A Roadmap for Developing Plasma Diagnostic and Prognostic Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH)

Neurosurgery. 2021 Feb 16;88(3):686-697. doi: 10.1093/neuros/nyaa478.


Background: Cerebral cavernous angioma (CA) is a capillary microangiopathy predisposing more than a million Americans to premature risk of brain hemorrhage. CA with recent symptomatic hemorrhage (SH), most likely to re-bleed with serious clinical sequelae, is the primary focus of therapeutic development. Signaling aberrations in CA include proliferative dysangiogenesis, blood-brain barrier hyperpermeability, inflammatory/immune processes, and anticoagulant vascular domain. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and iron deposition on magnetic resonance imaging are biomarkers that have been correlated with CA hemorrhage.

Objective: To optimize these biomarkers to accurately diagnose cavernous angioma with symptomatic hemorrhage (CASH), prognosticate the risk of future SH, and monitor cases after a bleed and in response to therapy.

Methods: Additional candidate biomarkers, emerging from ongoing mechanistic and differential transcriptome studies, would further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Integrative combinations of levels of plasma proteins and characteristic micro-ribonucleic acids may further strengthen biomarker associations. We will deploy advanced statistical and machine learning approaches for the integration of novel candidate biomarkers, rejecting noncorrelated candidates, and determining the best clustering and weighing of combined biomarker contributions.

Expected outcomes: With the expertise of leading CA researchers, this project anticipates the development of future blood tests for the diagnosis and prediction of CASH to clinically advance towards precision medicine.

Discussion: The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use, with an approach applicable to other neurological diseases with similar pathobiologic features.

Trial registration: ClinicalTrials.gov NCT04467489.

Keywords: Biomarkers; Cavernous angioma; Cavernous angioma with symptomatic hemorrhage (CASH); Cerebral cavernous malformation (CCM); Machine learning; Plasma; QSM; Symptomatic hemorrhage.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers / blood
  • Brain Neoplasms / blood*
  • Brain Neoplasms / diagnostic imaging
  • Capillary Permeability / physiology
  • Cerebral Hemorrhage / blood*
  • Cerebral Hemorrhage / diagnostic imaging
  • Female
  • Hemangioma, Cavernous / blood*
  • Hemangioma, Cavernous / diagnostic imaging
  • Hemangioma, Cavernous, Central Nervous System / blood*
  • Hemangioma, Cavernous, Central Nervous System / diagnostic imaging
  • Humans
  • Inflammation Mediators / blood
  • Longitudinal Studies
  • Machine Learning
  • Magnetic Resonance Imaging / methods
  • Male
  • Prognosis
  • Transcriptome / physiology


  • Biomarkers
  • Inflammation Mediators

Associated data

  • ClinicalTrials.gov/NCT04467489