title: The longitudinal cerebrospinal fluid metabolomic profile of amyotrophic lateral sclerosis.
abstract: Neurochemical biomarkers are urgently sought in ALS. Metabolomic analysis of cerebrospinal fluid (CSF) using proton nuclear magnetic resonance ((1)H-NMR) spectroscopy is a highly sensitive method capable of revealing nervous system cellular pathology. The (1)H-NMR CSF metabolomic signature of ALS was sought in a longitudinal cohort. Six-monthly serial collection was performed in ALS patients across a range of clinical sub-types (n = 41) for up to two years, and in healthy controls at a single time-point (n = 14). A multivariate statistical approach, partial least squares discriminant analysis, was used to determine differences between the NMR spectra from patients and controls. Significantly predictive models were found using those patients with at least one year's interval between recruitment and the second sample. Glucose, lactate, citric acid and, unexpectedly, ethanol were the discriminating metabolites elevated in ALS. It is concluded that (1)H-NMR captured the CSF metabolomic signature associated with derangements in cellular energy utilization connected with ALS, and was most prominent in comparisons using patients with longer disease duration. The specific metabolites identified support the concept of a hypercatabolic state, possibly involving mitochondrial dysfunction specifically. Endogenous ethanol in the CSF may be an unrecognized novel marker of neuronal tissue injury in ALS.
authors.affiliation: a Nuffield Department of Clinical Neuroscience , University of Oxford , Oxford , UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gray
authors.affiliation: b Cancer Research UK and Medical Research Council, Oxford Institute for Radiation Oncology, Department of Oncology , University of Oxford , Oxford , UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Larkin
authors.affiliation: c Department of Chemistry , University of Oxford , Oxford , UK.
authors.forename: Tim D W
authors.initials: TD
authors.lastname: Claridge
authors.affiliation: a Nuffield Department of Clinical Neuroscience , University of Oxford , Oxford , UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
authors.affiliation: b Cancer Research UK and Medical Research Council, Oxford Institute for Radiation Oncology, Department of Oncology , University of Oxford , Oxford , UK.
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
authors.affiliation: a Nuffield Department of Clinical Neuroscience , University of Oxford , Oxford , UK.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Turner
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D019343:Citric Acid / Q000134:cerebrospinal fluid*; D015331:Cohort Studies; D016002:Discriminant Analysis; D018450:Disease Progression; D000431:Ethanol / Q000134:cerebrospinal fluid*; D005260:Female; D005947:Glucose / Q000134:cerebrospinal fluid*; D006801:Humans; D019344:Lactic Acid / Q000134:cerebrospinal fluid*; D008137:Longitudinal Studies; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D015999:Multivariate Analysis; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D015415:Biomarkers; D019343:Citric Acid; D019344:Lactic Acid; D000431:Ethanol; D005947:Glucose
keywords: Nuclear magnetic resonance; biomarker; motor neuron disease; neurochemical; proton