{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:38:03Z","timestamp":1782272283867,"version":"3.54.5"},"reference-count":33,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T00:00:00Z","timestamp":1691971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The purpose of this study was to evaluate the extent to which treatment effect on magnetic resonance imaging (MRI)\u2010derived measures of brain atrophy and focal lesions can mediate, at the trial level, the treatment effect on cognitive outcomes in multiple sclerosis (MS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We collected all published randomized clinical trials in MS lasting at least 2\u2009years and including as end points: active MRI lesions (defined as new\/enlarging T2 lesions), brain atrophy (defined as a change in brain volume between month 12 and month 24), and change in cognitive performance (assessed by the Paced Auditory Serial Addition Test [PASAT]). Relative reductions were used to quantify the treatment effect on MRI markers (lesions and atrophy), whereas the standardized mean difference (Hedges g) between baseline and follow\u2010up cognitive assessment was used to quantify the treatment effects on cognition. A linear regression, weighted for trial size, was used to assess the relationship between the treatment effects on MRI markers and cognition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fourteen trials including more than 8,813 patients with MS were included in the meta\u2010regression. Treatment effect on cognition was strongly associated with the treatment effect on brain atrophy (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090.79, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), but was not correlated with the treatment effect on active MRI lesions (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090.16, <jats:italic>p<\/jats:italic>\u2009=\u20090.14).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Results reported here suggest that brain atrophy, a well\u2010established MRI marker in MS clinical trials, can be used as a main outcome for clinical trials with drugs targeting cognitive impairment and neurodegeneration. 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