The purpose of this work was to investigate the associations of serum cholesterol and apolipoproteins with measures of blood-brain barrier (BBB) permeability and CNS inflammation following the first clinical demyelinating event. This study included 154 patients [67% female; age, 29.5 ± 8.2 years (mean ± SD)] enrolled in a multi-center study of interferon β1-a treatment following the first demyelinating event. Blood and cerebrospinal fluid (CSF) were obtained at screening prior to treatment. A comprehensive serum lipid profile and multiple surrogate markers of BBB breakdown and CNS immune activity were obtained. Higher levels of serum HDL cholesterol (HDL-C) and ApoA-I were associated with lower CSF total protein level, CSF albumin level, albumin quotient, and CSF IgG level (all P ≤ 0.001 for HDL-C and all P < 0.01 for ApoA-I). HDL-C was also associated with CSF CD80+ (P < 0.001) and with CSF CD80+CD19+ (P = 0.007) cell frequencies. Higher serum HDL is associated with lower levels of BBB injury and decreased CD80+ and CD80+CD19+ cell extravasation into the CSF. HDL may potentially inhibit the initiation and/or maintenance of pathogenic BBB injury following the first demyelinating event.

Biotechnical and Clinical Laboratory Sciences State University of New York Buffalo NY

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

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

Departments of Pharmaceutical Sciences State University of New York Buffalo NY

Departments of Pharmaceutical Sciences State University of New York Buffalo NY Neurology State University of New York Buffalo NY

Institute of Immunology and Microbiology 1st Faculty of Medicine and General University Hospital Charles University Prague Prague Czech Republic

Neurology State University of New York Buffalo NY

Neurology State University of New York Buffalo NY Buffalo Neuroimaging Analysis Center Department of Neurology State University of New York Buffalo NY

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Minagar A., Alexander J. S. 2003. Blood-brain barrier disruption in multiple sclerosis. Mult. Scler. 9: 540–549. PubMed

Ortiz G. G., Pacheco-Moises F. P., Macias-Islas M. A., Flores-Alvarado L. J., Mireles-Ramirez M. A., Gonzalez-Renovato E. D., Hernandez-Navarro V. E., Sanchez-Lopez A. L., Alatorre-Jimenez M. A. 2014. Role of the blood-brain barrier in multiple sclerosis. Arch. Med. Res. 45: 687–697. PubMed

Lucchinetti C. F., Popescu B. F., Bunyan R. F., Moll N. M., Roemer S. F., Lassmann H., Bruck W., Parisi J. E., Scheithauer B. W., Giannini C., et al. 2011. Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med. 365: 2188–2197. PubMed PMC

Werring D. J., Brassat D., Droogan A. G., Clark C. A., Symms M. R., Barker G. J., MacManus D. G., Thompson A. J., Miller D. H. 2000. The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study. Brain. 123: 1667–1676. PubMed

Holmøy T. 2009. The discovery of oligoclonal bands: a 50-year anniversary. Eur. Neurol. 62: 311–315. PubMed

Henninger D. D., Gerritsen M. E., Granger D. N. 1997. Low-density lipoprotein receptor knockout mice exhibit exaggerated microvascular responses to inflammatory stimuli. Circ. Res. 81: 274–281. PubMed

Hansson G. K., Hermansson A. 2011. The immune system in atherosclerosis. Nat. Immunol. 12: 204–212. PubMed

Giubilei F., Antonini G., Di Legge S., Sormani M. P., Pantano P., Antonini R., Sepe-Monti M., Caramia F., Pozzilli C. 2002. Blood cholesterol and MRI activity in first clinical episode suggestive of multiple sclerosis. Acta Neurol. Scand. 106: 109–112. PubMed

Kardys A., Weinstock-Guttman B., Dillon M., Masud M. W., Weinstock N., Mahfooz N., Lang J. K., Weinstock A., Lincoff N., Zivadinov R., et al. 2013. Cholesterol affects retinal nerve fiber layer thickness in patients with multiple sclerosis with optic neuritis. Eur. J. Neurol. 20: 1264–1271. PubMed

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

Weinstock-Guttman B., Zivadinov R., Mahfooz N., Carl E., Drake A., Schneider J., Teter B., Hussein S., Mehta B., Weiskopf M., et al. 2011. Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis. J. Neuroinflammation. 8: 127. 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

Zivadinov R., Havrdova E., Bergsland N., Tyblova M., Hagemeier J., Seidl Z., Dwyer M. G., Vaneckova M., Krasensky J., Carl E., et al. 2013. Thalamic atrophy is associated with development of clinically definite multiple sclerosis. Radiology. 268: 831–841. PubMed

Kalincik T., Vaneckova M., Tyblova M., Krasensky J., Seidl Z., Havrdova E., Horakova D. 2012. Volumetric MRI markers and predictors of disease activity in early multiple sclerosis: a longitudinal cohort study. PLoS One. 7: e50101. PubMed PMC

Friedewald W. T., Levy R. I., 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

Browne R. W., Koury S. T., Marion S., Wilding G., Muti P., Trevisan M. 2007. Accuracy and biological variation of human serum paraoxonase 1 activity and polymorphism (Q192R) by kinetic enzyme assay. Clin. Chem. 53: 310–317. PubMed

Freedman M. S., Thompson E. J., Deisenhammer F., Giovannoni G., Grimsley G., Keir G., Ohman S., Racke M. K., Sharief M., Sindic C. J., et al. 2005. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch. Neurol. 62: 865–870. PubMed

Wada H. 1998. Blood-brain barrier permeability of the demented elderly as studied by cerebrospinal fluid-serum albumin ratio. Intern. Med. 37: 509–513. PubMed

Reiber H., Teut M., Pohl D., Rostasy K. M., Hanefeld F. 2009. Paediatric and adult multiple sclerosis: age-related differences and time course of the neuroimmunological response in cerebrospinal fluid. Mult. Scler. 15: 1466–1480. PubMed

Benjamini Y., Hochberg Y. 1995. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Series B Stat. Methodol. 57: 289–300.

