Neurodegeneration in MS has been related to local GM demyelination and inflammation together with connected WM tracts’ damage. However, their relative contribution to neurodegeneration is unknown.

To investigate the associations between cortical neurodegeneration and 1) local gray matter (GM) myelination and microglia density, and 2) remote white matter (WM) tract integrity in multiple sclerosis (MS) by combining postmortem MRI and histopathology.

Brain structural and diffusion-weighted postmortem in situ 3T MRI were obtained from 16 MS patients and 10 age- and sex-matched non-neurological controls (nNC). At subsequent autopsy, cortical regions were dissected from 6 standardized locations. Neuron density and volume, and axon density were determined as histopathological markers for cortical neurodegeneration, while myelin and microglia density were evaluated as markers for local GM damage. Using MRI, tissue blocks were matched to cortical AAL atlas regions and connected WM tract fractional anisotropy (FA), mean (MD), axial (AD) and radial (RD) diffusivities were determined as markers for remote damage. Using linear mixed model, between-group differences and within-group relations between neurodegeneration and local or remote damage were evaluated.

Compared to nNC, MS donors displayed significant axonal loss (p=0.003) and a trend to lower GM myelin density (p=0.107). In connected tracts, MS donors showed increased normal-appearing WM (NAWM) AD (p=0.013) and MD (p=0.037) and whole tract AD (p=0.018) compared to nNC. Axonal density was associated with myelin density in both nNC (β=0.63, p<0.001) and MS (β=0.61, p<0.001). In MS, axonal density was associated with NAWM AD, MD and RD (β=-0.41; β=-0.43; β=-0.42, p=0.03 for all) and whole tract MD (β=-0.36, p=0.041).

Cortical neurodegeneration, predominantly characterized by axonal loss, was observed in MS, and was associated with cortical demyelination and microstructural abnormalities in connected WM tracts. Both local GM damage and remote WM tract dysintegrity contribute to GM neurodegeneration in MS.