Tract-based χ-separation imaging differentiates multiple sclerosis from neuromyelitis optica spectrum disorder by mapping iron and myelin signatures

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Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) frequently present with overlapping clinical and radiological features, complicating differential diagnosis. Iron and myelin abnormalities are central to their pathophysiology, yet their distinct contributions in vivo remain poorly characterized. This study applied tract-based χ-separation imaging to evaluate susceptibility-related microstructural changes in normal-appearing white matter (NAWM) and lesions in MS and NMOSD, aiming to identify imaging patterns between these demyelinating diseases. Eighty patients (48 MS, 32 AQP4-IgG-positive NMOSD) and 39 healthy controls were included. Quantitative susceptibility mapping (QSM) with χ-separation was performed on a 3D multi-echo gradient-echo sequence to obtain bulk susceptibility and to derive model-based positive susceptibility (χ pos ) and negative susceptibility (χ neg) sources. After masking lesions, mean values of susceptibility, χ pos and χ neg were extracted from 20 JHU white matter tracts, and lesions were compared with tract-matched NAWM within each disease group. Key features were identified using LASSO with cross-validation, and receiver operating characteristic (ROC) analysis was used to assess discrimination between MS and NMOSD. The three groups were similar in age and sex distribution. Mean disease duration was 4.12 ± 4.58 years in MS and 3.61 ± 4.26 years in NMOSD. Compared with NMOSD, MS showed reduced χ pos in 12 NAWM tracts and increased χ neg in 5 tracts (all FDR-corrected P < 0.05), particularly in the forceps major, inferior fronto-occipital fasciculus, and inferior longitudinal fasciculus, whereas no significant NAWM differences were found between NMOSD and HCs. In lesion–NAWM comparisons, MS lesions showed reduced χ pos in 11 tracts and increased χ neg in 16 tracts, whereas NMOSD lesions showed corresponding changes in 4 tracts. Conventional QSM did not observe corresponding group differences. Tract-wise χ metrics showed exploratory discriminatory value, with the internally validated classification model yielding a pooled held-out AUC of 0.771 (95% CI: 0.660–0.868). Tract-based χ-separation sensitively captures susceptibility-related microstructural alterations and reveals distinct χ pos /χ neg patterns in MS and NMOSD. These findings support the potential of tract-wise χ metrics as imaging markers for characterizing disease-specific white matter changes.