Circulating biomarkers in familial cerebral cavernous malformation

Francesca Lazzaroni, Jennifer M.T.A. Meessen, Ying Sun, Silvia Lanfranconi, Elisa Scola, Quintino Giorgio D'Alessandris, Laura Tassi, Maria Rita Carriero, Marco Castori, Silvia Marino, Salvatore Marino, Adriana Blanda, Enrico B. Nicolis, Deborah Novelli, Roberta Calabrese, Nicolò M. Agnelli, Barbara Bottazzi, Roberto Leone, Selene Mazzola, Silvia BesanaCarlotta Catozzi, Luigi Nezi, Maria G. Lampugnani, Matteo Malinverno, Nastasja Grdseloff, Claudia J. Rödel, Behnam Rezai Jahromi, Niccolò Bolli, Francesco Passamonti, Peetra U. Magnusson, Salim Abdelilah-Seyfried, Elisabetta Dejana, Roberto Latini

Risultato della ricerca: Contributo in rivistaArticolo in rivista

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. Funding: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council.
Lingua originaleEnglish
pagine (da-a)N/A-N/A
RivistaEBioMedicine
Volume99
DOI
Stato di pubblicazionePubblicato - 2024

Keywords

  • Biomarkers
  • Vascular biology
  • Proteomics
  • Familial cerebral cavernous malformation

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