Implementation of a Program to Enhance Cognitive Reserve in Patients With Multiple Sclerosis (EM Reserva Program)

BACKGROUND: Cognitive reserve (CR) may help mitigate cognitive decline in people with multiple sclerosis (PwMS); however, few interventions have targeted CR enhancement, and none have focused on individuals without baseline cognitive impairment. The EM Reserva program is a multimodal intervention that combines cognitive leisure activities, aerobic exercise, and structured social engagement and is designed to strengthen CR in individuals with relapsing-remitting MS (RRMS). METHODS: This pragmatic, single-center, observer-blinded randomized controlled trial included PwMS aged 18-55 years with RRMS and no cognitive impairment. Participants were randomized in a 1:1 ratio to either the EM Reserva program or usual cognitive care. Outcomes were assessed at baseline and at 6-month and 12-month time points. The primary endpoint was the change in Symbol Digit Modalities Test (SDMT) scores at 6 months. Secondary outcomes included additional neuropsychological measures, Modified Fatigue Impact Scale-5 (MFIS-5), Perceived Deficits Questionnaire-5 (PDQ-5), and Multiple Sclerosis Quality of Life‑54 (MSQOL-54). Analyses followed a modified intention-to-treat approach. RESULTS: < 0.022) and higher Controlled Oral Word Association Test (COWAT) scores. These cognitive gains were not sustained at 12 months. Fatigue improved in both groups at 6 months but remained significantly lower only in the EM Reserva group at 12 months. No between-group differences were observed in PDQ-5, MSQOL-54, or other neuropsychological measures. CONCLUSION: The EM Reserva program produced short-term improvements in processing speed and verbal fluency in cognitively preserved PwMS, along with sustained reductions in fatigue. However, cognitive benefits were not maintained at 12 months, and subjective cognitive functioning remained unchanged. These findings suggest that multimodal CR-oriented interventions may offer temporary cognitive advantages, but long-term maintenance strategies are likely required to sustain gains. CLINICAL TRIAL REGISTRATION: No: NCT05546424. https://clinicaltrials.gov/study/NCT05546424.