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Background and Objectives:Cognitive impairment is a common and impactful symptom of relapsing-remitting multiple sclerosis (RRMS). Cognitive outcome measures are often used in cross-sectional studies, but their performance as longitudinal outcome measures in clinical trials is not widely researched. In this study, we used data from a large clinical trial to describe change on the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) over up to 144 weeks of follow-up.Methods:We used the dataset from DECIDE (clinicaltrials.gov identifierNCT01064401), a large randomized controlled RRMS trial to describe change on the SDMT and PASAT over 144 weeks of follow-up. We compared change on these cognitive outcomes with change on the timed 25-foot walk (T25FW), a well-established physical outcome measure. We investigated several definitions for clinically meaningful change: any change, 4-point change, 8-point change, and 20% change for the SDMT, any change, 4-point change and 20% change for the PASAT, and 20% change for the T25FW.Results:DECIDE included 1,814 trial participants. SDMT and PASAT scores steadily improved throughout follow-up: the SDMT from a mean 48.2 (standard deviation, SD, 16.1) points at baseline to 52.6 (SD 15.2) at 144 weeks, and the PASAT from 47.0 (SD 11.3) at baseline to 50.0 (SD 10.8) at 144 weeks. This improvement in scores is most likely due to a practice effect. Throughout the trial, participants were more likely to experience improvement than worsening of their SDMT and PASAT performance, while the number of worsening events on the T25FW steadily increased. Changing the definition of clinically meaningful change for the SDMT and PASAT, or using a 6-month confirmation changed the overall number of worsening or improvement events, but did not affect the overall behaviour of these measures.Discussion:Our findings suggests that the SDMT and PASAT scores do not accurately reflect the steady cognitive decline that people with RRMS experience. Both outcomes show post baseline increases in scores, which complicates the interpretation of these outcome measures in clinical trials. More research into the size of these changes is needed before recommending a general threshold for clinically meaningful longitudinal change.

Autopsy cases show that cortical lesions (CLs) in multiple sclerosis (MS) lack lymphocyte/macrophage influx, blood-brain barrier breakdown, and complement activation. However, some CLs were demonstrated to harbor activated microglia. Here, we assessed the clinical significance of microglia activation in CLs in a large autopsy sample, and we investigated possible interrelationships with other pathologic characteristics.We cross-sectionally investigated the clinicopathologic characteristics of 22 patients with MS with extensive subpial demyelination (CL group) and 19 patients with MS with only little demyelination of the cerebral cortex (non-CL group).A subset of the patients in the CL group (12 patients) showed rims of activated microglia (RAM) at the border of the CLs (RAM-CL group), whereas the other 10 patients in this group did not show microglia activation (non-RAM-CL group). A subsequent comparison between groups showed that patients with MS harboring RAM-CLs were significantly younger at the time of their death (53.5 years) than patients harboring mainly non-RAM-CLs (68.7 years; p0.05) or patients without extensive numbers of CLs (66.9 years; p0.01). In addition, a significantly shorter disease duration was found for the RAM-CL group (mean 20.9 years) than for the non-CL group (mean 34.5 years; p0.05). We also found that the presence of RAM-CLs is associated with a higher number of chronic active white matter (WM) lesions (Spearman ρ = 0.74; p0.0001).RAM-CLs were found in a subset of patients with MS who also have more active WM inflammation and a less favorable disease course.