Diffusivity anisotropy signature of slowly expanding lesions predicts progression independent of relapse activity in multiple sclerosis

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BACKGROUND: Slowly expanding lesions (SELs) in multiple sclerosis (MS) are markers of chronic active lesions and seem to trigger disability. This study aimed to analyse spatial features of SELs through diffusion MRI and their clinical impact on progression independent of relapse activity (PIRA). METHODS: An observational study of MS subjects prospectively followed since 2011; inclusion required at least three longitudinal T1/T2-weighted and diffusion-weighted MRIs. Subjects followed clinical assessments, using Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale. At MRI, lesions were categorised using non-linear deformation as definite or possible SELs, and non-SELs. Fractional anisotropy (FA) was extracted from each lesion core and perilesional area. Differences in FA values across core and perilesional areas by SEL category were assessed using the Mann-Whitney test. Associations with PIRA and clinical outcomes were evaluated using mixed-effects, logistic and Cox regression models. RESULTS: 130 subjects underwent MRI (median 25 months) and clinical assessments (median follow-up 9.2 years), of which 29 (22%) developed PIRA. Of 4811 lesions, 8% were definite SELs. Definite SELs exhibited FA decline over time in core and perilesional areas compared with other lesions. Longitudinal core FA reductions within definite SELs were associated with worse MSFC z-score evolution (β=0.03, 95% CI 0.01 to 0.05, p=0.003), higher odds for PIRA (OR=0.01, 95% CI 0.01 to 0.12, p=0.001) and predicted faster time to reach first PIRA event (HR=0.03, 95% CI 0 to 0.49, p=0.015). CONCLUSIONS: Definite SELs show distinct greater microstructural damage and are associated with PIRA, making their FA signature a potential predictor of MS progression.

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