Plasma 24-hydroxycholesterol is associated with narrower common carotid artery and greater flow velocities in relapsing multiple sclerosis

Dejan Jakimovski; Robert Zivadinov; Laura Pelizzari; Cynthia Dunne-Jaffe; Richard W. Browne; Niels Bergsland; Michael G. Dwyer; Bianca Weinstock-Guttman; Murali Ramanathan

doi:10.4081/vl.2022.10965

Authors

Dejan Jakimovski
djakimovski@bnac.net
Department of Neurology, Buffalo Neuroimaging Analysis Center (BNAC), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
Robert Zivadinov Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York, Buffalo, United States.
Laura Pelizzari IRCCS, Fondazione Don Carlo Gnocchi, Milan, United States.
Cynthia Dunne-Jaffe Department of Neurology, Buffalo Neuroimaging Analysis Center (BNAC), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
Richard W. Browne Department of Biotechnical and Clinical Laboratory Sciences, State University of New York, Buffalo, United States.
Niels Bergsland IRCCS, Fondazione Don Carlo Gnocchi, Milan,, United States.
Michael G. Dwyer Department of Neurology, Buffalo Neuroimaging Analysis Center (BNAC), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
Bianca Weinstock-Guttman Department of Neurology, Jacobs Comprehensive MS Treatment and Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
Murali Ramanathan Department of Pharmaceutical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.

Background: Multiple sclerosis (MS) studies suggest greater cardiovascular disease burden and disturbances in the cholesterol pathways^1,2 The potential impact of oxidized cholesterol molecules (oxysterols) on MS is emerging (Figure 1).³

Objective: To determine the relationship between multiple oxysterol molecules and atherosclerosis burden in MS patients.

Materials and methods: A total of 99 MS patients (61 relapsing-remitting MS (RRMS) and 38 progressive MS (PMS)) patients and 38 healthy controls (HCs) underwent magnetic resonance angiography (MRA) and the cross-sectional area (CSA) of the common carotid artery (CCA) was determined at three different levels before the bifurcation (C7, C6 and C5). Additionally, an echo-color Doppler ultrasound was performed and measures of blood flow velocities were derived. Blood samples acquired at the time of the imaging examinations were analyzed and 24-, 25-, 27-hydroxycholesterol (24HC, 25HC, 27HC) and 7-ketocholesterol (7KC) were quantified in ng/mL.

Results: In the MS patients, higher levels of 24HC were significantly associated with smaller CCA CSA measured at all three cervical levels (r=-0.201, p=0.046; r=-0.228, p=0.023, and r=-0.215, p=0.032, for C7, C6 and C5, respectively). These associations were driven by the RRMS group only (r=-0.407, p=0.002 for C7; r=-0.414, p=0.002, for C6; and r=-0.368, p=0.006 for C5). No associations were seen in the HCs. Despite adjusting for the significant age effect (B=0.445, p=0.004), higher 24HC levels were independently associated with smaller CCA CSA (B=-0.20, p=0.045). 24HC was additionally associated with greater time-averaged and peak diastolic CCA velocities. RRMS patients treated with potent anti-inflammatory therapies had lower oxysterol levels (p=0.019). RRMS patients in the lower 24HC quartiles had significantly higher expanded disability status scale (EDSS) scores when compared to RRMS patients in the higher two 24HC quartiles (2.5 (IQR 1.9-3.1) vs 2.0 (1.5-2.5), p=0.038).

Conclusions: Greater 24HC levels are associated with smaller CSA CCA and greater flow velocities in RRMS patients. The higher inflammatory activity in RRMS patients may contribute to the production of highly reactive oxysterols and worsen the atherosclerotic burden in the MS population. Potent anti-inflammatory medications can significantly decrease oxysterol levels.

1. Jakimovski D, Zivadinov R, Dwyer MG, et al. High density lipoprotein cholesterol and apolipoprotein A-I are associated with greater cerebral perfusion in multiple sclerosis. J Neurol Sci 2020;418:117120.
2. McComb M, Parambi R, Browne RW, et al. Apolipoproteins AI and E are associated with neuroaxonal injury to gray matter in multiple sclerosis. Mult Scler Relat Disord 2020;45:102389.
3. Fellows Maxwell K, Bhattacharya S, Bodziak ML, et al. Oxysterols and apolipoproteins in multiple sclerosis: a 5 year follow-up study. J Lipid Res 2019;60:1190-1198.

Jakimovski, D., Zivadinov, R., Pelizzari, L., Dunne-Jaffe, C., Browne, R. W., Bergsland, N., Dwyer, M. G., Weinstock-Guttman, B., & Ramanathan, M. (2022). Plasma 24-hydroxycholesterol is associated with narrower common carotid artery and greater flow velocities in relapsing multiple sclerosis. Veins and Lymphatics, 11(1). https://doi.org/10.4081/vl.2022.10965