Abstract
The purpose of this work was to investigate whether changes in oxysterol and apolipoprotein levels over 5 years are associated with disease course and disability progression in multiple sclerosis (MS). This study included 139 subjects [39 healthy controls (HCs), 61 relapsing-remitting MS (RR-MS) patients, and 39 progressive MS (P-MS) patients]. Oxysterols [24-hydroxycholesterol (24HC), 25-hydroxycholesterol (25HC), 27-hydroxycholesterol (27HC), 7α-hydroxycholesterol (7αHC), and 7-ketocholesterol (7KC)] were measured at baseline and 5 years using a novel mass spectrometric method, and apolipoproteins were measured using immunoturbidometric diagnostic kits. Levels of 24HC (P = 0.004), 25HC (P = 0.029), and 27HC (P = 0.026) increased in P-MS patients. 7KC (P = 0.047) and 7αHC (P = 0.001) levels decreased in RR-MS patients, and there were no changes in any oxysterols in HCs. In MS patients, ApoC-II (all P ≤ 0.01) and ApoE (all P ≤ 0.01) changes were positively associated with all oxysterol levels. Increases in 24HC (P = 0.038) and ApoB (P = 0.038) and decreases in 7KC (P = 0.020) were observed in RR-MS patients who converted to secondary P-MS (SP-MS) at follow-up and in SP-MS patients compared with RR-MS patients. Oxysterols and their associations with apolipoproteins differed between MS patients and HCs over 5 years. Oxysterol and apolipoprotein changes were associated with conversion to SP-MS.
Highlights
7 7 -hydroxycholesterol (HC) is the product of the rate-limiting step in the bile acid pathway of cholesterol elimination [17], and it is a surrogate marker for bile acid synthesis and cholesterol excretion [17]. 27HC is produced by CYP27A1 in the acidic pathway [18]. 7KC results from oxidative stress and can induce apoptosis [19], inflammation in endothelial cells, and neuronal injury in the brain [20]. van de Kraats et al [21] found that Multiple sclerosis (MS) patients had lower levels of serum 24HC and 27HC compared with healthy controls (HCs), and higher 24HC levels were associated with decreased normalized brain volume measures
The higher average age and median Expanded Disability Status Scale (EDSS) scores observed in progressive MS (P-MS) patients are representative of the progressive disease course
We measured oxysterol and apolipoprotein levels from baseline to 5 years in MS patients and HCs, and investigated whether these changes were associated with disease course conversion and disability progression. 24HC, 25HC, and 27HC levels increased in P-MS patients, whereas 7KC and 7 -hydroxycholesterol (7 HC) decreased in relapsing-remitting MS (RR-MS) patients over 5 years
Summary
B.W-G. received honoraria for serving in advisory boards and educational programs from Teva Pharmaceuticals, Biogen Idec, Novartis, Acorda, EMD Serono, Pfizer, Novartis, Genzyme, and Sanofi She received support for research activities from the National Institutes of Health, National Multiple Sclerosis Society, National Science Foundation, Department of Defense, EMD Serono, Biogen Idec, Teva Neuroscience, Cyberonics, Novartis, Acorda, and the Jog for the Jake Foundation. Oxysterols are ligands for LXR [7, 8] and are involved in Abbreviations: BBB, blood-brain barrier; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; HC, healthy control; 24HC, 24-hydroxycholesterol; 25HC, 25-hydroxycholesterol; 27HC, 27-hydroxycholesterol; 7 HC, 7 -hydroxycholesterol; 7KC, 7-ketocholesterol; MS, multiple sclerosis; P-MS, progressive multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SP-MS, secondary progressive multiple sclerosis; TC, total cholesterol. Our group found that 24HC, 27HC, and 7 HC (all P < 0.015) were lower in MS patients compared with HCs, and 7KC was higher in progressive MS (P-MS) compared with relapsing-remitting MS (RR-MS) (P < 0.001) [22]
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