Pediatric Onset Multiple Sclerosis: Cognitive Assessment and Neuropsychological Correlates of Theory of Mind

Multiple Sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by inflammation, demyelination, and neurodegeneration, and represents the leading non-traumatic cause of disability in young adults (Dobson & Giovannoni, 2019). Although typically diagnosed between the ages of 20 and 40, a significant subset of patients experience disease onset during childhood or adolescence, condition known as pediatric-onset multiple sclerosis (POMS), which accounts for 3–10% of all MS cases (Langille et al., 2019; Deiva, 2020). Compared to adult-onset MS (AOMS), POMS is characterized by a more inflammatory course, earlier cognitive involvement, and a longer disease duration leading to earlier disability accumulation (Chitnis et al., 2018; Portaccio et al., 2021). Among the most concerning aspects of POMS is the high prevalence of cognitive impairment, affecting between 30–50% of patients, often manifesting early in the disease course and exerting a profound impact on academic achievement, psychosocial functioning, and quality of life (Cardoso et al., 2015; Parrish & Fields, 2019). Cognitive domains most frequently impaired include attention, processing speed, working memory, and executive functions, reflecting both disease-related damage and the disruption of normal developmental trajectories (Amato et al., 2014; Hubacher et al., 2015). Given these challenges, the development of reliable neuropsychological tools for the assessment and monitoring of cognitive functions in POMS has become a clinical priority. The Brief Repeatable Battery (BRB) has been adapted for pediatric populations but remains time-consuming and less feasible in daily practice (Falco et al., 2019). In recent years, the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has emerged as a rapid and validated screening tool for AOMS, and its adaptation to pediatric cohorts may offer an efficient method to identify cognitive impairment, track changes over time and compare data across centers (Goretti et al., 2014a; Falco et al., 2024). The development of normative data for BICAMS in Italian adolescents therefore represents a crucial step to ensure its applicability in routine clinical practice, allowing the detection of subtle deficits and the implementation of tailored cognitive rehabilitation strategies (Lin et al., 2020). Among cognitive domains, growing attention has been given to the study of Theory of Mind (ToM) in MS, as deficits in social cognition appear to be a prominent feature of the disease (Bora et al., 2016; Lin et al., 2021). ToM, the ability to attribute mental states to oneself and others, is a multidimensional construct involving both cognitive and affective components and first- and second-order meta-representational attributions (Shamay-Tsoory & Aharon-Peretz, 2007; Rossetto et al., 2024). Its disruption in POMS may compromise social interactions, academic functioning, and quality of life, since the inflammatory and neurodegenerative processes occur during critical periods of brain growth, myelination, and maturation of neural networks (Portaccio et al., 2021). However, the specific neuropsychological correlates of ToM in POMS remain poorly understood, and it is unclear to what extent deficits in ToM depend on other cognitive domains. The present thesis is therefore structured in two main empirical studies, each addressing a distinct but complementary aspect of cognition in POMS. The first study provides normative data for BICAMS in an Italian adolescent population, with attention to demographic variables such as age, sex, and education, thereby establishing a foundation for its clinical use in pediatric cohorts (Falco et al., 2024). The second study explores the neuropsychological correlates of ToM and its relation with quality of life in adults with POMS, employing the Yoni-48 task to assess both cognitive and affective components within a single paradigm (Isernia et al., 2023b). By integrating these lines of investigation, the thesis aims to advance understanding of cognitive and social cognition profiles in POMS, improve early detection of impairment, and support the design of targeted interventions for this vulnerable population.