Biochemical alterations associated with ALS

Abstract

Our objective was to identify metabolic pathways affected by ALS using non-targeted metabolomics in plasma, comparing samples from healthy volunteers to those from ALS patients. This discovery could become the basis for the identification of therapeutic targets and diagnostic biomarkers of ALS. Two distinct cross-sectional studies were conducted. Plasma was collected from 62 (Study 1) and 99 (Study 2) participants meeting El Escorial criteria for possible, probable, or definite ALS; 69 (Study 1) and 48 (Study 2) healthy controls samples were collected. Global metabolic profiling was used to detect and evaluate biochemical signatures of ALS. Twenty-three metabolites were significantly altered in plasma from ALS patients in both studies. These metabolites include biochemicals in pathways associated with neuronal change, hypermetabolism, oxidative damage, and mitochondrial dysfunction, all of which are proposed disease mechanisms in ALS. The data also suggest possible hepatic dysfunction associated with ALS. In conclusion, the data presented here provide insight into the pathophysiology of ALS while suggesting promising areas of focus for future studies. The metabolomics approach can generate novel hypotheses regarding ALS disease mechanisms with the potential to identify therapeutic targets and novel diagnostic biomarkers.

Key words::

• ALS
• biomarker
• metabolomics
• pathophysiology

Acknowledgements

The project was supported, in part, by support from the following: ALS Association, National Institutes of Health, National Institute of Neurological Disorders and Stroke, and National Institutes of Health/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. Support for MVB was received from the North Carolina Biotechnology Center Industrial Fellowship program. The authors would also like to acknowledge project input and support from David Lacomis at the University of Pittsburgh School of Medicine, the North-East ALS Consortium (NEALS), the NEALS Biofluid Repository Committee and the committee co-Chairs, Robert Bowser and Carol Milligan. The authors thank Lucie Bruijn and ALSA for guidance; the NEALS Consortium for sample collection; Darlene Sawicki for overseeing protocol development, informed consent design, supervising clinical operations, and research coordination; Lisa Paige, Bruce McCreedy and Jeff Shuster for contributions to preliminary studies; and Matthew Mitchell, and the Metabolon Analytical Team for contributing to statistical analyses and data acquisition. The analysis for this paper was generated using Array Studio software. Array Studio, Array Viewer and Array Server and all other Omicsoft products or service names are registered trademarks or trademarks of Omicsoft Corporation., Research Triangle Park, NC, USA.

Declaration of interest: Kay Lawton, Meredith Brown, Danny Alexander, Jacob Wulff, Rebecca Caffrey, 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, and Biogen Idec. She has also received funding from NIH grants. Robert Bowser is a cofounder of Knopp Neurosciences and consultant to Cytonics Corporation. Robert Lawson and Matt Jaffa have no disclosures. James Berry is on the editorial board of the Neurology Resident and Fellow Section and is supported by an NIH training grant. 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.