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Background Grey matter (GM) atrophy is associated with cognitive impairment (CI) in multiple sclerosis (MS). We aimed to investigate the predictive role of early regional GM damage for long-term CI.Methods A post-hoc cluster analysis was conducted on 175 patients with MS followed for 20 years from onset. Participants underwent a 1.5T-MRI scanning at diagnosis and after 2 years, and a comprehensive neuropsychological assessment after 20 years.Results Three clusters have been identified: cluster 1 (primarily patients with long-term normal cognition), cluster 2 (primarily patients with long-term mild CI) and cluster 3 (primarily patients with long-term severe CI). Five brain regions have been identified showing a significant difference in early atrophy from cluster 1 and both clusters 2 and 3: precuneus (1 vs 2: p<0.001, relative risk ratio (RRR)=4.9, 95% confidence intervals (95% CIs) =2.4-10.1; 1 vs 3: p<0.001, RRR=5.5, 95% CIs=3.1-9.7), insula (1 vs 2: p<0.001, RRR=4.1, 95% CIs=1.9-8.6; 1 vs 3: p<0.001, RRR=4.3, 95% CIs=2.5-7.5), parahippocampal gyrus (1 vs 2: p<0.001, RRR=3.2, 95% CIs=1.8-5.7; 1 vs 3: p<0.001, RRR=3.1, 95% CIs=2.1-4.6), cingulate gyrus (1 vs 2: p<0.001, RRR=3.0, 95% CIs=1.7-5.3; 1 vs 3: p<0.001, RRR=2.2, 95% CIs=1.6-5.3) and cerebellum (1 vs 2: p=0.027, RRR=2.6, 95% CIs=1.5-4.6; 1 vs 3: p<0.001, RRR=2.1, 95% CIs=1.5-2.9). Four additional brain regions showed a significant difference in terms of early atrophy between cluster 1 and cluster 3: precentral gyrus (p<0.001, RRR=7.3, 95% CIs=3.1-17.3), postcentral gyrus (p<0.001, RRR=4.6, 95% CIs=2.2-9.8), superior frontal gyrus (p<0.001, RRR=4.0, 95% CIs=2.0-8.0) and hippocampus (p<0.001, RRR=2.4, 95% CIs=1.6-3.6).Conclusions Cluster analysis identified the most specific brain regions whose early atrophy best distinguished future patients with CI. Long-term CI accumulation in MS can be predicted by early GM volume loss of specific cortical/deep GM regions.