Biomarkers of cavernous angioma with symptomatic hemorrhage

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-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. 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.

Permissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma

“…Combined contributions of microbiome and plasma biomarkers. We had previously probed the relationship between circulating plasma inflammatory cytokines and angiogenic protein levels, and disease characteristics [17][18][19] . We now tested if the microbial taxa identified as biomarkers of CA ( Figs.…”

“…We have previously observed that CA patients have differences in circulating cytokines and other factors related to angiogenesis and inflammation [17][18][19] . We were able to detect direct associations between several CA distinctive bacterial species and plasma proteins implicated in disease activity (Fig.…”

“…Plasma biomarker measurements. Whole blood was collected in a subset of patients (n = 47) from the University of Chicago site [17][18][19] . Plasma were separated from cellular components of the blood, aliquoted, and stored at −80°C until analysis.…”

“…It has been increasingly recognized that CA disease course can be affected by inflammatory processes. Immune cells accumulate within CA lesions 15 , B cell depletion blunts lesion development and bleeding in mouse models 16 , and plasma inflammatory cytokines may be used to differentiate CA patients with distinctive disease characteristics [17][18][19] . Furthermore, a genome-wide association study of CA patients with the same common Hispanic mutation of KRIT1 showed that CA lesion number is associated with pro-inflammatory genotypes 13 , including polymorphisms in the lipopolysaccharide (LPS) receptors TLR4 and CD14 20 .…”

CCM signaling complex (CSC) is a master regulator governing homeostasis of progestins and their mediated signaling cascades

“…Biomarkers have been long sought for early diagnosis of strokes (104)(105)(106)(107), but only with a limited success in ischemic strokes (108)(109)(110). Efforts to define diagnostic biomarkers for hemorrhagic strokes are underway (111)(112)(113)(114). Inflammatory cytokines have been on target as risk factors or biomarkers for stroke (115).…”