Metabolic changes in normal-appearing white matter associate with MRI measures of disease burden in relapsing-remitting multiple sclerosis over three years

Myo-inositol (mI) and total N-acetylaspartate (tNAA) are potential MR spectroscopic imaging (MRSI) biomarkers of smouldering-associated worsening in multiple sclerosis (MS). In this study, we explored metabolic changes in normal-appearing white matter (NAWM) in patients with relapsing-remitting MS (pwRRMS) using 7 T MRSI. 20 pwRRMS were scanned annually with 2D-MRSI, with follow-up ranging up to three years. Metabolic ratios were calculated within NAWM for each measurement and assessed cross-sectionally and longitudinally with established and emerging MRI measures of disease burden, including paramagnetic rim lesions (PRLs), brain atrophy, and T2 lesion load. At baseline, pwRRMS showed higher mI/tNAA (β = 0.058; p = 0.047) and lower tNAA/total creatine (tCr) (β = - 0.106; p = 0.029) compared to controls. tNAA/tCr was further reduced in pwRRMS with PRLs (β = - 0.138; p = 0.022). mI/tNAA was associated negatively with cerebral WM volume (β = - 0.001, p = 0.015) and positively with T2 lesion volume (β = 0.009; p = 0.044). mI/tNAA increased longitudinally in pwRRMS (β = 0.014; p = 0.022), especially with higher PRL count (β_{timepoint:PRLcount} = 0.016; p = 0.045). An association between tNAA/tCr and the interaction of time with total GM volume was observed but did not survive FDR-correction (β = 0.001; p = 0.078). These findings further support the clinical relevance of mI and tNAA alterations as imaging biomarkers of underlying pathology in MS. They highlight the value of 7 T MRSI in capturing subclinical disease burden and underscore the association of PRLs with overall widespread WM damage.