Potential Biomarkers of Acute Ischemic Stroke Etiology Revealed by Mass Spectrometry-Based Proteomic Characterization of Formalin-Fixed Paraffin-Embedded Blood Clots

Rossi, Rosanna; Mereuta, Oana Madalina; Silva, Mariel Barbachan e; Gil, Sara M.; Douglas, Andrew; Pandit, Abhay; Gilvarry, Michael; McCarthy, Ray; O’Connell, Shane; Tierney, Ciara; Psychogios, Klearchos; Tsivgoulis, Georgios; Szikora, István; Tatlısumak, Turgut; Rentzos, Alexandros; Thornton, John; Broin, Pilib Ó; Doyle, Karen M.

doi:10.3389/fneur.2022.854846

Cited by 17 publications

(12 citation statements)

References 91 publications

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“…Proteomics analysis by Rao et al further found that APOE levels were negatively related to erythrocyte sedimentation rate levels, suggesting greater inflammation associated with APOE expression 25. Protein levels of glycoprotein IX platelet (GP9), which was differentially expressed across all comparisons in our study (higher in CE), were also found to be greater in CE cases by a proteomics characterization by Rossi et al 28. Similarly, integrin subunit β3 (ITGB3), which was also differentially expressed across all comparisons (greater in CE) in our study was also found to higher in CE by Suissa et al 29 in their proteomic study.…”

Section: Discussionsupporting

confidence: 73%

Gene expression profiles of ischemic stroke clots retrieved by mechanical thrombectomy are associated with disease etiology

Tutino

Fricano

Chien

et al. 2022

J NeuroIntervent Surg

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BackgroundDetermining stroke etiology is crucial for secondary prevention, but intensive workups fail to classify ~30% of strokes that are cryptogenic.ObjectiveTo examine the hypothesis that the transcriptomic profiles of clots retrieved during mechanical thrombectomy are unique to strokes of different subtypes.MethodsWe isolated RNA from the clots of 73 patients undergoing mechanical thrombectomy. Samples of sufficient quality were subjected to 100-cycle, paired-end RNAseq, and transcriptomes with less than 10 million unique reads were excluded from analysis. Significant differentially expressed genes (DEGs) between subtypes (defined by the Trial of Org 10 172 in Acute Stroke Treatment) were identified by expression analysis in edgeR. Gene ontology enrichment analysis was used to study the biologic differences between stroke etiologies.ResultsIn all, 38 clot transcriptomes were analyzed; 6 from large artery atherosclerosis (LAA), 21 from cardioembolism (CE), 5 from strokes of other determined origin, and 6 from cryptogenic strokes. Among all comparisons, there were 816 unique DEGs, 174 of which were shared by at least two comparisons, and 20 of which were shared by all three. Gene ontology analysis showed that CE clots reflected high levels of inflammation, LAA clots had greater oxidoreduction and T-cell processes, and clots of other determined origin were enriched for aberrant platelet and hemoglobin-related processes. Principal component analysis indicated separation between these subtypes and showed cryptogenic samples clustered among several different groups.ConclusionsExpression profiles of stroke clots were identified between stroke etiologies and reflected different biologic responses. Cryptogenic thrombi may be related to multiple etiologies.

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Section: Discussionsupporting

confidence: 73%

Gene expression profiles of ischemic stroke clots retrieved by mechanical thrombectomy are associated with disease etiology

Tutino

Fricano

Chien

et al. 2022

J NeuroIntervent Surg

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“…Metabolomics combined with machine learning techniques used in this study may be a promising new approach for stroke etiology. Proteomics is also a promising technique to assess stroke etiology 13 14. Rossi et al found that proteins in the ubiquitin–proteasome pathway, blood coagulation or plasminogen activating cascade, cytoskeletal remodeling of platelets, platelet adhesion, or blood coagulation were different between the two types of thrombi 14.…”

Section: Discussionmentioning

confidence: 99%

“…Proteomics is also a promising technique to assess stroke etiology 13 14. Rossi et al found that proteins in the ubiquitin–proteasome pathway, blood coagulation or plasminogen activating cascade, cytoskeletal remodeling of platelets, platelet adhesion, or blood coagulation were different between the two types of thrombi 14. Proteomics indicates events that are occurring, whereas metabolomics closest to the phenotype of biological system reflect events that have occurred.…”

