Regional normal-appearing white matter metabolic profiles and cognition in early relapsing-remitting multiple sclerosis: a multi-voxel proton magnetic resonance spectroscopy study.

Background

Cognitive impairment in multiple sclerosis (MS) is common but only weakly explained by conventional magnetic resonance imaging. Proton magnetic resonance spectroscopy (¹H-MRS) detects microstructural damage in normal-appearing white matter (NAWM). We examined whether regional NAWM metabolic profiles are spatially patterned in early relapsing-remitting MS (RRMS) and whether they relate to cognition.

Methods

In this cross-sectional study, 52 patients with early RRMS (Expanded Disability Status Scale 0-3; 51 with usable spectroscopy) and 44 matched controls underwent multi-voxel three-dimensional ¹H-MRS at 3 tesla across six supracallosal NAWM regions. Group differences used Mann-Whitney tests with false discovery rate correction, and a group × region analysis tested for disease-related disruption. NAA/Cr-cognition associations used Spearman and partial correlations and multivariable models.

Results

NAA/Cr differed between groups in four of six regions, and a group × region interaction (p < 0.001) indicated that the regional NAA/Cr pattern in RRMS was disrupted beyond the physiological anterior-posterior gradient seen in controls. Frontal NAA/Cr correlated with processing speed (ρ = 0.350, p = 0.012) and parietal NAA/Cr with verbal learning (ρ = 0.327, p = 0.019), but neither survived adjustment for age or parsimonious modelling, in which disability was the main independent correlate of processing speed.

Conclusion

Early RRMS shows spatially organised NAWM metabolic disruption. Regional NAA/Cr-cognition associations are detectable but weak and not independent of age or disability, and frontal NAWM integrity relates more to physical function than cognition, supporting a network-disconnection model with limited cognitive specificity. These findings are preliminary and need longitudinal confirmation.