A biochemical signature of progressive multiple sclerosis

• Currently, very few treatments for patients in the progressive phases of multiple sclerosis (PMS) are available. To enable sensitive evaluation of future treatments, prognostic and predictive markers for therapeutic response are needed, as well as robust markers for early detection of PMS. We have previously demonstrated that a signature of 28 cerebrospinal fluid (CSF) biochemical markers could distinguish PMS from relapsing-remitting multiple sclerosis (RRMS) patients.Herein, we aimed to characterize the 28 previously extracted metabolites by assessing independent differences between 35 PMS and 35 RRMS patients as well as 49 healthy control subjects. Twenty-two of the PMS patients were part of a controlled clinical trial evaluating the effect of intrathecal rituximab for PMS. Using follow-up assessments, we related the metabolites to clinical outcomes of the trial and investigated if they could predict a poor or beneficial treatment response. Finally, we investigated the metabolites’ associations to a panel of six CSF protein biomarkers of axonal, myelin and astrocyte damage as well as T- and B- cell activation and differentiation.The composite signature was predominantly classifying patients as having a poor treatment outcome, achieving an estimated area under the curve (AUC) of 0.63 (sensitivity = 0.90, specificity = 0.38). Univariately, C4H6N6O4 and phenolic phosphate were significantly (p-value<0.05) increased in patients with a poor outcome. We also demonstrated that a majority (n=22) of the metabolites showed PMS distinctive alterations, including increased CSF levels of 4-acetamidobutanoate, 4-hydroxybenzoate and thymine. 4-Acetamidobutanoate did also display significant associations with the results from the symbol digit modalities test (SDMT) and the 9-hole peg test (9-HPT) using the dominant hand, and the protein markers myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp), whereas 4-hydroxybenzoate displayed significant associations with NFL. Only six metabolites showed significant differences between RRMS and healthy control subjects, suggesting that this is a PMS specific signature.To summarize, most of the individual metabolites did show significantly distinctive CSF levels in the PMS patients and some of them were also related to cognitive and motoric performance. This suggests that some of the investigated metabolites might have potential as individual markers.

Ämnesord

NATURVETENSKAP  -- Data- och informationsvetenskap -- Bioinformatik (hsv//swe)

NATURAL SCIENCES  -- Computer and Information Sciences -- Bioinformatics (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

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