Authors: Alberto Calvi | Francesc Vivó | Elisabeth Solana | Elisabet López-Soley | Baris Kanber | Salut Albà-Arbalat | María Sepúlveda | Eugenia Martínez‐Hernández | José María Cabrera‐Maqueda | Eduardo Fonseca | Santiago Medrano-Martorell | Albert Saiz | Yolanda Blanco | Pablo Villoslada | Ferrán Prados | Eloy Martínez‐Heras | Sara Llufriú
Source: medRxiv (preprint, 2025-07-25)
Field: Chemistry — Physical and Theoretical Chemistry

Diffusivity anisotropy signature of the slowly expanding lesions predicts progression independent of relapse activity in multiple sclerosis Abstract 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 (EDSS). 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 to other lesions. Longitudinal core FA reductions within definite SELs associated with worse MSFC z-score evolution (β=0.03, 95%CI 0.01-0.05, p=0.003), higher odds for PIRA (OR=0.01, 95% CI 0.01-0.12, p=0.001), and predicted faster time to reach first PIRA event (HR=0.03 95% CI 0-0.49, 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. What is already known on this topic early detection of neuroaxonal damage in chronic active multiple sclerosis (MS) lesions is highly relevant for evaluating progression independent of relapse. MRI can identify such damage by detecting slowly expanding lesions (SELs) and assessing spatial diffusivity measures. Analysing damage within the core and perilesional areas of these lesions and their relationship to disability may clarify the mechanisms driving MS progression. What this study adds This research demonstrates that diffusion MRI reveals distinct microstructural damage in chronic active MS lesions, providing valuable markers for predicting disease progression. By examining fractional anisotropy (FA) within the core and perilesional regions of SELs, a distinctive diffusion pattern of microstructural damage was identified. This SEL-specific FA reduction correlates with higher odds and earlier onset of progression in an MS cohort assessed shortly after diagnosis. How this study might affect research and clinical practice This study underscores the potential of FA reductions in SELs as early indicators of MS progression. Incorporating diffusion MRI, to assess lesion evolution into clinical practice could enhance the early detection of subclinical disease progression, enabling timely therapeutic interventions. Implementing these techniques may improve MS management protocols and patient outcomes. Multiple sclerosis ; Signature (topology) ; Anisotropy ; Medicine ; Thermal diffusivity ; Fractional anisotropy ; Neuroscience ; Psychology ; Physics ; Diffusion MRI ; Immunology ; Mathematics ; Optics ; Radiology thermodynamics and calorimetric analyses ; Field-Flow Fractionation Techniques ; Multiple Sclerosis Research Studies