Plasma metabolomic biomarker panel to distinguish patients with amyotrophic lateral sclerosis from disease mimics

Abstract

Our objective was to identify plasma biomarkers of ALS that can aid in distinguishing patients with ALS from those with disease mimics. In this multi-center study, plasma samples were collected from 172 patients recently diagnosed with ALS, 50 healthy controls, and 73 neurological disease mimics. Samples were analyzed using metabolomics. Using all identified biochemicals detected in > 50% of all samples in the metabolomics analysis, samples were classified as ALS or mimic with 65% sensitivity and 81% specificity by LASSO analysis (AUC of 0.76). A subset panel of 32 candidate biomarkers classified these diagnosis groups with a specificity of 90%/sensitivity 58% (AUC of 0.81). Creatinine was lower in subjects with lower revised ALS Functional Rating Scale (ALSFRS-R) scores. In conclusion, ALS can be distinguished from neurological disease mimics by global biochemical profiling of plasma samples. Our analysis identified ALS versus mimics with relatively high sensitivity. We identified a subset of 32 metabolites that identify patients with ALS with a high specificity. Interestingly, lower creatinine correlates significantly with a lower ALSFRS-R score. Finally, molecules previously reported to be important in disease pathophysiology, such as urate, are included in our metabolite panel.

Key words::

• Biomarker
• metabolomics
• diagnostics

Acknowledgements

The project was supported, in part, by support from the following: ALS Association; National Institutes of Health; and National Institutes of Health (NIH)/National Center for Research Resources/General Clinical Research Centers Program. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, or ALS Association. The authors thank the Metabolon platform team and chemical spectra analysts for contributing to data acquisition. Support for MB was received from the North Carolina Biotechnology Center Industrial Fellowship Program.

The authors would also like to acknowledge project input and support from the Northeast ALS Consortium (NEALS), the NEALS Biofluid Repository Committee and the committee Co-Chairs, Robert Bowser and Terry Heiman-Patterson. The authors thank Lucie Bruijn and ALSA for guidance, the NEALS Consortium for sample collection, Daniela Grasso for overseeing protocol development, informed consent design, supervising clinical operations, and research coordination.

Declaration of interest: Kay Lawton, Meredith Brown, Danny Alexander, Zhen Li, Jacob Wulff, Mike Milburn, and John Ryals are employees of Metabolon, Inc.

Merit Cudkowicz has worked as a consultant for Shire, Trophos, and GlaxoSmithKline. She has received industry-sponsored grants from Neuralstem Inc, ISIS Pharmaceuticals Inc, Knopp Biosciences LLC, and Biogen Idec. She has also received funding from NIH grants.

Robert Bowser is a co-Founder of Knopp Biosciences LLC and Iron Horse Diagnostics, Inc, and a consultant to Cytonics Corporation.

James Berry has served as a paid speaker for Oakstone Publishing and a consultant for Biogen Idec and Neuraltus Pharamceuticals. He receives research support from the Muscular Dystrophy Association, ALS Association, American Brain Foundation, and ALS Therapy Alliance.

This study was funded by the ALS Association, National Institutes of Health, National Institutes of Health/National Center for Research Resources/General Clinical Research Centers Program; and Metabolon, Inc.

Robert Lawson and Matt Jaffa have no disclosures.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. The authors alone are responsible for the content and writing of the paper.