Non-invasive Urinary Biomarkers in Moyamoya Disease.

Julie Sesen,Darren B Orbach,David Zurakowski,Jessica Driscoll,Alexander Moses-Gardner,Edward R Smith

doi:10.3389/fneur.2021.661952

Julie Sesen, Darren B Orbach + Show 4 more

Open Access

https://doi.org/10.3389/fneur.2021.661952

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Abstract

Introduction: A major difficulty in treating moyamoya disease is the lack of effective methods to detect novel or progressive disease prior to the onset of disabling stroke. More importantly, a tool to better stratify operative candidates and quantify response to therapy could substantively complement existing methods. Here, we present proof-of-principle data supporting the use of urinary biomarkers as diagnostic adjuncts in pediatric moyamoya patients.Methods: Urine and cerebrospinal fluid specimens were collected from pediatric patients with moyamoya disease and a cohort of age and sex-matched control patients. Clinical and radiographic data were paired with measurements of a previously validated panel of angiogenic proteins quantified by ELISA. Results were compared to age and sex-matched controls and subjected to statistical analyses.Results: Evaluation of a specific panel of urinary and cerebrospinal fluid biomarkers by ELISA demonstrated significant elevations of angiogenic proteins in samples from moyamoya patients compared to matched controls. ROC curves for individual urinary biomarkers, including MMP-2, MMP-9, MMP-9/NGAL, and VEGF, showed excellent discrimination. The optimal urinary biomarker was MMP-2, providing a sensitivity of 88%, specificity of 100%, and overall accuracy of 91%. Biomarker levels changed in response to therapy and correlated with radiographic evidence of revascularization.Conclusions: We report, for the first time, identification of a panel of urinary biomarkers that predicts the presence of moyamoya disease. These biomarkers correlate with presence of disease and can be tracked from the central nervous system to urine. These data support the hypothesis that urinary proteins are useful predictors of the presence of moyamoya disease and may provide a basis for a novel, non-invasive method to identify new disease and monitor known patients following treatment.

Highlights

A major difficulty in treating moyamoya disease is the lack of effective methods to detect novel or progressive disease prior to the onset of disabling stroke
We present initial proof-of-principle data demonstrating that a novel, non-invasive panel of urinary biomarkers can identify the presence of moyamoya disease and that the biomarkers track from the central nervous system in cerebrospinal fluid (CSF) to urine
Current data from our lab and others supports the hypothesis of angiogenesis and extracellular matrix (ECM) remodeling as essential processes in many central nervous system (CNS) disorders, including moyamoya disease, involving vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), a multigene family of degradative enzymes and neutrophil gelatinase associated lipocalin (NGAL), an enzyme that binds with MMP-9 to protect it from degradation—and elevated levels of MMPs and VEGF have been reported in the serum of moyamoya disease patients [2, 4, 5, 22,23,24,25,26,27,28,29,30]

Summary

Introduction

A major difficulty in treating moyamoya disease is the lack of effective methods to detect novel or progressive disease prior to the onset of disabling stroke. We show that levels of these biomarkers vary in response to therapeutic intervention and correlate with radiographic changes post-surgery To our knowledge, this is the first report of this application of urinary biomarkers in this population and we hope that these data provide a foundation for expanded study of this approach. Recent studies from our laboratory, confirmed by others, support the utility of urinary levels of growth factors and MMPs as markers of disease, including our work first describing the use of this technique in the CNS [4, 5, 11, 21, 26, 37, 40,41,42,43,44,45,46,47,48]. We anticipate that molecules that regulate mechanisms of vascular morphogenesis and arteriogenesis (including, but not limited to, axon guidance factors, for example), may be useful as future areas of investigation to enhance the functionality of biomarker profiling in moyamoya disease

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