High-density lipoprotein cholesterol is associated with multiple sclerosis fatigue: A fatigue-metabolism nexus?

J Clin Lipidol. 2019 Jul-Aug;13(4):654-663.e1. doi: 10.1016/j.jacl.2019.06.003. Epub 2019 Jun 18.


Background: Fatigue is a frequent symptom in multiple sclerosis (MS). The role of cholesterol and lipids in MS fatigue has not been investigated.

Objective: To investigate the associations of cholesterol biomarkers and serum neurofilament light chain (sNfL) with fatigue in relapsing-remitting MS.

Methods: This cross-sectional study included 75 relapsing-remitting MS patients (69% female, mean age ± SD: 49.6 ± 11 years and median Expanded Disability Status Scale score: 2.0). Fatigue, disability, and depression were assessed with Fatigue Severity Scale (FSS), Expanded Disability Status Scale, and the Beck Depression Index-Fast Screen, respectively. sNfL was measured using single-molecule array technology. Plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and an apolipoprotein panel data were obtained. Soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), chemokine (C-C motif) ligand 5 (CCL5 or RANTES), and CCL18 levels were measured to assess inflammation.

Results: The mean FSS was 4.27 ± 1.73, and 57% had severe fatigue status (SFS, FSS ≥ 4.0). In regression analyses adjusted for age, sex, disability, and depression, lower FSS and SFS were associated with greater HDL-C (P = .006 for FSS, and P = .016 for SFS) and lower TC to HDL-C ratio (P = .011 for FSS, and P = .009 for SFS). Apolipoprotein A-II was also associated with FSS (P = .022). sNfL, CCL5, CCL18, sICAM-1, and sVCAM-1 levels were not associated with fatigue after adjusting for disability and depression.

Conclusions: TC to HDL-C ratio is associated with MS fatigue. Our results implicate a potential role for the HDL-C pathway in MS fatigue and could provide possible targets for the treatment of MS fatigue.

Keywords: Cholesterol; Fatigue; HDL; Multiple sclerosis; Neurofilaments.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Apolipoprotein A-II / blood
  • Area Under Curve
  • Biomarkers / blood
  • Cholesterol, HDL / blood*
  • Cross-Sectional Studies
  • Cytokines / blood
  • Depression / diagnosis
  • Depression / etiology
  • Fatigue / etiology
  • Fatigue / pathology*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Multiple Sclerosis / complications
  • Multiple Sclerosis / pathology*
  • ROC Curve
  • Recurrence
  • Severity of Illness Index


  • Apolipoprotein A-II
  • Biomarkers
  • Cholesterol, HDL
  • Cytokines