. Immunohistochemistry and H&E staining examined secondary brain injury. Third, rats had an IVH with NAH or vehicle. Serial MRIs on day 1 and 28 assessed ventricular volume and iron accumulation. H&E staining and immunofluorescence evaluated choroid plexus phagocytes. Complement activation was found 4 h after IVH, and co-injection of NAH inhibited that activation. NAH administration attenuated erythrolysis, reduced ventricular volume, alleviated periventricular and choroid plexus injury at 4 h and 1 day after IVH. NAH decreased iron accumulation, the number of choroid plexus phagocytes, and attenuated hydrocephalus at 28 days after IVH. Inhibiting complement can reduce early erythrolysis, attenuates hydrocephalus and iron accumulation after IVH in aged animals.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470963","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}