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. 2025 May 30;11(2):20552173251344555.
doi: 10.1177/20552173251344555. eCollection 2025 Apr-Jun.

Metabolic labeling kinetics of brain-derived 24S-hydroxycholesterol in blood in multiple sclerosis: Effects of treatment with the remyelinating antibody rHIgM22

Mahalakshmi Shankaran, Kelvin W Li, Hussein A Mohammed  1   2 , Joan Protasio  2 , Mark Fitch, Marcy Matthews, Edna Nyangau  1 , Gordon Smith, Samuel Klein  3 , Andrew Eisen  4 , Scott Turner  2 , Marc K Hellerstein  1
Affiliations

Metabolic labeling kinetics of brain-derived 24S-hydroxycholesterol in blood in multiple sclerosis: Effects of treatment with the remyelinating antibody rHIgM22

Mahalakshmi Shankaran et al. Mult Scler J Exp Transl Clin. .

Abstract

Background: Cholesterol is an essential and major component of myelin. Brain cholesterol turnover in humans can be studied noninvasively by metabolic labeling of the brain-specific cholesterol metabolite, 24S-hydroxycholesterol (24-OHC), which is released into blood.

Objectives: We examined the effects on brain cholesterol turnover in healthy individuals and in multiple sclerosis (MS) following treatment with placebo or the remyelinating monoclonal antibody, rHIgM22, which binds to oligodendrocytes and myelin.

Methods: In vivo synthesis rates of brain cholesterol were measured by label incorporation and die-away of 24-OHC sampled from blood during and after heavy water (D2O) intake in age- and sex-matched non-MS and clinically stable relapsing-remitting MS subjects.

Results: Incorporation and die-away of labeled 24-OHC revealed biphasic kinetics, with two kinetically distinct pools of brain cholesterol: a large, slow turnover pool and a smaller, metabolically more active pool of newly synthesized cholesterol. The latter showed significantly higher turnover rates in MS compared to non-MS subjects, which was significantly reduced in patients with MS treated with rHIgM22.

Conclusions: Plasma 24-OHC kinetics provide a minimally invasive biomarker of brain cholesterol metabolism and revealed differences between healthy and clinically stable MS subjects, with increased turnover of the metabolically active 24-OHC pool that normalized in response to rHIgM22 therapy.

Keywords: 24S-hydroxycholesterol; Multiple sclerosis; biomarkers; cholesterol turnover; myelin; virtual biopsy.

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Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
24-OHC kinetics in non-MS and MS human subjects. (a) 2H enrichment of 24-OHC in the blood of 6 non-MS and 6 MS human subjects during D2O incorporation and label die-away. (b) Synthesis rate (s) in mixed 24-OHC pool in non-MS and MS subjects. (c) Dilution rate (d) of 24-OHC in fast pool (higher turnover pool) in non-MS and MS subjects, *p < 0.05 compared to non-MS. (d) Calculated fast pool size of 24-OHC in non-MS and MS subjects. 24-OHC: 24S-hydroxycholesterol; D2O: duration of heavy water label; MS: multiple sclerosis.
Figure 2.
Figure 2.
24-OHC kinetics in patients with MS treated with placebo or rHIgM22. (a) 2H enrichment in 24-OHC in patients with MS during D2O incorporation and label die-away. (b) Synthesis rate (s) in mixed 24-OHC pool in MS subjects treated with placebo or rHIgM22 (1 or 2 mg/kg). (c) Dilution rate (d) of 24-OHC in fast pool (higher turnover pool) in MS subjects treated with placebo or rHIgM22 (1 or 2 mg/kg) (d) Calculated fast pool size of 24-OHC in MS subjects treated with placebo or rHIgM22 (1 or 2 mg/kg). *p < 0.05 compared to placebo. 24-OHC: 24S-hydroxycholesterol; D2O: duration of heavy water label; MS: multiple sclerosis; rHIgM22: monoclonal recombinant human antibody IgM22.
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