Grey matter pathology in multiple sclerosis: in vivo and post mortem magnetic resonance imaging studies

The extent and clinical relevance of grey matter (GM) pathology in multiple sclerosis (MS) is increasingly recognised. Previous work has shown that GM pathology is more closely associated with some aspects of clinical disability than white matter (WM) injury, which has been suggested to arise independently. Magnetic resonance imaging (MRI) allows the study of GM lesions, atrophy, and non-lesional injury with techniques including double inversion recovery (DIR), volumetric scans, and magnetisation transfer ratio (MTR), respectively. This thesis includes three independent in vivo and post mortem MRI studies specifically addressing (1) the clinical impact and spatial distribution of DIR-detected GM lesions and atrophy, (2) the longitudinal development of MTR changes in thalamo-cortical systems, and (3) the histopathological substrates underlying MTR in the MS brain. This work shows that (1) DIR-detected GM lesions are mainly found throughout the cerebellar and cerebral cortex, whereas particularly subcortical GM structures show atrophy. Both GM lesions and atrophy contribute to disability, suggesting that the substrates of disability in MS are both pathologically and spatially heterogeneous. (2) WM injury to thalamo-cortical systems is most likely to precede (both thalamic and cortical) GM damage. In addition, lower regional cortical MTR is found not to be consistently associated with lower cortical volume, suggesting that significant cortical microstructural damage can occur in the absence of atrophy. Furthermore, observed hemispheric asymmetries and WM tract inhomogeneities emphasise the need for more refined statistical models to detect disease-specific changes. (3) MTR is associated with histologically quantified myelin (and to a lesser extent neuronal content) in normal appearing grey matter and normal appearing white matter, but not in cortical lesions and chronic inactive WM lesions. Finally, the cytological make-up differs significantly between normal appearing and lesional WM and GM, and provides extra evidence for microglia-mediated mitochondria damage in normal appearing MS tissue.