GSE130174
Biomarkers of Cavernous Angioma with Symptomatic Hemorrhage (CASH) [RNA-seq]
Background: Cerebral cavernous angiomas with a symptomatic hemorrhage (CASH) have a high-risk of recurrent hemorrhage and serious morbidity. Methods: Eighteen plasma molecules with postulated mechanistic roles in cavernous angioma (CA) pathobiology were investigated in 114 patients and 12 healthy subjects. The diagnostic biomarker of a CASH in the prior year was derived as minimizing the Akaike Information Criterion (AIC) and validated using machine-learning, and then compared to the prognostic CASH biomarker predicting bleeding in the subsequent year. Both biomarkers were longitudinally followed in a subset of cases. The biomarkers were queried in the transcriptome of human lesional micro-dissected neurovascular units (NVUs) and in relation to plasma miRNAs from CASH and non-CASH patients. Results: The diagnostic CASH biomarker included a weighted combination of four molecules (sCD14, VEGF, CRP, and IL-10) distinguishing CASH patients with 76% sensitivity and 80% specificity (p=0.0003). The prognostic CASH biomarker included two of these molecules (sCD14 and VEGF) and two others (IL-1ß 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 the diagnostic and prognostic CASH biomarkers were differentially expressed in CASH lesional NVUs. Thirteen miRNAs were also differentially expressed in the plasma of CASH patients compared to non-CASH. Conclusion: There are shared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in CA, and are mechanistically linked to the lesional transcriptome and miRNA regulation. The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice. Overall design: 13 total RNA samples, including 10 laser microdissected  neurovascular units (NVUs) from 10 human cerebral cavernous malformations and from 3 human brain autopsy controls