Original article| Volume 69, 104402, January 2023

Are we ready to define cognitive worsening in MS? How different cutoffs detect future cognitive worsening after six years of follow-up

Published:November 06, 2022DOI:


      • The definition of cognitive progression is not yet clear.
      • Fixed cutoffs (e.g. 4-point) may not address variability at the individual level.
      • Most patients classified with worsening using fixed cutoffs had later improvement.
      • Using a regression-based cutoff, subsequent improvement was noticeably reduced.
      • These data raise concerns about how we are defining cognitive worsening so far.



      Although cognitive evaluation has been incorporated in recent MS clinical trials, the definition of cognitive progression is not clear and recent data are questioning the 4-point cutoff using the SDMT at the individual level. We aimed to evaluate the behavior of cognitive performance over time using different cutoffs.


      Cognitive performance over six years was analyzed in a cohort of 42 relapsing-remitting MS patients and 30 controls using verbal/visual memory and information processing speed tests. Fixed cutoffs were: 10% and 20% change (all tests) and a 4- and 8-point change (SDMT). The relative cutoff established by regression-based models was a 1SD change.


      The distributions of “worsening”, “stability”, and “improvement” showed low concordance rates across the cutoffs (p < 0.001 for most comparisons). Most patients classified with worsening initially using fixed cutoffs had subsequent improvement in all cognitive tests, yielding a low sensitivity to predict later cognitive worsening. Using the relative cutoff, the proportion of patients with subsequent improvement was noticeably smaller.


