# Molecular Pathways and Circulating Biomarkers in Cerebral Cavernous Malformations—A Systematic Review

## TL;DR

This review explores molecular pathways and biomarkers in cerebral cavernous malformations to improve diagnosis and treatment.

## Contribution

The paper systematically reviews molecular and circulating biomarkers in CCMs for potential diagnostic and prognostic use.

## Key findings

- Circulating biomarkers like CRP and interleukins reflect inflammation and endothelial dysfunction in CCMs.
- Imaging biomarkers such as QSM correlate with iron deposition and vascular leakage in CCM patients.
- Genetic mutations in the CCM gene cluster disrupt endothelial integrity and activate MEKK3/KLF2/4 pathways.

## Abstract

Cerebral Cavernous Malformations (CCMs) are low-flow vascular lesions located within the central nervous system, with a reported prevalence in the general population of 0.16–0.5%. Patients with CCMs may remain asymptomatic or present new onset symptoms such as seizures or focal neurological deficits often related to the occurrence of intracerebral hemorrhage. CCM may appear sporadic or as part of familial forms linked to mutations in the CCM-gene cluster, affecting endothelial cell integrity and triggering molecular cascades, including the MEKK3/KLF2/4 signaling pathway. Recent studies have highlighted the roles of inflammatory, angiogenic, and coagulation pathways alongside the emerging evidence of a gut–brain axis influencing microbiome-driven TLR4 signaling. This systematic review aims to describe molecular biomarkers associated with CCM pathophysiology, emphasizing their potential use as diagnostic and prognostic tools. Circulating plasma biomarkers such as CRP, vitamin D, and interleukins may reflect ongoing inflammatory and endothelial processes, while some imaging biomarkers like Quantitative Susceptibility Mapping (QSM) have shown a correlation with iron deposition and vascular leakage. Leveraging both circulating and imaging biomarkers may improve the therapeutic decision-making process. Further studies are encouraged to validate these findings and to facilitate the development of personalized, evidence-based strategies for the management of CCM.