Circulating biomarkers in familial cerebral cavernous malformation
eBioMedicine, 2023
Lazzaroni F., Meessen J., Sun Y., Lanfranconi S., Scola E., D'Alessandris Q., Tassi L., Carriero M., Castori M., Marino S., Blanda A., Nicolis E., Novelli D., Calabrese R., Agnelli N., Bottazzi B., Leone R., Mazzola S., Besana S., Catozzi C., Nezi L., Lampugnani M., Malinverno M., Grdseloff N., Rödel C., Rezai Jahromi B., Bolli N., Passamonti F., Magnusson P., Abdelilah-Seyfried S., Dejana E., Latini R.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Neurovascular Diseases | Patient Stratification | Plasma |  Olink Target 96 |
Abstract
Background
Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression.
Methods
Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n = 17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches.
Findings
Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM.
Interpretation
Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease.