Dysregulated Cholesterol Metabolism, Chronic Inflammation, and Disability in Severe Progressive Multiple Sclerosis

BACKGROUND: Dysregulated lipid metabolism, which can affect remyelination and neural repair, has not been extensively investigated in progressive multiple sclerosis (PMS). The goal was to examine whether dysregulated cholesterol metabolism was associated with disability in PMS. METHODS: The study sample comprised 53 Severe PMS patients (Expanded Disability Status Scale, EDSS score: 7.0-9.5) requiring skilled nursing and 53 age, sex- and disease duration-matched community-dwelling Control PMS patients (EDSS score: 3.0-6.5). Patients underwent neurological examinations and provided blood samples. Cholesterol and apolipoprotein (Apo) profiles, nuclear magnetic resonance spectroscopy metabolomic profiles, inflammatory cytokines, neuroaxonal, and glial injury biomarkers were obtained. Disability was measured on the EDSS and the Combinatorial Weight-Adjusted Disability (CombiWISE) scales. RESULTS: The Severe PMS group had lower high-density lipoprotein cholesterol (HDL-C), ApoA-I, and ApoA-II levels (all p < 0.001) and higher ApoB and ApoE levels. The nutritional status biomarker, albumin, was lower, and the chronic inflammation marker, GlycA, was higher in Severe PMS versus Control PMS (all p < 0.001). Total cholesterol, ApoA-II, and ApoB were associated with disability on the EDSS and CombiWISE scale. Difference-correlogram analyses revealed substantial remodeling of biomarker interdependencies in Severe PMS. ApoE showed stronger associations with lipid and nutritional biomarkers in Severe PMS, but with neuroaxonal markers (serum neurofilament light chain, glial fibrillary acidic protein) in Control PMS. Inflammatory cytokines (tumor necrosis factor, interleukin-6) showed stronger associations with apolipoproteins in Severe PMS, whereas several lipid-inflammation and lipid nutritional correlations were attenuated. CONCLUSIONS: Disrupted cholesterol metabolism and chronic inflammation are strongly linked to greater disability in Severe PMS. Our results also indicate marked alterations in metabolic, inflammatory, nutritional, and neuroglial biomarker networks in Severe PMS.