title: A type 2 biomarker separates relapsing-remitting from secondary progressive multiple sclerosis.
abstract: OBJECTIVE
  We tested whether it is possible to differentiate relapsing-remitting (RR) from secondary progressive (SP) disease stages in patients with multiple sclerosis (MS) using a combination of nuclear magnetic resonance (NMR) metabolomics and partial least squares discriminant analysis (PLS-DA) of biofluids, which makes no assumptions on the underlying mechanisms of disease.
  
  
  METHODS
  Serum samples were obtained from patients with primary progressive MS (PPMS), SPMS, and RRMS; patients with other neurodegenerative conditions; and age-matched controls. Samples were analyzed by NMR and PLS-DA models were derived to separate disease groups.
  
  
  RESULTS
  The PLS-DA models for serum samples from patients with MS enabled reliable differentiation between RRMS and SPMS. This approach also identified significant differences between the metabolite profiles of each of the MS groups (PP, SP, and RR) and the healthy controls, as well as predicting disease group membership with high specificity and sensitivity.
  
  
  CONCLUSIONS
  NMR metabolomics analysis of serum is a sensitive and robust method for differentiating between different stages of MS, yielding diagnostic markers without a priori knowledge of disease pathogenesis. Critically, this study identified and validated a type II biomarker for the RR to SP transition in patients with MS. This approach may be of considerable benefit in categorizing patients for treatment and as an outcome measure in future clinical trials.
  
  
  METHODS
  This study provides Class II evidence that serum metabolite profiles accurately distinguish patients with different subtypes and stages of MS.
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Dickens
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Larkin
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Cavey
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Matthews
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Turner
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Wilcock
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Davis
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.
authors.forename: Timothy D W
authors.initials: TD
authors.lastname: Claridge
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Palace
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK. Daniel.Anthony@pharm.ox.ac.uk.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
authors.affiliation: From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000097:blood; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D015331:Cohort Studies; D016002:Discriminant Analysis; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000097:blood / Q000175:diagnosis*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000175:diagnosis*; D012372:ROC Curve; D015203:Reproducibility of Results
chemical_list: D015415:Biomarkers