Identification of risk factors and biomarkers of diagnostic and prognostic value associated with clinical progression and severity of cerebral cavernous malformations

Cerebral Cavernous Malformation (CCM) is a major cerebrovascular disease with a prevalence of 0.3–0.5% in the general population and highly variable clinical expressivity. It may cause various symptoms at any age, including recurrent headaches, neurological deficits, seizures, and intracerebral hemorrhage, and has been associated with loss-of-function mutations in three CCM genes, CCM1 (KRIT1), CCM2 and CCM3. However, growing evidence in animal models demonstrates that loss of CCM genes is not sufficient to cause CCM disease, suggesting the contribution of additional triggers occurring locally in the neurovascular microenvironment, including stress factors. Indeed, we found that both cellular and animal models of CCM disease show an enhanced sensitivity to oxidative stress and inflammatory insults due to defects in mechanisms involved in cellular defense against these stressful conditions, including antioxidant responses and autophagy. Furthermore, we provide novel insights into the identification of risk factors and biomarkers associated with CCM disease progression and severity, including the accumulation of major glycation and oxidation products, which may serve as early objective predictors of disease outcome and provide better options for disease prevention and treatment.