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Short-term practice effects on cognitive tests predict future brain atrophy progressionand treatment response to fingolimod in multiple sclerosis
Cognitive impairment occurs in more than half of patients with multiple sclerosis (MS) and is a leading cause of disability.1 The Paced Auditory Serial Addition Test (PASAT) is part of the Multiple Sclerosis Functional Composite (MSFC) and has been widely used in clinical research to assess cognitive status of patients with MS because it is a sensitive assessment of information processing speed, attention and working memory, which are the cognitive domains most frequently affected in MS. However, repeated exposures to the PASAT can lead to improvements in performance, which is referred to as practice effects. Since practice effects are most evident for the PASAT among three measures of the MSFC,2 its susceptibility to practice effects potentially could raise important clinical issues concerning how to interpret PASAT scores. Such improvements are generally observed in cognitive and neuropsychological tests and have traditionally been considered to be error variance that should be minimised. Thus, methods capable of attenuating practice effects are warranted to avoid misinterpretation of cognitive outcomes in clinical trials. In contrast to their potential problem in clinical trials with cognitive outcomes, however, there is growing evidence that practice effects may be an early marker of pathological cognitive decline in older adults because they can provide predictive information about future cognitive performance.3 For example, presence of short-term practice effects differentiates cognitively intact older adults from those with cognitive impairment. In addition, practice effects are diminished in asymptomatic older adults who subsequently progress to symptomatic Alzheimer’s disease.
In their JNNP paper, Sormani et al 4 assessed performance changes in PASAT scores from screening to baseline in 1009 patients with relapsing–remitting MS as a measure of learning ability and cognitive reserve, using post hoc analysis of pooled data from two phase III trials comparing fingolimod and placebo: FREEDOMS and FREEDOMS II. There was an inverse correlation between PASAT score at screening and PASAT change, thus, the authors quantified learning ability after adjusting for the impact of baseline cognitive performance. The study showed that learning ability was associated with normalised brain volume at baseline, disease severity and age, and provided predictive information about future clinical outcomes. Higher learners showed less brain atrophy over 2 years and better treatment response to fingolimod assessed by 6-month confirmed disability progression.
Although the PASAT is a sensitive measure of cognitive impairment in MS, low performance on the PASAT does not necessarily confirm cognitive impairment. Its specificity may be limited by confounding factors and performance on the PASAT is easily affected by arithmetic ability and emotional state. Therefore, replication of current findings in other cohort and clinical trial data will further confirm the potential impact of short-term practice effects on the PASAT to predict future disease outcomes and treatment response in MS. From a research standpoint, this study might have a potential implication for the design of future MS clinical trials. Performance changes in the PASAT from screening to baseline might be used as a factor to be considered in patient randomisation.
Contributors HO is the sole contributor of this editorial commentary.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Commissioned; internally peer reviewed.