Abstract
ObjectivesInflammatory demyelinating diseases of the CNS comprise a broad spectrum of diseases like neuromyelitis optica (NMO), NMO spectrum disorders (NMO-SD) and multiple sclerosis (MS). Despite clear classification criteria, differentiation can be difficult. We hypothesized that the urine proteome may differentiate NMO from MS.MethodsThe proteins in urine samples from anti-aquaporin 4 (AQP4) seropositive NMO/NMO-SD patients (n = 32), patients with MS (n = 46) and healthy subjects (HS, n = 31) were examined by quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) after trypsin digestion and iTRAQ labelling. Immunoglobulins (Ig) in the urine were validated by nephelometry in an independent cohort (n = 9–10 pr. groups).ResultsThe analysis identified a total of 1112 different proteins of which 333 were shared by all 109 subjects. Cluster analysis revealed differences in the urine proteome of NMO/NMO-SD compared to HS and MS. Principal component analysis also suggested that the NMO/NMO-SD proteome profile was useful for classification. Multivariate regression analysis revealed a 3-protein profile for the NMO/NMO-SD versus HS discrimination, a 6-protein profile for NMO/NMO-SD versus MS discrimination and an 11-protein profile for MS versus HS discrimination. All protein panels yielded highly significant ROC curves (AUC in all cases >0.85, p≤0.0002). Nephelometry confirmed the presence of increased Ig-light chains in the urine of patients with NMO/NMO-SD.ConclusionThe urine proteome profile of patients with NMO/NMO-SD is different from MS and HS. This may reflect differences in the pathogenesis of NMO/NMO-SD versus MS and suggests that urine may be a potential source of biomarkers differentiating NMO/NMO-SD from MS.
Highlights
Inflammatory demyelinating diseases of the CNS include putative autoimmune diseases like multiple sclerosis (MS), neuromyelitis optica (NMO), and NMO spectrum diseases (NMO-SD) e.g. relapsing and/or bilateral inflammatory optic neuritis (RION/BON), and longitudinally extensive transverse myelitis (LETM)
The urine proteome profile of patients with NMO/NMO-SD is different from MS and healthy subjects (HS)
This may reflect differences in the pathogenesis of NMO/NMO-SD versus MS and suggests that urine may be a potential source of biomarkers differentiating NMO/NMO-SD from MS
Summary
Inflammatory demyelinating diseases of the CNS include putative autoimmune diseases like multiple sclerosis (MS), neuromyelitis optica (NMO), and NMO spectrum diseases (NMO-SD) e.g. relapsing and/or bilateral inflammatory optic neuritis (RION/BON), and longitudinally extensive transverse myelitis (LETM). Despite recognition of pathogenic antibodies against the water channel aquaporin 4 (AQP4) in the majority of patients with NMO/ NMO-SD[1,2,3], diagnosis of especially seronegative cases can be challenging and underlines the need for additional biomarkers[4, 5]. Mass spectrometry has made it possible to uncover distinct molecular components in both serum and CSF of patients with NMO[7, 8] and MS[9]. Proteomic pattern analysis can globally and quantitatively characterize the protein population and may effectively reveal distinct and complex pathogenesis of seemingly closely related diseases, such as MS and NMO/NMO-SD. Previous non-quantitative studies have isolated biomarkers from CSF and serum[7, 8], while other body fluids remain to be been explored
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