Circulating Blood Prognostic Biomarker Signatures for Hemorrhagic Cerebral Cavernous Malformations (CCMs).

Cerebral cavernous malformations (CCMs) are a neurological disorder characterized by enlarged intracranial capillaries in the brain, increasing the susceptibility to hemorrhagic strokes, a major cause of death and disability worldwide. The limited treatment options for CCMs underscore the importance of prognostic biomarkers to predict the likelihood of hemorrhagic events, aiding in treatment decisions and identifying potential pharmacological targets. This study aimed to identify blood biomarkers capable of diagnosing and predicting the risk of hemorrhage in CCM1 patients, establishing an initial set of circulating biomarker signatures. By analyzing proteomic profiles from both human and mouse CCM models and conducting pathway enrichment analyses, we compared groups to identify potential blood biomarkers with statistical significance. Specific candidate biomarkers primarily associated with metabolism and blood clotting pathways were identified. These biomarkers show promise as prognostic indicators for CCM1 deficiency and the risk of hemorrhagic stroke, strongly correlating with the likelihood of hemorrhagic cerebral cavernous malformations (CCMs). This lays the groundwork for further investigation into blood biomarkers to assess the risk of hemorrhagic CCMs.

Calm the raging hormone - A new therapeutic strategy involving progesterone-signaling for hemorrhagic CCMs.

Cerebral cavernous malformations (CCMs), one of the most common vascular malformations, are characterized by abnormally dilated intracranial microvascular capillaries resulting in increased susceptibility to hemorrhagic stroke. As an autosomal dominant disorder with incomplete penetrance, the majority of CCMs gene mutation carriers are largely asymptomatic but when symptoms occur, the disease has typically reached the stage of focal hemorrhage with irreversible brain damage, while the molecular "trigger" initiating the occurrence of CCM pathology remain elusive. Currently, the invasive neurosurgery removal of CCM lesions is the only option for the treatment, despite the recurrence of the worse symptoms frequently occurring after surgery. Therefore, there is a grave need for identification of molecular targets for therapeutic treatment and biomarkers as risk predictors for hemorrhagic stroke prevention. Based on reported various perturbed angiogenic signaling cascades mediated by the CCM signaling complex (CSC), there have been many proposed candidate drugs, targeting potentially angiogenic-relevant signaling pathways dysregulated by loss of function of one of the CCM proteins, which might not be enough to correct the pathological phenotype, hemorrhagic CCMs. In this review, we describe a new paradigm for the mechanism of hemorrhagic CCM lesions, and propose a new concept for the assurance of the CSC-stability to prevent the devastating outcome of hemorrhagic CCMs.