Sociocognitive Intervention and Rehabilitation Program in Multiple Sclerosis

The REACT-MS project is designed as a Phase IIa, single-center, randomized, pragmatic, and prospective clinical trial with blinded outcome assessment, following the PROBE methodology. Its overarching aim is to evaluate the efficacy of an innovative sociocognitive rehabilitation program in patients with multiple sclerosis (MS). Beyond this primary goal, the study also intends to characterize cognitive phenotypes in MS, investigate the role of cognitive reserve and metacognition in modulating the effectiveness of the intervention, and correlate neuropsychological performance with clinical, neuroimaging, and biochemical biomarkers in order to propose a predictive model of cognitive disease progression.

The research team is composed of neurologists and neuropsychologists from the ULS Coimbra and University of Coimbra, with extensive expertise in MS care, clinical neuropsychology, biomarker research, and clinical trial coordination. The principal investigator and co-investigators bring a strong record of clinical studies, competitive funding and international publications.

Multiple sclerosis is a chronic, autoimmune, demyelinating disease of the central nervous system characterized by inflammation, neurodegeneration, and an unpredictable clinical course. It is the leading non-traumatic cause of disability in young adults. In addition to motor and sensory symptoms, cognitive impairment affects between 40 and 65 percent of patients and can appear even in the earliest stages of the disease. Often underestimated, these deficits may precede structural abnormalities detectable by magnetic resonance imaging, functioning as early markers of disease activity. Timely diagnosis and the implementation of patient-tailored cognitive rehabilitation programs have shown sustained benefits that extend beyond the intervention period, which underscores the rationale for this study.

The study will randomize participants into an intervention arm and a control arm. Only those in the intervention group will undergo a combined program consisting of weekly sociocognitive rehabilitation sessions using the COGWEB platform and an emotional processing intervention called EMOPRINT. Most sessions will be home-based and delivered online, with only one in-person session scheduled every three months to minimize dropout and fatigue. This intervention will last for one year. A comprehensive baseline assessment will be conducted, including clinical and demographic data, disability scoring with the EDSS, magnetic resonance imaging parameters such as lesion load and brain atrophy, and serum biomarkers including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Neuropsychological testing will encompass measures of global cognition, processing speed, memory, language, attention, executive functions, and social cognition. Questionnaires addressing fatigue, mood, quality of life, and cognitive reserve will also be included, and several instruments will be adapted to assess metacognition. Participants will be reassessed at 12 and 24 months to enable longitudinal monitoring of cognitive and clinical outcomes.

Data will be collected through both direct clinical assessment and electronic health records. Each participant will be assigned a unique identifier to ensure confidentiality, and data will be managed using an electronic case report form (eCRF) implemented on the REDCap platform. Secure data storage, anonymization procedures, and standardized operational protocols will be applied in strict compliance with the General Data Protection Regulation (GDPR), national legislation, and the principles of the Declaration of Helsinki. Data will be archived for five years, while scientific results may be shared in peer-reviewed publications and open-access databases with full protection of participant privacy.

The study aims to recruit 130 patients, with 65 participants per arm. Statistical analyses will include both descriptive and inferential methods using SPSS and R. The trial has been planned over a period of 36 months, comprising two months of preparation, one month for ethical approvals, three months for project implementation, twelve months for recruitment, six months for data analysis, and six months for reporting and publication. Ethical oversight will be provided by the Research Ethics Committee of ULS Coimbra, and the study will adhere to ICH-GCP standards and the Declaration of Helsinki.

The project incorporates contingency planning to address recruitment challenges, including referral collaborations with other hospitals in the central region of Portugal. Adherence is not expected to be a major limitation given the home-based structure of the intervention, which minimizes burden and facilitates patient compliance.

The main innovation of REACT-MS lies in the implementation of a combined sociocognitive and emotional rehabilitation program, delivered largely online and adapted to the needs of MS patients. This dual approach aims to enhance cognitive performance and facial emotion recognition while reducing fatigue-related barriers to participation. Moreover, the study integrates clinical, neuroimaging, and biochemical biomarkers into a predictive framework that could inform individualized prognostic modeling of cognitive outcomes.

The expected impact is significant at both clinical and scientific levels. By shifting from a dichotomous classification of preserved versus impaired cognition to the definition of cognitive phenotypes, the project may contribute to more personalized rehabilitation strategies. The integration of cognitive reserve and metacognition is anticipated to explain individual variability in rehabilitation outcomes, as these concepts have been associated with improved coping mechanisms and resilience of brain networks in the context of MS. Ultimately, the project has the potential to establish new predictive markers of disease progression, to inform clinical practice, and to set the stage for future multicenter trials, while offering MS patients sustainable and effective rehabilitation approaches that improve long-term quality of life.

• Modified Fatigue Impact Scale - MFIS (PROM: Patient Reported Outcome Measure) [Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months]
• Cognitive Reserve Index Questionnaire - CRIq [Time frame: At baseline]
• Hospital Anxiety and Depression Scale - HADS (PROM: Patient Reported Outcome Measure) [Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months]
• World Health Organization Quality of Life short-form - WHOQOL-Bref (PROM: Patient Reported Outcome Measure) [Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months]
• Neurofilament Light chain (NfL): pg/mL [Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months]
• Glial Fibrillary Acidic Protein (GFAP): pg/mL [Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months]
• Number of T2 lesions in brain MRI [Time frame: At baseline, follow-up 12 months and follow-up 24 months]
• Status of MRI T2 lesions [Time frame: At baseline, 12 months and 24 months.]
• MRI lesion load (mm3) [Time frame: At baseline, 12 months, 18 months and 24 months.]
• MRI- affected brain region (cerebellum) [Time frame: At baseline, 12 months and 24 months.]
• MRI- affected brain region (spinal cord) [Time frame: At baseline, 12 months and 24 months.]
• MRI- affected brain region (cortical/juxtacortical) [Time frame: At baseline, 12 months and 24 months.]