Section: Discussionmentioning

confidence: 99%

Thrombosis origin identification of cardioembolism and large artery atherosclerosis by distinct metabolites

Bai

Hao

et al. 2022

J NeuroIntervent Surg

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BackgroundThe diagnosis of cerebral thrombosis origin is challenging and remains unclear. This study aims to identify thrombosis due to cardioembolism (CE) and large artery atherosclerosis (LAA) from a new perspective of distinct metabolites.MethodsDistinct metabolites between 26 CE and 22 LAA origin thrombi, which were extracted after successful mechanical thrombectomy in patients with acute ischemic stroke in the anterior circulation, were analyzed with a ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) system. Enriched metabolic pathways related to the metabolites were identified. Least absolute shrinkage selection operator regression analyses and a filtering method were used to select potential predictors. Furthermore, four machine learning classifiers, including decision tree, logistic regression, random forest (RF), and k means unsupervised classification model, were used to evaluate the predictive ability of the selected metabolites.ResultsUPLC-QTOF-MS analysis revealed that levels of 88 and 55 metabolites were elevated in LAA and CE thrombi, respectively. Kyoto Encyclopedia of Genes and Genomes analysis revealed a significant difference between the pathways enriched in the two types of thrombi. Six metabolites (diglyceride (DG, 18:3/24:0), DG (22:0/24:0), phytosphingosine, galabiosylceramide (18:1/24:1), triglyceride (15:0/16:1/o–18:0), and glucosylceramide (18:1/24:0)) were finally selected to build a predictive model. The predictive RF model was confirmed to be the best, with a satisfactory stability and prediction capacity (area under the curve=0.889).ConclusionsSix metabolites as potential predictors for distinguishing between cerebral thrombi of CE and LAA origin were identified. The results are useful for understanding the pathogenesis and for secondary stroke prevention.

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“…Rossi et al used mass spectrometry to compare 16 CE vs. 15 LAA thrombi in AIS patients [ 35 ]. They found 14 DEPs among 1581 identified proteins.…”

Section: Multiomic Studiesmentioning

confidence: 99%

Advancing Stroke Research on Cerebral Thrombi with Omic Technologies

Costamagna

Bonato

Corti

et al. 2023

IJMS

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Cerebrovascular diseases represent a leading cause of disability, morbidity, and death worldwide. In the last decade, the advances in endovascular procedures have not only improved acute ischemic stroke care but also conceded a thorough analysis of patients’ thrombi. Although early anatomopathological and immunohistochemical analyses have provided valuable insights into thrombus composition and its correlation with radiological features, response to reperfusion therapies, and stroke etiology, these results have been inconclusive so far. Recent studies applied single- or multi-omic approaches—such as proteomics, metabolomics, transcriptomics, or a combination of these—to investigate clot composition and stroke mechanisms, showing high predictive power. Particularly, one pilot studies showed that combined deep phenotyping of stroke thrombi may be superior to classic clinical predictors in defining stroke mechanisms. Small sample sizes, varying methodologies, and lack of adjustments for potential confounders still represent roadblocks to generalizing these findings. However, these techniques hold the potential to better investigate stroke-related thrombogenesis and select secondary prevention strategies, and to prompt the discovery of novel biomarkers and therapeutic targets. In this review, we summarize the most recent findings, overview current strengths and limitations, and present future perspectives in the field.

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Potential Biomarkers of Acute Ischemic Stroke Etiology Revealed by Mass Spectrometry-Based Proteomic Characterization of Formalin-Fixed Paraffin-Embedded Blood Clots

Cited by 17 publications

References 91 publications

Gene expression profiles of ischemic stroke clots retrieved by mechanical thrombectomy are associated with disease etiology

Gene expression profiles of ischemic stroke clots retrieved by mechanical thrombectomy are associated with disease etiology

Thrombosis origin identification of cardioembolism and large artery atherosclerosis by distinct metabolites

Advancing Stroke Research on Cerebral Thrombi with Omic Technologies

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