      Fixed cutoffs classify a high proportion of patients with cognitive improvement. Most patients categorized with worsening initially presented subsequent improvement. Instead, the relative cutoff generally had a better performance. These data raise concerns about how we are defining cognitive worsening so far, especially at the individual level.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Morrow S.A.
        • Drake A.
        • Zivadinov R.
        • et al.
        Predicting loss of employment over three years in multiple sclerosis: clinically meaningful cognitive decline.
        Clin. Neuropsychol. 2010; 24: 1131-1145
        • Strober L.
        • DeLuca J.
        • Benedict R.H.
        • et al.
        Multiple sclerosis outcome assessments consortium (MSOAC). Symbol digit modalities test: a valid clinical trial endpoint for measuring cognition in multiple sclerosis.
        Mult. Scler. 2019; 25: 1781-1790
        • Attix D.K.
        • Story T.J.
        • Chelune G.J.
        • et al.
        The prediction of change: normative neuropsychological trajectories.
        Clin. Neuropsychol. 2009; 23: 21-38
        • Bosma L.
        • Kragt J.J.
        • Brieva L.
        • et al.
        Progression on the multiple sclerosis functional composite in multiple sclerosis: what is the optimal cut-off for the three components?.
        Mult. Scler. 2010; 16: 862-867
        • Portaccio E.
        • Goretti B.
        • Zipoli V.
        • et al.
        Reliability, practice effects, and change indices for Rao's brief repeatable battery.
        Mult. Scler. 2010; 16: 611-617
        • Benedict R.H.B.
        • Tomic D.
        • Cree B.A.
        • et al.
        Siponimod and cognition in secondary progressive multiple sclerosis: EXPAND secondary analyses.
        Neurology. 2021; 96: e376-e386
        • Koch M.W.
        • Mostert J.
        • Repovic P.
        • et al.
        Is the symbol digit modalities test a useful outcome in secondary progressive multiple sclerosis?.
        Eur. J. Neurol. 2021; 28: 2115-2120
        • Damasceno A.
        • Pimentel-Silva L.R.
        • Damasceno B.P.
        • et al.
        Exploring the performance of outcome measures in MS for predicting cognitive and clinical progression in the following years.
        Mult. Scler. Relat. Disord. 2020; 46102513
        • Strober L.B.
        • Bruce J.M.
        • Arnett P.A.
        • et al.
        A much needed metric: defining reliable and statistically meaningful change of the oral version symbol digit modalities test (SDMT).
        Mult. Scler. Relat. Disord. 2022; 57103405
        • Sandry J.
        • Simonet D.V.
        • Brandstadter R.
        • et al.
        The symbol digit modalities test (SDMT) is sensitive but non-specific in MS: lexical access speed, memory, and information processing speed independently contribute to SDMT performance.
        Mult. Scler. Relat. Disord. 2021; 51102950
        • Damasceno A.
        • Damasceno B.P.
        • Cendes F.
        No evidence of disease activity in multiple sclerosis: Implications on cognition and brain atrophy.
        Mult. Scler. 2016; 22: 64-72
        • Damasceno A.
        • Pimentel-Silva L.R.
        • Damasceno B.P.
        • Cendes F.
        Cognitive trajectories in relapsing-remitting multiple sclerosis: a longitudinal 6-year study.
        Mult. Scler. 2020; 26: 1740-1751
        • Rao S.M.
        • Leo G.J.
        • Bernardin L.
        • et al.
        Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction.
        Neurology. 1991; 41: 685-691
        • Damasceno A.
        • Amaral J.
        • Barreira A.A.
        • et al.
        Normative values of the brief repeatable battery of neuropsychological tests in a Brazilian population sample: discrete and regression-based norms.
        Arq. Neuropsiquiatr. 2018; 76: 163-169
        • Dale A.M.
        • Fischl B.
        • Sereno M.I.
        Cortical surface-based analysis. I. Segmentation and surface reconstruction.
        Neuroimage. 1999; 9: 179-194
        • Fischl B.
        • Sereno M.I.
        • Dale A.M.
        Cortical surface-based analysis. II: inflation, flattening, and a surface- based coordinate system.
        Neuroimage. 1999; 9: 195-207
        • Reuter M.
        • Schmansky N.J.
        • Rosas H.D.
        • et al.
        Within-subject template estimation for unbiased longitudinal image analysis.
        Neuroimage. 2012; 61: 1402-1418
        • Batista S.
        • Zivadinov R.
        • Hoogs M.
        • et al.
        Basal ganglia, thalamus and neocortical atrophy predicting slowed cognitive processing in multiple sclerosis.
        J. Neurol. 2012; 259: 139-146
        • Benedict R.H.
        • Morrow S.
        • Rodgers J.
        • et al.
        Characterizing cognitive function during relapse in multiple sclerosis.
        Mult. Scler. 2014; 20: 1745-1752
        • Koch M.W.
        • Mostert J.P.
        • Uitdehaag B.
        • et al.
        A comparison of clinical outcomes in PPMS in the INFORMS original trial data set.
        Mult. Scler. 2021; 27: 1864-1874
        • Goldman M.D.
        • LaRocca N.G.
        • Rudick R.A.
        • et al.
        Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data.
        Neurology. 2019; 93: e1921-e1931
        • Weber E.
        • Goverover Y.
        • DeLuca J.
        Beyond cognitive dysfunction: relevance of ecological validity of neuropsychological tests in multiple sclerosis.
        Mult. Scler. 2019; 25: 1412-1419
        • Koch M.W.
        • Mostert J.
        • Repovic P.
        • et al.
        Reliability of outcome measures in clinical trials in secondary progressive multiple sclerosis.
        Neurology. 2021; 96: e111-e120
        • McKay K.A.
        • Bedri S.K.
        • Manouchehrinia A.
        • et al.
        Reduction in cognitive processing speed surrounding multiple sclerosis relapse.
        Ann. Neurol. 2022; 91: 417-423
        • Kalincik T.
        • Cutter G.
        • Spelman T.
        • et al.
        Defining reliable disability outcomes in multiple sclerosis.
        Brain. 2015; 138: 3287-3298
        • Healy B.C.
        • Glanz B.I.
        • Swallow E.
        • et al.
        Confirmed disability progression provides limited predictive information regarding future disease progression in multiple sclerosis.
        Mult. Scler. J. Exp. Transl. Clin. 2021; 72055217321999070