BACKGROUNDCerebral cavernous angiomas (CAs) with a symptomatic
hemorrhage (CASH) have a high risk of recurrent
hemorrhage and serious morbidity.METHODSEighteen 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.RESULTSThe 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-1β, 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.CONCLUSIONShared 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.FUNDINGNIH, William and Judith Davis Fund in Neurovascular Surgery Research, Be Brave for Life Foundation, Safadi Translational Fellowship, Pritzker School of Medicine, and Sigrid Jusélius Foundation.