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

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 (D 2 O) 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.