Cognitive reserve in multiple sclerosis: Exploring MS-related factors and engagement in enriching activities

Introduction: Cognitive reserve (CR) refers to an individual’s ability to adapt cognitive processes in response to brain atrophy. CR may protect against cognitive impairment in multiple sclerosis (MS). However, common CR measures were originally developed for a general older adult population. People with MS (pwMS) are a younger population and MS-related factors (e.g., disability, fatigue, depression) may impact on engagement with enriching activities that build CR after the diagnosis (e.g., occupation, leisure activities). It is unclear to what extent CR research in MS had accounted for the potential impact of living with MS on CR-building. It is also unclear how pwMS and people without MS differed in CR, and whether common MS symptoms relate to CR-building in pwMS. These gaps are addressed through three original research studies. Study 1: Study 1 is a systematic review of 115 studies on CR in MS. Less than half (47.8%) of the studies assessed engagement in enriching activities beyond the MS diagnosis. Of these studies, 27.3% did not account for MS symptoms in analyses investigating the relationship of CR with study outcomes; 20.0% accounted for MS symptoms, but only through their eligibility criteria (e.g., excluding pwMS with depression). The remaining 52.7% accounted for MS symptoms in statistical analyses. Four studies conducted their analyses with and without controlling for common MS symptoms, showing that CR was less or not at all protective when accounting for MS-impact. Study 2: Study 2 is a cross-sectional study examining how CR differs between pwMS and a neurologically healthy age- and gender-matched control group. PwMS (n = 206) and people without MS (n = 150) did not differ in self-reported engagement in cognitively enriching leisure activities during their early 20s. However, pwMS reported a lower level of recent engagement during the last year compared to people without MS. PwMS self- reporting high levels of recent engagement in cognitively enriching leisure activities experienced low levels of self-reported cognitive difficulty. However, the association between recent engagement in cognitively enriching leisure activities and self- reported cognitive difficulty was no longer significant when controlling for fatigue and depression in a partial correlation. Study 3: Study 3 is a cross-sectional study conducted in collaboration with a specialist MS outpatient clinic to test if CR interacts with MS neuropathology to predict cognitive outcomes in pwMS (n = 54), whilst considering the potential impact of MS-related factors. MRI markers of MS neuropathology, CR, and their respective interaction terms, did not predict cognitive outcomes. However, higher age and disease-free years were positively associated with CR levels. In contrast, a self-reported history of anxiety before the MS diagnosis, and a self-reported history of depression after the MS diagnosis were negatively associated with CR levels. Conclusion: This research programme demonstrates that previous research reporting an association between CR and cognitive outcomes, without considering the potential impact of MS-related factors, may have overestimated the protective nature of CR. This thesis offers suggestions for a new approach to assessing and investigating CR in MS. The findings of this thesis also have the potential to inform CR theory and the development of clinical interventions for pwMS.