The purpose of this work was to determine whether changes in cholesterol profiles after interferon-β (IFN-β)1a treatment initiation following the first demyelinating event suggestive of multiple sclerosis are associated with clinical and MRI outcomes over 4 years. A group of 131 patients (age: 27.9 ± 7.8 years, 63% female) with serial 3-monthly clinical and 12-monthly MRI follow-ups over 4 years were investigated. Serum cholesterol profiles, including total cholesterol (TC), HDL cholesterol (HDL-C), and LDL cholesterol (LDL-C) were obtained at baseline, 1 month, 3 months, and every 6 months thereafter. IFN-β1a initiation caused rapid decreases in serum HDL-C, LDL-C, and TC within 1 month of IFN-β1a initiation (all P < 0.001) that returned slowly toward baseline. In predictive mixed model analyses, greater percent decreases in HDL-C after 3 months of IFN-β1a treatment initiation were associated with less brain atrophy over the 4 year time course, as assessed by percent brain volume change (P < 0.001), percent gray matter volume change (P < 0.001), and percent lateral ventricle volume change (P = 0.005). Decreases in cholesterol biomarkers following IFN-β1a treatment are associated with brain atrophy outcomes over 4 years. Pharmacological interventions targeting lipid homeostasis may be clinically beneficial for disrupting neurodegenerative processes.

Buffalo Neuroimaging Analysis Center Department of Neurology Jacobs School of Medicine and Biomedical Sciences University at Buffalo State University of New York Buffalo NY

Department of Neurology and Center of Clinical Neuroscience Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Pharmaceutical Sciences State University of New York Buffalo NY

Department of Radiology Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Statistics and Probability University of Economics Prague Czech Republic

Istituto di Ricovero e Cura a Carattere Scientifico S Maria Nascente Don Gnocchi Foundation Milan Italy

Jacobs Multiple Sclerosis Center Department of Neurology Jacobs School of Medicine and Biomedical Sciences University at Buffalo State University of New York Buffalo NY

MR Imaging Clinical Translational Research Center Jacobs School of Medicine and Biomedical Sciences University at Buffalo State University of New York Buffalo NY

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1993. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 43: 655–661. PubMed

Yong V. W., Chabot S., Stuve O., and Williams G.. 1998. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology. 51: 682–689. PubMed

Jacobs L. D., Cookfair D. L., Rudick R. A., Herndon R. M., Richert J. R., Salazar A. M., Fischer J. S., Goodkin D. E., Granger C. V., Simon J. H., et al. . 1996. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann. Neurol. 39: 285–294. PubMed

Comi G., Filippi M., Barkhof F., Durelli L., Edan G., Fernandez O., Hartung H., Seeldrayers P., Sorensen P. S., Rovaris M., et al. . 2001. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 357: 1576–1582. PubMed

Hartung H. P. 2005. Early treatment and dose optimisation BENEFIT and BEYOND. J. Neurol. 252(Suppl 3): iii44–iii50. PubMed

Jacobs L. D., Beck R. W., Simon J. H., Kinkel R. P., Brownscheidle C. M., Murray T. J., Simonian N. A., Slasor P. J., and Sandrock A. W.. 2000. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N. Engl. J. Med. 343: 898–904. PubMed

Rudick R. A., Fisher E., Lee J. C., Simon J., and Jacobs L.. 1999. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology. 53: 1698–1704. PubMed

Benedict R. H., Bakshi R., Simon J. H., Priore R., Miller C., and Munschauer F.. 2002. Frontal cortex atrophy predicts cognitive impairment in multiple sclerosis. J. Neuropsychiatry Clin. Neurosci. 14: 44–51. PubMed

Benedict R. H., Weinstock-Guttman B., Fishman I., Sharma J., Tjoa C. W., and Bakshi R.. 2004. Prediction of neuropsychological impairment in multiple sclerosis: comparison of conventional magnetic resonance imaging measures of atrophy and lesion burden. Arch. Neurol. 61: 226–230. PubMed

