A1 Refereed original research article in a scientific journal
Biomarkers of cavernous angioma with symptomatic hemorrhage
Authors: Lyne SB, Girard R, Koskimaki J, Zeineddine HA, Zhang DD, Cao Y, Li Y, Stadnik A, Moore T, Lightle R, Shi C, Shenkar R, Carrion-Penagos J, Polster SP, Romanos S, Akers A, Lopez-Ramirez M, Whitehead KJ, Kahn ML, Ginsberg MH, Marchuk DA, Awad IA
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Publication year: 2019
Journal name in source: JCI INSIGHT
Journal acronym: JCI INSIGHT
Article number: ARTN e128577
Volume: 4
Number of pages: 16
DOI: https://doi.org/10.1172/jci.insight.128577
Abstract
BACKGROUND. Cerebral cavernous angiomas (CAs) with a symptomatic hemorrhage (CASH) have a high risk of recurrent hemorrhage and serious morbidity.METHODS. Eighteen plasma molecules with mechanistic roles in CA pathobiology were investigated in 114 patients and 12 healthy subjects. The diagnostic biomarker of a CASH in the prior year was derived as that minimizing the Akaike information criterion and validated using machine learning, and was compared with the prognostic CASH biomarker predicting bleeding in the subsequent year. Biomarkers were longitudinally followed in a subset of cases. The biomarkers were queried in the lesional neurovascular unit (NVU) transcriptome and in plasma miRNAs from CASH and non-CASH patients.RESULTS. The diagnostic CASH biomarker included a weighted combination of soluble CD14 (sCD14), VEGF, C-reactive protein (CRP), and IL-10 distinguishing CASH patients with 76% sensitivity and 80% specificity (P = 0.0003). The prognostic CASH biomarker (sCD14, VEGF, IL-1 beta, and sROBO-4) was confirmed to predict a bleed in the subsequent year with 83% sensitivity and 93% specificity (P = 0.001). Genes associated with diagnostic and prognostic CASH biomarkers were differentially expressed in CASH lesional NVUs. Thirteen plasma miRNAs were differentially expressed between CASH and non-CASH patients.CONCLUSION. Shared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in CA are mechanistically linked to lesional transcriptome and miRNA. The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice.
BACKGROUND. Cerebral cavernous angiomas (CAs) with a symptomatic hemorrhage (CASH) have a high risk of recurrent hemorrhage and serious morbidity.METHODS. Eighteen plasma molecules with mechanistic roles in CA pathobiology were investigated in 114 patients and 12 healthy subjects. The diagnostic biomarker of a CASH in the prior year was derived as that minimizing the Akaike information criterion and validated using machine learning, and was compared with the prognostic CASH biomarker predicting bleeding in the subsequent year. Biomarkers were longitudinally followed in a subset of cases. The biomarkers were queried in the lesional neurovascular unit (NVU) transcriptome and in plasma miRNAs from CASH and non-CASH patients.RESULTS. The diagnostic CASH biomarker included a weighted combination of soluble CD14 (sCD14), VEGF, C-reactive protein (CRP), and IL-10 distinguishing CASH patients with 76% sensitivity and 80% specificity (P = 0.0003). The prognostic CASH biomarker (sCD14, VEGF, IL-1 beta, and sROBO-4) was confirmed to predict a bleed in the subsequent year with 83% sensitivity and 93% specificity (P = 0.001). Genes associated with diagnostic and prognostic CASH biomarkers were differentially expressed in CASH lesional NVUs. Thirteen plasma miRNAs were differentially expressed between CASH and non-CASH patients.CONCLUSION. Shared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in CA are mechanistically linked to lesional transcriptome and miRNA. The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice.
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