Choroid Plexus Enlargement is Associated with Disease Severity and Elevated White Matter Myo-inositol in Progressive Multiple Sclerosis

Introduction- Choroid plexus (CP) enlargement on brain MRI has been identified as an emerging neuroinflammatory biomarker in multiple sclerosis (MS), yet its relationship to downstream parenchymal neurochemical abnormalities remains unknown. Proton magnetic resonance spectroscopy (1H MRS) enables non-invasive in vivo quantification of neurometabolites, making it well-suited to probe downstream consequences of CP pathology in MS. Methods- Ultra-high-field 7T 1H MRS was performed in 45 people with MS (pwMS) (28 Relapsing Remitting MS, RRMS; 17 Progressive MS, PMS) and 43 age- and sex-matched healthy controls (HCs) in the posterior cingulate cortex (PCC) and centrum semiovale white matter (CSWM). CP volume, EDSS, and MS Functional Composite measures were also acquired. Group differences in metabolite concentrations were evaluated using Mann-Whitney U tests with correction for multiple comparisons, and associations between CP volume, altered metabolites, and clinical disability and functional measures were investigated. Results- Myo-inositol (mI) was significantly elevated and total N-acetylaspartate was reduced in both MS subtypes, in the CSWM. In PMS, CP volume was positively associated with CSWM mI/total creatine (tCr) ({rho} = 0.63, p = 0.008), an association absent in RRMS. Across the combined MS cohort, CP volume correlated significantly with EDSS ({rho} = 0.40, p = 0.006). Conclusions- WM mI/tCr was elevated and tNAA/tCr was reduced across MS phenotypes compared with controls, reflecting a dual metabolic signature consistent with concurrent glial overactivation and neuroaxonal compromise. Increased CP volume was associated with greater neurological disability across MS phenotypes. The association of CP enlargement with CSWM mI/tCr in PMS suggests a potential link between CP-mediated periventricular inflammation and progressive WM glial pathology. Collectively, these findings support CP volume as a clinically relevant, non-invasive biomarker and restoring CP integrity as a potential therapeutic target in PMS, where effective treatments remain limited.