Cognitive impairment (CI) is widely recognized as a core feature of multiple sclerosis (MS) clinical manifestations (Chiaravalloti and DeLuca, 2008). The mechanisms underlying MS-related CI are not completely known (Di Filippo et al., 2018); focal structural damage of neuronal circuits due to MS lesions and pathological changes within the normal appearing white matter play a significant role, by disrupting brain connectivity (Dineen et al., 2009; Mollison et al., 2017). Moreover, independent of focal lesions, the immune system also exerts detrimental effects on neuronal survival and synaptic plasticity, the cellular mechanism responsible for shaping connections between neurons (Nisticò et al., 2017). Among the immune system components involved in MS, B cells have emerged as key players (Cencioni et al., 2021). Indeed, B cells contribute to the organization of lymphoid aggregates in the cerebral meninges, an important site of immune cell activation and expansion in the MS brain (Magliozzi et al., 2007). These structures have been associated with the presence of cortical lesions in MS, and a negative effect on the function of cortical neurons has been hypothesized (Farina et al., 2017; Magliozzi et al., 2018).

A contribute in the understanding of CI determinants in MS may come from studies based on pathophysiological biomarkers measured in matrices that closely reflect biological changes occurring in the central nervous system (CNS) (Gaetani et al., 2021). Currently, one of the most robust biomarkers of intrathecal B cell activation is the presence of immunoglobulin G (IgG) oligoclonal bands (OCB) in the cerebrospinal fluid (CSF) (Link and Huang, 2006). CSF OCB assessment has limitations, including subjectivity in interpretation and qualitative outcomes (Link and Huang, 2006). An alternative measure of intrathecal B cell activation are CSF immunoglobulin free light chains (FLC) (Leurs et al., 2019). They can be quantitatively measured using automated nephelometry or turbidimetry. Two types of FLC, kappa (κ) and lambda (λ), can be measured, with κ-index being a reliable indicator of intrathecal IgG synthesis in MS (Gaetani et al., 2019a).

Given these considerations, the primary objective of this study was to explore the hypothesis that intrathecal activation of B cells may negatively affect cognitive performance in MS, independent of the well-established role of focal and diffuse MRI-visible brain damage in causing CNS networks disconnection. To accomplish this, we conducted a retrospective investigation on the association between κ-index and cognitive performance in a cross-sectional cohort of individuals with MS. Our analysis involved a multimodal approach incorporating κ-index measurements together with brain magnetic resonance imaging (MRI) T2 lesion load and regional volumes.