Measuring cognitive change in secondary progressive MS: an analysis of the ASCEND cognition substudy

Cognitive impairment is common in multiple sclerosis (MS). Accurate measurement of cognitive change is essential for clinical trials.

The change in cognitive scores, clinical metrics of physical disability, and neuroradiological metrics was quantified in data from a phase-3 randomized controlled trial of natalizumab in secondary progressive MS (SPMS). The adults diagnosed with SPMS for ≥ 2 years and Expanded Disability Status Scale (EDSS) scores from 3 to 6.5 were randomized to receive natalizumab or placebo for 96 weeks. We evaluated change in Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), Selective Reminding Test (SRT), Brief Visuospatial Memory Test (BVMT-R), two subjective cognitive measures, Beck Depression Inventory (BDI-FS), Timed 25-foot Walk Test, Nine Hole Peg Test, measures of brain volume, and T2 lesion volume.

The outcomes were evaluated at baseline, 48-, and 96-week follow-up. There were no significant differences in cognitive change between treatment arms. SDMT and PASAT scores improved over 96-weeks: mean SDMT scores by 4.5 points (SD 9.3), mean PASAT scores by 2.4 points (SD 9.4). Verbal and visuospatial memory test performance showed no consistent change. All MRI measures showed decreased brain volumes. NHPT scores worsened little and T25FW showed steadily worsening scores.

Improvements in SDMT and PASAT performance were observed regardless of treatment arm. These findings are consistent with prior studies in MS. As it is unlikely that cognition improves over time in people with a chronic neurologic disease, these results support the need for cognitive outcomes that overcome practice and learning effects to accurately quantify change.