Serum Lipid Profiles Are Associated With Disability and MRI Outcomes in Multiple Sclerosis

Bianca Weinstock-Guttman; Robert Zivadinov; Naeem Mahfooz; Ellen Carl; Allison Drake; Jaclyn Schneider; Barbara Teter; Sara Hussein; Bijal Mehta; Marc Weiskopf; Jacqueline Durfee; Niels Bergsland; Murali Ramanathan

Disclosures

J Neuroinflammation. 2011;8(127) 

In This Article

Discussion

In this paper, we have reported results indicating that lipid profile variables such as increased LDL, triglycerides and total cholesterol levels are associated with increased disability progression in MS. Higher HDL levels and lower levels of triglycerides were associated with decreased CEL activity whereas higher total cholesterol levels were associated with lower BPF.

The recruitment and extravasation of immune cells across the activated vascular endothelium of the blood brain is considered to a critical step in MS pathogenesis.[1] MS is also associated with significant amounts of cerebral vascular endothelial dysfunction[28,29] and with cerebral hypoperfusion.[30,31] Our working hypothesis is that the pro-inflammatory and thrombogenic processes associated with dyslipidemia could plausibly contribute to disease progression in MS via diverse mechanisms at the blood brain barrier vascular endothelium, e.g., by enhancing leukocyte recruitment, increasing endothelial dysfunction and by increasing the risk of hypoperfusion.

The effects size contributions of individual lipid profile variables to disability change were modest but significant: the partial correlation coefficient rp values were in the 0.10 - 0.15 range. We found greater EDSS worsening in patients with higher cholesterol (p = 0.001) and LDL (p = 0.006) levels at baseline. Similar associations were seen for MSSS, a disability measure with better metric properties that corrects the EDSS for disease duration. Nonetheless, our results provide mechanistic support, albeit indirect to the epidemiological findings of Marrie et al. who found that vascular comorbidities are associated with a substantially increased risk of disability progression in MS.[22] Long-term adherence to a low saturated fat diet has been implicated in better clinical outcomes in MS.[32] Although the MS cases in the Nurse Health Study cohort did not indicate associations between diet and the risk of developing MS, an association between obesity during adolescence has been reported.[33]

The primary limitations of our study stem from its retrospective study design. Another caveat is the inclusion of statin-treated patients (22.2% of sample). Because hypercholesterolemia occurs with greater frequency in older male patients, the inclusion of the statin-treated sub-group introduces demographic heterogeneity. We did not find evidence for differences in overall lipid profiles in the statin-treated subset but the group on statin treatment was more frequently male, had greater mean age, disease duration, BMI, baseline EDSS scores and also a somewhat higher proportion of progressive MS, all of which would also be expected in an older and male MS patient group. This cluster of demographic characteristics is generally representative of statin treated patients in the population. All of our statistical analyses were corrected for age and sex to address demographic differences. In addition to their direct effects on cholesterol production, statins exhibit pleiotropic immunomodulatory effects in vitro[34] and in chronic and relapsing experimental autoimmune encephalomyelitis, an animal model of MS.[35] Cholesterol is a major component of myelin and statins may hinder remyelination by inhibiting cholesterol synthesis in the brain.[36,37] The studies of statin treatment in MS have likewise also yielded mixed results.[38–42] Therefore, to further address limitations imposed by the pleiotropic effects of statins and the representative demographic differences, we conducted sub-analyses in patients who were not on statin therapy. Our statin treated group did show a lower CEL number and CE-LV, with a higher T1-LV and a trend toward decreased BPF compared to the non-statin group. We avoided comparing the groups with and without statin treatment in results because this study was not designed to address the specific role if any of statins in MS therapeutics.

In a study of 30 MS patients, statin treatment resulted in a significant decrease in the number and volume of CEL on serial monthly MRI.[39] A post hoc analysis of the interferon-beta treated control arm of the SENTINEL study did not indicate an effect of statins on adjusted annualized relapse rate, disability progression, number of CEL, or number of new or enlarging T2-hyperintense lesions over 2 years.[40] The STAYCIS trial to assess statin treatment in slowing the conversion of CIS did not meet its primary endpoint.[41] The SIMCOMBIN trial indicated that statin treatment did not provide benefit in MS patients on interferon-beta.[43]

Our data suggest a negative influence of high cholesterol and triglycerides on disease course and a favorable influence of higher HDL levels on acute inflammatory activity in MS patients. Lifestyle changes including adoption of a healthier diet and regular exercise in order to improve the serum lipid profile may be beneficial for MS patients to improve their neurological condition.

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