title: Cerebrospinal fluid ATP metabolites in multiple sclerosis.
abstract: Increased axonal energy demand and mitochondrial failure have been suggested as possible causes for axonal degeneration and disability in multiple sclerosis. Our objective was to test whether ATP depletion precedes clinical, imaging and biomarker evidence for axonal degeneration in multiple sclerosis. The method consisted of a longitudinal study which included 21 patients with multiple sclerosis. High performance liquid chromatography was used to quantify biomarkers of the ATP metabolism (oxypurines and purines) from the cerebrospinal fluid at baseline. The Expanded Disability Status Scale, MRI brain imaging measures for brain atrophy (ventricular and parenchymal fractions), and cerebrospinal fluid biomarkers for axonal damage (phosphorylated and hyperphosphorylated neurofilaments) were quantified at baseline and 3-year follow-up. Central ATP depletion (sum of ATP metabolites >19.7 micromol/litre) was followed by more severe progression of disability if compared to normal ATP metabolites (median 1.5 versus 0, p< 0.05). Baseline ATP metabolite levels correlated with change of Expanded Disability Status Scale in the pooled cohort (r= 0.66, p= 0.001) and subgroups (relapsing-remitting patients: r= 0.79, p< 0.05 and secondary progressive/primary progressive patients: r= 0.69, p< 0.01). There was no relationship between central ATP metabolites and either biomarker or MRI evidence for axonal degeneration. The data suggests that an increased energy demand in multiple sclerosis may cause a quantifiable degree of central ATP depletion. We speculate that the observed clinical disability may be related to depolarisation associated conduction block.
authors.affiliation: Department of Chemical Sciences, Laboratory of Biochemistry, University of Catania, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Lazzarino
authors.forename: A M
authors.initials: AM
authors.lastname: Amorini
authors.forename: M J
authors.initials: MJ
authors.lastname: Eikelenboom
authors.forename: J
authors.initials: J
authors.lastname: Killestein
authors.forename: A
authors.initials: A
authors.lastname: Belli
authors.forename: V
authors.initials: V
authors.lastname: Di Pietro
authors.forename: B
authors.initials: B
authors.lastname: Tavazzi
authors.forename: F
authors.initials: F
authors.lastname: Barkhof
authors.forename: C H
authors.initials: CH
authors.lastname: Polman
authors.forename: B M J
authors.initials: BM
authors.lastname: Uitdehaag
authors.forename: A
authors.initials: A
authors.lastname: Petzold
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid* / Q000473:pathology*; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D000255:Adenosine Triphosphate