The Iceberg Revealed: Visualizing the Impact of Cortical Pathology on Cognitive Impairment in Multiple Sclerosis

The main aim of this thesis was to better understand cognitive impairment in multiple sclerosis using advanced methods to identify relevant clinical and radiological patterns. We quantified the macro- and microstructural substrates of multiple sclerosis-related gray matter pathology in vivo to study the relevance of these substrates for cognitive functioning. The main research questions of this thesis were the following: (1) Which patterns of clinical and radiological findings aid in understanding and explaining cognitive dysfunction in multiple sclerosis? (2) Which substrates of cognitively relevant gray matter pathology can we identify using novel in vivo diffusion-weighted imaging techniques? (3) Can we improve our understanding and prediction of cognitive decline over time employing (advanced) quantifications of cortical pathology? (4) Can we use advanced techniques for visualizing cortical lesions to identify treatment effects in individuals with multiple sclerosis? This dissertation describes the possible "routes" through which cortical damage contributes to cognitive decline: from cortical lesions directly affecting cognition, through brain atrophy following lesion formation, or through brain atrophy occurring independently of visible lesions. Taken together, an important mechanism of disease progression may be that cortical lesions extend their effects into the surrounding normal-appearing cortex, leading to brain atrophy and subsequent network disruption. At a certain point, when the affected networks can no longer compensate for the accumulating damage, they begin to malfunction, ultimately resulting in cognitive decline. To fully capture the extent of cortical damage, advanced diffusion MRI (i.e., the SANDI model) can detect subtle changes in gray matter even before lesions become visible to the naked eye. Clinically, cortical damage does not affect all cognitive functions to the same extent. Some functions are more vulnerable than others, possibly because certain functions rely more heavily on the affected functional networks. Therefore, beyond monitoring global cognitive ability, it is important to examine individual cognitive skills, as well as the sequence in which they deteriorate relative to one another. Measuring and monitoring cortical lesions in the clinic is relevant for predicting who is at higher risk of cognitive decline. Advanced imaging of cortical lesions may also provide valuable insights for the development of future therapies. Targeting these lesions could mitigate subsequent brain atrophy and thereby slow cognitive decline.