• Vincenzo Daniele Boccia, Elisa Leveraro, Emilio Cipriano, Caterina Lapucci, Tommaso Sirito, Maria Cellerino, Giacomo Rebella, Lorenza Nasone, Giacomo Boffa, and Matilde Inglese.
• Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università degli Studi di Genova Dipartimento di Neuroscienze Riabilitazione Oftalmologia Genetica e Scienze Materno-Infantili, Genova, Liguria, Italy.
• J. Neurol. Neurosurg. Psychiatr. 2025 Jan 31.

BackgroundHigh-efficacy disease-modifying therapies (HETs) have substantially improved multiple sclerosis (MS) management, yet ongoing cognitive decline remains a concern. This study aims to assess Symbol Digit Modalities Test (SDMT) changes in patients with stable relapsing-remitting MS (RRMS) treated with HETs and to evaluate the role of baseline MRI biomarkers as predictors of SDMT changes.MethodsConsecutive patients with RRMS treated with HETs underwent clinical, SDMT and MRI assessment at baseline with SDMT and clinical re-evaluation after 24 months. Patients presenting relapses or MRI activity (new T2 and/or gadolinium-enhancing lesions) during follow-up were excluded. Cognitive changes were defined using the 90% CI regression-based reliable change index methodology accounting for sex, age, education and baseline score. Baseline MRI examination included three-dimensional-sagittal Fluid Attenuated Inversion Recovery (FLAIR), T1-Magnetization Prepared - RApid Gradient Echo (T1-MPRAGE) and quantitative susceptibility mapping (QSM) for paramagnetic rim lesions (PRLs) and QSM-isointense lesions (ISO) assessment. Univariate and multivariable regression analyses were performed to predict SDMT changes.Results90 patients (mean age: 40.3 years, median Expanded Disability Status Scale: 2.0) were included. PRLs were present in 46 (51.1%) patients. After 24 months, 13 (14.4%) patients showed SDMT decline and 8 (8.9%) showed improvement. At multivariable analyses, PRLs were associated with higher risk of SDMT decline (β: 2.70, p: 0.02, OR: 14.82) while higher ISO lesion volumes were weakly associated with SDMT improvement (β: 0.07, p: 0.01, OR: 1.07).ConclusionsSDMT decline and improvement are detectable in patients with RRMS without clinical or MRI activity over 2 years. PRLs seem to predict SDMT decline in MS, underscoring the critical role of compartmentalised chronic inflammation in disease progression.© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.

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