Irreversible tissue loss occurs from the earliest phases of multiple sclerosis (MS) and is correlated with clinical disability and cognitive impairment.To investigate the regional patterns of gray matter (GM) and white matter (WM) atrophy progression over a five year follow-up in MS patients and their association with clinical and cognitive deterioration.Clinical (Expanded Disability Status Scale [EDSS] score and phenotype changes), neuropsychological (Rao’s battery) and brain MRI (dual-echo and 3D T1-weighted sequences) assessment were performed at baseline (T0) and after 5 years (Y5) from 66 MS patients with different clinical phenotypes and 7 controls. At T0 and Y5, measures of brain lesion volume and regional atrophy were obtained. Tensor-based morphometry (1) and SPM12 (http://www.fil.ion.ucl.ac.uk/spm/software/spm12/) was used to map regional changes of volumes over time in the two groups of subjects: pairwise longitudinal registration (2) was used to align the first and second scan of each subject. The method is based on pairwise inverse-consistent registration and incorporates a bias field correction. The rate of volume change was quantified by saving the map of divergence of the velocity field, where positive values indicate expansion and negative values contraction. The mid-point average template image was also saved and used for groupwise alignment (3) to the final customized template and then to the standard space (MNI atlas). Voxelwise longitudinal changes of GM and WM volumes in MS patients were evaluated according to the presence of neurologic deterioration, phenotype modification and cognitive worsening.At Y5, 36/66 (55%) MS patients showed a significant disability worsening, 14/66 (21%) evolved to a worse clinical phenotype and 18/63 (29%) had a cognitive deterioration (Table 1). At T0, compared to controls, MS patients showed a widespread pattern of GM and WM atrophy. At Y5, MS patients developed further GM atrophy of deep GM nuclei (thalami, putamen and caudate nuclei), as well as of several fronto-temporo-parieto-occipital regions and cerebellum. Progression of atrophy of the main WM tracts was also detected. Compared to stable MS patients, those with clinical and cognitive worsening showed a left-lateralized pattern of GM and WM atrophy, involving the thalamus, caudate nucleus and putamen, several fronto-temporo-parieto-occipital regions, the cerebellum and the majority of WM tracts (Figure 1).GM and WM atrophy of relevant brain regions occurs in MS after 5 years. A different vulnerability of the two brain hemispheres to irreversible structural damage may be among the factors contributing to clinical and cognitive worsening in these patients.