Systematic review of cognitive reserve in multiple sclerosis: Accounting for physical disability, fatigue, depression, and anxiety

Background: Cognitive reserve (CR) describes an individual's ability to adapt cognitive processes in response to brain atrophy, and has been reported to explain some of the discrepancy between brain atrophy and cognitive functioning outcomes in multiple sclerosis (MS). CR in MS is typically investigated by assessing an individual's pre- and/or post-diagnosis enrichment, which includes premorbid intellectual abilities, educational level, occupational attainment, and engagement in cognitively enriching leisure activities. Common MS symptoms (e.g., physical disability, fatigue, depression, anxiety) may impact an individual's ability to engage in various CR-enhancing activities post-diagnosis. It is unknown to what extent these MS symptoms have been taken into account in MS research on CR. As such, we identified whether studies assessed CR using measures of premorbid or continuous (including post-diagnosis) enrichment. For studies investigating continuous enrichment, we identified whether studies accounted for MS-impact, which MS symptoms were accounted for, and how, and whether studies acknowledged MS symptoms as potential CR-confounds. Methods: Three electronic databases (PsycINFO, PubMed, Scopus) were searched. Eligible studies investigated CR proxies (e.g., estimated premorbid intellectual abilities, vocabulary knowledge, educational level, occupational attainment, cognitively enriching leisure activities, or a combination thereof) in relation to cognitive, brain atrophy or connectivity, or daily functioning outcomes in adult participants with MS. We extracted data on methods and measures used, including any MS symptoms taken into account. Objectives were addressed using frequency analyses and narrative synthesis. Results: 115 studies were included in this review. 47.8% of all studies investigated continuous enrichment. Approximately half of the studies investigating continuous enrichment accounted for potential MS-impact in their analyses, with only 31.0% clearly identifying that they treated MS symptoms as potential confounds for CR-enhancement. A narrative synthesis of studies which investigated CR with and without controlling statistically for MS-impact indicated that accounting for MS symptoms may impact findings concerning the protective nature of CR. Conclusion: Fewer than half of the studies investigating CR proxies in MS involved continuous enrichment. Just over half of these studies accounted for potential MS-impact in their analyses. To achieve a more complete and accurate understanding of CR in MS, future research should investigate both pre-MS and continuous enrichment. In doing so, MS symptoms and their potential impact should be considered. Establishing greater consistency and rigour across CR research in MS will be crucial to produce an evidence base for the development of interventions aimed at improving quality of care and life for pwMS.