Bakshi R., Czarnecki D., Shaikh Z. A., Priore R. L., Janardhan V., Kaliszky Z., and Kinkel P. R.. 2000. Brain MRI lesions and atrophy are related to depression in multiple sclerosis. Neuroreport. 11: 1153–1158. PubMed

Stone L. A., Frank J. A., Albert P. S., Bash C. N., Calabresi P. A., Maloni H., and McFarland H. F.. 1997. Characterization of MRI response to treatment with interferon beta-1b: contrast-enhancing MRI lesion frequency as a primary outcome measure. Neurology. 49: 862–869. PubMed

1996. Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology. 47: 889–894. PubMed

PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group. 2001. PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. Neurology. 56: 1628–1636. PubMed

Filippini G., Munari L., Incorvaia B., Ebers G. C., Polman C., D’Amico R., and Rice G. P.. 2003. Interferons in relapsing remitting multiple sclerosis: a systematic review. Lancet. 361: 545–552. PubMed

Sorensen P. S., Ross C., Clemmesen K. M., Bendtzen K., Frederiksen J. L., Jensen K., Kristensen O., Petersen T., Rasmussen S., Ravnborg M., et al. . 2003. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet. 362: 1184–1191. PubMed

Novick D., Cohen B., and Rubinstein M.. 1994. The human interferon alpha/beta receptor: characterization and molecular cloning. Cell. 77: 391–400. PubMed

Colamonici O., Yan H., Domanski P., Handa R., Smalley D., Mullersman J., Witte M., Krishnan K., and Krolewski J.. 1994. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Mol. Cell. Biol. 14: 8133–8142. PubMed PMC

Santos R., Weinstock-Guttman B., Tamano-Blanco M., Badgett D., Zivadinov R., Justinger T., Munschauer F. III, and Ramanathan M.. 2006. Dynamics of interferon-beta modulated mRNA biomarkers in multiple sclerosis patients with anti-interferon-beta neutralizing antibodies. J. Neuroimmunol. 176: 125–133. PubMed

Bertolotto A., Sala A., Malucchi S., Marnetto F., Caldano M., Di Sapio A., Capobianco M., and Gilli F.. 2004. Biological activity of interferon betas in patients with multiple sclerosis is affected by treatment regimen and neutralising antibodies. J. Neurol. Neurosurg. Psychiatry. 75: 1294–1299. PubMed PMC

Pachner A. R. 1997. Anticytokine antibodies in beta interferon-treated MS patients and the need for testing: plight of the practicing neurologist. Neurology. 49: 647–650. PubMed

Blanc M., Hsieh W. Y., Robertson K. A., Watterson S., Shui G., Lacaze P., Khondoker M., Dickinson P., Sing G., Rodriguez-Martin S., et al. . 2011. Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis. PLoS Biol. 9: e1000598. PubMed PMC

Browne R. W., Weinstock-Guttman B., Horakova D., Zivadinov R., Bodziak M. L., Tamano-Blanco M., Badgett D., Tyblova M., Vaneckova M., Seidl Z., et al. . 2014. Apolipoproteins are associated with new MRI lesions and deep grey matter atrophy in clinically isolated syndromes. J. Neurol. Neurosurg. Psychiatry. 85: 859–864. PubMed

Weinstock-Guttman B., Zivadinov R., Horakova D., Havrdova E., Qu J., Shyh G., Lakota E., O’Connor K., Badgett D., Tamano-Blanco M., et al. . 2013. Lipid profiles are associated with lesion formation over 24 months in interferon-beta treated patients following the first demyelinating event. J. Neurol. Neurosurg. Psychiatry. 84: 1186–1191. PubMed

Tettey P., Simpson S. Jr., Taylor B., Blizzard L., Ponsonby A. L., Dwyer T., Kostner K., and van der Mei I.. 2014. An adverse lipid profile is associated with disability and progression in disability, in people with MS. Mult. Scler. 20: 1737–1744. PubMed

