Abstract
Multiple sclerosis (MS) is a CNS disease characterized by immune-mediated demyelination and progressive axonal loss. MS-related CNS damage and its clinical course have two main phases: active and inactive/progressive. Reliable biomarkers are being sought to allow identification of MS pathomechanisms and prediction of its course. The purpose of this study was to identify sphingolipid (SL) species as candidate biomarkers of inflammatory and neurodegenerative processes underlying MS pathology. We performed sphingolipidomic analysis by HPLC-tandem mass spectrometry to determine the lipid profiles in post mortem specimens from the normal-appearing white matter (NAWM) of the normal CNS (nCNS) from subjects with chronic MS (active and inactive lesions) as well as from patients with other neurological diseases. Distinctive SL modification patterns occurred in specimens from MS patients with chronic inactive plaques with respect to NAWM from the nCNS and active MS (Ac-MS) lesions. Chronic inactive MS (In-MS) lesions were characterized by decreased levels of dihydroceramide (dhCer), ceramide (Cer), and SM subspecies, whereas levels of hexosylceramide and Cer 1-phosphate (C1P) subspecies were significantly increased in comparison to NAWM of the nCNS as well as Ac-MS plaques. In contrast, Ac-MS lesions were characterized by a significant increase of major dhCer subspecies in comparison to NAWM of the nCNS. These results suggest the existence of different SL metabolic pathways in the active versus inactive phase within progressive stages of MS. Moreover, they suggest that C1P could be a new biomarker of the In-MS progressive phase, and its detection may help to develop future prognostic and therapeutic strategies for the disease.
Highlights
Multiple sclerosis (MS) is a CNS disease characterized by immune-mediated demyelination and progressive axonal loss
Both processes were shown to be initiated at the disease onset, but they develop with different dynamics: the peak of inflammatory activity occurs in the early stages of MS, while neurodegeneration with axonal loss is gradually escalating toward more advanced progressive stages [5]
Brain tissue specimens were derived from autopsy of patients with clinically diagnosed and neuropathologically confirmed MS (n = 13) and other neurological disease (OND) (n = 15) as well as from three controls who had been diagnosed with diseases without CNS involvement, with essentially normal brain confirmed on autopsy findings, normal CNS (nCNS)
Summary
Multiple sclerosis (MS) is a CNS disease characterized by immune-mediated demyelination and progressive axonal loss. Ac-MS lesions were characterized by a significant increase of major dhCer subspecies in comparison to NAWM of the nCNS These results suggest the existence of different SL metabolic pathways in the active versus inactive phase within progressive stages of MS. Extensive studies have not yet established the predominant target antigenic structures involved in the autoimmune response most relevant for MS background [4] Both processes were shown to be initiated at the disease onset, but they develop with different dynamics: the peak of inflammatory activity occurs in the early stages of MS, while neurodegeneration with axonal loss is gradually escalating toward more advanced progressive stages [5]. There is a need to investigate new and more relevant biomarkers potentially useful in MS [7, 8]
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