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

Overview

Journal Neurosurgery

Specialty Neurosurgery

Date 2021 Jan 20

PMID 33469662

Citations 15

Authors

Romuald Girard

Yan Li

Agnieszka Stadnik

Robert Shenkar

Nicholas Hobson

Sharbel Romanos

Abhinav Srinath

Thomas Moore

Rhonda Lightle

Abdallah Shkoukani

Amy Akers

Timothy Carroll

Gregory A Christoforidis

James I Koenig

Cornelia Lee

Kristina Piedad

Steven M Greenberg

Helen Kim

Kelly D Flemming

Yuan Ji

Issam A Awad

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Circulating molecules reflect imaging biomarkers of hemorrhage in cerebral cavernous malformations.

Hage S, Bi D, Kinkade S, Vera Cruz D, Srinath A, Jhaveri A J Cereb Blood Flow Metab. 2025; :271678X251314366.

PMID: 39829356 PMC: 11748132. DOI: 10.1177/0271678X251314366.

Recent novelties in research and management of cerebrospinal cavernous malformations.

Rauschenbach L, Dammann P, Sure U Acta Neurochir (Wien). 2024; 166(1):489.

PMID: 39613863 PMC: 11607096. DOI: 10.1007/s00701-024-06378-3.

Plasma biomarkers in patients with familial cavernous malformation and their first-degree relatives.

Li C, Huang S, Li Q, Zhuo L, Kang Y, Liu P Res Sq. 2024; .

PMID: 39011103 PMC: 11247933. DOI: 10.21203/rs.3.rs-4545797/v1.

Infratentorial Cerebral Cavernous Malformation May be a Risk Factor for Symptomatic Bleeding and Precocity of Symptoms: A Multicenter, Propensity Score Matched, Case-Control Study.

Galvao G, Filho R, Cunha A, Guimaraes Soares A, Filho M, de Souza J Curr Neurovasc Res. 2024; 21(2):177-183.

PMID: 38482623 DOI: 10.2174/0115672026304601240307051654.

Transcriptomic signatures of individual cell types in cerebral cavernous malformation.

Li Y, Girard R, Srinath A, Vera Cruz D, Ciszewski C, Chen C Cell Commun Signal. 2024; 22(1):23.

PMID: 38195510 PMC: 10775676. DOI: 10.1186/s12964-023-01301-2.

References

Koskimaki J, Girard R, Li Y, Saadat L, Zeineddine H, Lightle R . Comprehensive transcriptome analysis of cerebral cavernous malformation across multiple species and genotypes. JCI Insight. 2019; 4(3). PMC: 6413775. DOI: 10.1172/jci.insight.126167. View

Elahy M, Jackaman C, Mamo J, Lam V, Dhaliwal S, Giles C . Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment. Immun Ageing. 2015; 12:2. PMC: 4362825. DOI: 10.1186/s12979-015-0029-9. View

Hart B, Taheri S, Rosenberg G, Morrison L . Dynamic contrast-enhanced MRI evaluation of cerebral cavernous malformations. Transl Stroke Res. 2013; 4(5):500-6. PMC: 3939060. DOI: 10.1007/s12975-013-0285-y. View

Avraham-Davidi I, Ely Y, Pham V, Castranova D, Grunspan M, Malkinson G . ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1. Nat Med. 2012; 18(6):967-73. PMC: 3959651. DOI: 10.1038/nm.2759. View

Girard R, Khanna O, Shenkar R, Zhang L, Wu M, Jesselson M . Peripheral plasma vitamin D and non-HDL cholesterol reflect the severity of cerebral cavernous malformation disease. Biomark Med. 2016; 10(3):255-64. PMC: 4926533. DOI: 10.2217/bmm.15.118. View

Noshiro S, Mikami T, Kataoka-Sasaki Y, Sasaki M, Ohnishi H, Ohtaki S . Co-expression of tissue factor and IL-6 in immature endothelial cells of cerebral cavernous malformations. J Clin Neurosci. 2017; 37:83-90. DOI: 10.1016/j.jocn.2016.12.023. View