Tettey P., Simpson S. Jr., Taylor B., Blizzard L., Ponsonby A. L., Dwyer T., Kostner K., and van der Mei I.. 2014. Adverse lipid profile is not associated with relapse risk in MS: results from an observational cohort study. J. Neurol. Sci. 340: 230–232. PubMed

Tettey P., Simpson S. Jr., Taylor B. V., and van der Mei I. A.. 2014. Vascular comorbidities in the onset and progression of multiple sclerosis. J. Neurol. Sci. 347: 23–33. PubMed

Horakova D., Zivadinov R., Weinstock-Guttman B., Havrdova E., Qu J., Tamano-Blanco M., Badgett D., Tyblova M., Bergsland N., Hussein S., et al. . 2013. Environmental factors associated with disease progression after the first demyelinating event: results from the multi-center SET study. PLoS One. 8: e53996. PubMed PMC

Friedewald W. T., Levy R. I., and Fredrickson D. S.. 1972. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin. Chem. 18: 499–502. PubMed

Uher T., Horakova D., Bergsland N., Tyblova M., Ramasamy D. P., Seidl Z., Vaneckova M., Krasensky J., Havrdova E., and Zivadinov R.. 2014. MRI correlates of disability progression in patients with CIS over 48 months. Neuroimage Clin. 6: 312–319. PubMed PMC

Uher T., Horakova D., Kalincik T., Bergsland N., Tyblova M., Ramasamy D. P., Seidl Z., Vaneckova M., Krasensky J., Havrdova E. ,et al. . 2015. Early magnetic resonance imaging predictors of clinical progression after 48 months in clinically isolated syndrome patients treated with intramuscular interferon beta-1a. Eur. J. Neurol. 22: 1113–1123. PubMed

Weinstock-Guttman B., Horakova D., Zivadinov R., Tamano-Blanco M., Badgett D., Tyblova M., Vaneckova M., Seidl Z., Krasensky J., Bergsland N., et al. . 2013. Interactions of serum cholesterol with anti-herpesvirus responses affect disease progression in clinically isolated syndromes. J. Neuroimmunol. 263: 121–127. PubMed

Chataway J., Schuerer N., Alsanousi A., Chan D., MacManus D., Hunter K., Anderson V., Bangham C. R., Clegg S., Nielsen C., et al. . 2014. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 383: 2213–2221. PubMed

Marrie R. A., Rudick R., Horwitz R., Cutter G., Tyry T., Campagnolo D., and Vollmer T.. 2010. Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis. Neurology. 74: 1041–1047. PubMed PMC

Zivadinov R., Marr K., Cutter G., Ramanathan M., Benedict R. H., Kennedy C., Elfadil M., Yeh A. E., Reuther J., Brooks C., et al. . 2011. Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology. 77: 138–144. PubMed

Morra V. B., Coppola G., Orefice G., De Michele G., Vacca G., Filla A., and Bonavita V.. 2004. Interferon-beta treatment decreases cholesterol plasma levels in multiple sclerosis patients. Neurology. 62: 829–830. PubMed

Dixon R. M., Borden E. C., Keim N. L., Anderson S., Spennetta T. L., Tormey D. C., and Shrago E.. 1984. Decreases in serum high-density-lipoprotein cholesterol and total cholesterol resulting from naturally produced and recombinant DNA-derived leukocyte interferons. Metabolism. 33: 400–404. PubMed

Shinohara E., Yamashita S., Kihara S., Hirano K., Ishigami M., Arai T., Nozaki S., Kameda-Takemura K., Kawata S., and Matsuzawa Y.. 1997. Interferon alpha induces disorder of lipid metabolism by lowering postheparin lipases and cholesteryl ester transfer protein activities in patients with chronic hepatitis C. Hepatology. 25: 1502–1506. PubMed

Chen Y., Wang S., Yi Z., Tian H., Aliyari R., Li Y., Chen G., Liu P., Zhong J., Chen X., et al. . 2014. Interferon-inducible cholesterol-25-hydroxylase inhibits hepatitis C virus replication via distinct mechanisms. Sci. Rep. 4: 7242. PubMed PMC

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