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Background and Objectives: Magnetic resonance imaging (MRI) and neurohistopathology are important correlates for evaluation of disease progression in multiple sclerosis (MS). Here we used experimental autoimmune encephalomyelitis (EAE) as an animal model of MS to determine the correlation between clinical EAE severity, MRI and histopathological parameters., Methods: N = 11 female C57BL/6J mice were immunized with human myelin oligodendrocyte glycoprotein 1-125, while N = 9 remained non-immunized. Mice were scanned longitudinally over a period of 13 weeks using a 11.7 Tesla (T) Bruker BioSpec® preclinical MRI instrument, and regional volume changes of the lumbar spinal cord were analyzed using Voxel-Guided Morphometry (VGM). Following the final in vivo T1-weighted MRI scan, the lumbar spinal cord of each mouse was subjected to an ex vivo MRI scan using T1-, T2*- and diffusion tensor imaging (DTI)-weighted sequences. Tissue sections were then stained for immune cell infiltration, demyelination, astrogliosis, and axonal damage using hematoxylin-eosin staining and immunohistochemistry., Results: While in vivo MRI VGM detected an overall increase in volume over time, no differences were observed between EAE animals and controls. Ex vivo MRI showed a generalized atrophy of the spinal cord, which was pronounced in the anterolateral tract. The most striking correlation was observed between EAE score, white matter atrophy in ex vivo T1-weighted scans and histological parameters., Discussion: The data demonstrate that ex vivo MRI is a valuable tool to assess white matter atrophy in EAE, which was shown to be directly linked to the severity of EAE and spinal cord histopathology., Competing Interests: Declaration of competing interest A.L., H.D., A.W., M.H. have nothing to declare. A.D. and M.K. are the founders of VGMorph GmbH. R.C. received funding from the DFG under Germany's Excellence Strategy – EXC2151–390873048 and from Novartis (Oppenheim-Förderpreis für Multiple Sklerose 2023). S.K. reports funding from Novartis, F. Hoffmann-La Roche and Sanofi; and speaker fees and consultancy honoraria from Novartis, F. Hoffmann-La Roche, Sanofi, and Teva. S.K. is also supported by the DFG IRTG 2168, grant no. 272482170, the DFG project 460,333,672 CRC1540 EBM, and she is a member of the Excellence Cluster “ImmunoSensation(2)” EXC2151–390873048., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)