Ng C, Fong L, Sulaiman M, Mohd Moklas M, Yong Y, Hakim M . Interferon-Gamma Increases Endothelial Permeability by Causing Activation of p38 MAP Kinase and Actin Cytoskeleton Alteration. J Interferon Cytokine Res. 2015; 35(7):513-22. DOI: 10.1089/jir.2014.0188. View

Robinson Jr J, Awad I, Masaryk T, Estes M . Pathological heterogeneity of angiographically occult vascular malformations of the brain. Neurosurgery. 1993; 33(4):547-54; discussion 554-5. DOI: 10.1227/00006123-199310000-00001. View

Huang J, Song J, Qu M, Wang Y, An Q, Song Y . MicroRNA-137 and microRNA-195* inhibit vasculogenesis in brain arteriovenous malformations. Ann Neurol. 2017; 82(3):371-384. DOI: 10.1002/ana.25015. View

10.

Zhou Z, Tang A, Wong W, Bamezai S, Goddard L, Shenkar R . Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 2016; 532(7597):122-6. PMC: 4864035. DOI: 10.1038/nature17178. View

11.

Wustehube J, Bartol A, Liebler S, Brutsch R, Zhu Y, Felbor U . Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci U S A. 2010; 107(28):12640-5. PMC: 2906569. DOI: 10.1073/pnas.1000132107. View

12.

Bicer A, Guclu B, Ozkan A, Kurtkaya O, Yalcinkaya Koc D, Pamir M . Expressions of angiogenesis associated matrix metalloproteinases and extracellular matrix proteins in cerebral vascular malformations. J Clin Neurosci. 2009; 17(2):232-6. DOI: 10.1016/j.jocn.2009.06.008. View

13.

Gao Y, Zhao Z, Yang L, Liu X, Xing X, Zhang H . Arsenic exposure assists ccm3 genetic polymorphism in elevating blood pressure. Oncotarget. 2018; 9(4):4915-4923. PMC: 5797022. DOI: 10.18632/oncotarget.23518. View

14.

Hsuchou H, Kastin A, Mishra P, Pan W . C-reactive protein increases BBB permeability: implications for obesity and neuroinflammation. Cell Physiol Biochem. 2012; 30(5):1109-19. PMC: 4099000. DOI: 10.1159/000343302. View

15.

Horne M, Flemming K, Su I, Stapf C, Jeon J, Li D . Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol. 2015; 15(2):166-173. PMC: 4710581. DOI: 10.1016/S1474-4422(15)00303-8. View

16.

Shenkar R, Shi C, Austin C, Moore T, Lightle R, Cao Y . RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations. Stroke. 2016; 48(1):187-194. PMC: 5183488. DOI: 10.1161/STROKEAHA.116.015013. View

17.

Mikati A, Khanna O, Zhang L, Girard R, Shenkar R, Guo X . Vascular permeability in cerebral cavernous malformations. J Cereb Blood Flow Metab. 2015; 35(10):1632-9. PMC: 4640319. DOI: 10.1038/jcbfm.2015.98. View

18.

Bake S, Friedman J, Sohrabji F . Reproductive age-related changes in the blood brain barrier: expression of IgG and tight junction proteins. Microvasc Res. 2009; 78(3):413-24. PMC: 2784250. DOI: 10.1016/j.mvr.2009.06.009. View

19.

Salman R, Hall J, Horne M, Moultrie F, Josephson C, Bhattacharya J . Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study. Lancet Neurol. 2012; 11(3):217-24. PMC: 3282211. DOI: 10.1016/S1474-4422(12)70004-2. View

20.

Tang A, Choi J, Kotzin J, Yang Y, Hong C, Hobson N . Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017; 545(7654):305-310. PMC: 5757866. DOI: 10.1038/nature22075. View