Multiple sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS). We have measured the levels of over 20 non-esterified
sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory
CNS disease,
neurodegenerative disease and control patients. Analysis was performed following
enzyme-assisted derivatisation by liquid chromatography-mass spectrometry (LC-MS) exploiting multistage fragmentation (MS n ). We found increased concentrations of
bile acid precursors in CSF from each of the disease states and that patients with inflammatory
CNS disease classified as suspected
autoimmune disease or of unknown aetiology also showed elevated concentrations of 25-hydroxycholestertol (25-HC, P < 0.05) in CSF.
Cholesterol concentrations in CSF were not changed except for patients diagnosed with
amyotrophic lateral sclerosis (P < 0.01) or pathogen-based
infections of the CNS (P < 0.05) where they were elevated. In plasma, we found that 25-HC (P < 0.01), (25R)26-hydroxycholesterol ((25R)26-HC, P < 0.05) and 7α-hydroxy-3-oxocholest-4-enoic
acid (7αH,3O-CA, P < 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls. The pattern of reduced plasma levels of 25-HC, (25R)26-HC and 7αH,3O-CA was unique to RRMS. In summary, in plasma, we find that the concentration of 25-HC in RRMS patients is significantly lower than in controls. This is consistent with the hypothesis that a lower propensity of macrophages to synthesise 25-HC will result in reduced negative feedback by 25-HC on
IL-1 family
cytokine production and exacerbated MS. In CSF, we find that the dominating metabolites reflect the acidic pathway of
bile acid biosynthesis and the elevated levels of these in
CNS disease is likely to reflect
cholesterol release as a result of
demyelination or neuronal death. 25-HC is elevated in patients with inflammatory
CNS disease probably as a consequence of up-regulation of the type 1
interferon-stimulated gene
cholesterol 25-hydroxylase in macrophages.