Clinical, structural, and functional MRI features predicting PIRMA at 5-year follow-up in multiple sclerosis

Objective: To identify baseline clinical, structural, and functional magnetic resonance imaging (MRI) features predicting progression independent of relapse and magnetic resonance imaging activity (PIRMA) in multiple sclerosis (MS). Methods: We included patients from the Italian Neuroimaging Network Initiative who showed no clinical or MRI activity at 5-year follow-up. PIRMA progressors versus stable patients were defined by confirmed Expanded Disability Status Scale (EDSS) progression. Baseline clinical features, white matter (WM) lesion, WM, cortical and deep gray matter (GM) volumes, C2-C3 spinal cord area, and functional connectivity (FC) from nine resting-state networks (RSNs) were compared. Step-wise logistic regressions tested PIRMA predictors among clinical and structural MRI features, RSNs, and kernel principal component analysis (k-PCA) characteristics. Results: Of 208 patients, 99 were excluded for clinical (n = 30) and MRI activity (n = 69). Among 109, 33% experienced PIRMA. PIRMA progressors were older, more disabled, had higher WM lesion volume, GM atrophy, and FC alterations. Logistic regressions identified higher EDSS (p < 0.001), age (p = 0.02), cortical atrophy (p = 0.04), and FC alterations as predictors (all p ⩽ 0.02). Six k-PCA components emerged; four (linked to GM atrophy, FC decrements, age, EDSS) predicted PIRMA (pseudo-R²= 0.61). Conclusion: PIRMA is linked to aging, GM atrophy, and disrupted FC, highlighting the value of integrating structural and functional MRI markers to detect silent progression in MS.