Cowdrey G. N., Tasker P. J., Gould B. J., Rice-Oxley M., Firth G. B. 1993. Isoelectric focusing in an immobilized pH gradient for the detection of intrathecal IgG in cerebrospinal fluid: sensitivity and specificity for the diagnosis of multiple sclerosis. Ann. Clin. Biochem. 30: 463–468. PubMed

Stukas S., Robert J., Lee M., Kulic I., Carr M., Tourigny K., Fan J., Namjoshi D., Lemke K., DeValle N., et al. 2014. Intravenously injected human apolipoprotein A-I rapidly enters the central nervous system via the choroid plexus. J. Am. Heart Assoc. 3: e001156. PubMed PMC

Vitali C., Wellington C. L., Calabresi L. 2014. HDL and cholesterol handling in the brain. Cardiovasc. Res. 103: 405–413. PubMed

Alexander J. S., Harris M. K., Wells S. R., Mills G., Chalamidas K., Ganta V. C., McGee J., Jennings M. H., Gonzalez-Toledo E., Minagar A. 2010. Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b. Mult. Scler. 16: 801–809. PubMed

Alexander J. S., Zivadinov R., Maghzi A. H., Ganta V. C., Harris M. K., Minagar A. 2011. Multiple sclerosis and cerebral endothelial dysfunction: mechanisms. Pathophysiology. 18: 3–12. PubMed

Minagar A., Carpenter A., Alexander J. S. 2007. The destructive alliance: interactions of leukocytes, cerebral endothelial cells, and the immune cascade in pathogenesis of multiple sclerosis. Int. Rev. Neurobiol. 79: 1–11. PubMed

Minagar A., Jy W., Jimenez J. J., Alexander J. S. 2006. Multiple sclerosis as a vascular disease. Neurol. Res. 28: 230–235. PubMed

Ganda A., Magnusson M., Yvan-Charvet L., Hedblad B., Engstrom G., Ai D., Wang T. J., Gerszten R. E., Melander O., Tall A. R. 2013. Mild renal dysfunction and metabolites tied to low HDL cholesterol are associated with monocytosis and atherosclerosis. Circulation. 127: 988–996. PubMed PMC

Terasaka N., Yu S., Yvan-Charvet L., Wang N., Mzhavia N., Langlois R., Pagler T., Li R., Welch C. L., Goldberg I. J., et al. 2008. ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet. J. Clin. Invest. 118: 3701–3713. PubMed PMC

Meyers L., Groover C. J., Douglas J., Lee S., Brand D., Levin M. C., Gardner L. A. 2014. A role for Apolipoprotein A-I in the pathogenesis of multiple sclerosis. J. Neuroimmunol. 277: 176–185. PubMed

Bowman G. L., Kaye J. A., Quinn J. F. Dyslipidemia and blood-brain barrier integrity in Alzheimer’s disease. 2012. Curr. Gerontol. Geriatr. Res. 2012: 184042. PubMed PMC

Genç K., Dona D. L., Reder A. T. 1997. Increased CD80(+) B cells in active multiple sclerosis and reversal by interferon beta-1b therapy. J. Clin. Invest. 99: 2664–2671. PubMed PMC

Trabattoni D., Saresella M., Pacei M., Marventano I., Mendozzi L., Rovaris M., Caputo D., Borelli M., Clerici M. 2009. Costimulatory pathways in multiple sclerosis: distinctive expression of PD-1 and PD-L1 in patients with different patterns of disease. J. Immunol. 183: 4984–4993. PubMed

Balashov K. E., Rottman J. B., Weiner H. L., Hancock W. W. 1999. CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions. Proc. Natl. Acad. Sci. USA. 96: 6873–6878. PubMed PMC

Remaley A. T. 2013. Apolipoprotein A-II: still second fiddle in high-density lipoprotein metabolism? Arterioscler. Thromb. Vasc. Biol. 33: 166–167. PubMed PMC

Chan D. C., Ng T. W., Watts G. F. 2012. Apolipoprotein A-II: evaluating its significance in dyslipidaemia, insulin resistance, and atherosclerosis. Ann. Med. 44: 313–324. PubMed

Uher T., Horakova D., Tyblova M., Zeman D., Krasulova E., Mrazova K., Seidl Z., Vaneckova M., Krasensky J., Weinstock-Guttman B., et al. 2015. Increased albumin quotient (QAlb) in patients after first clinical event suggestive of multiple sclerosis is associated with development of brain atrophy and greater disability 48 months later. Mult. Scler. DOI: 10.1177/1352458515601903. In press. PubMed

Lipid and brain volumetric measures in multiple sclerosis patients: findings from a large observational study