Phd in CLINICAL EXPERIMENTAL NEUROSCIENCE AND PSYCHIATRY

Thesis title: In vivo analyses of the correlates of cortical and white matter pathology in patients with multiple sclerosis by quantitative 7 Tesla and 3 Tesla MRI and molecular imaging

This thesis is divided in two sections. The first reports the results from a project regarding the application of ultra-high-field quantitative MRI for the study of cortical grey matter pathology in patients with early multiple sclerosis (MS). Applying a Combined Myelin Estimation method, obtained by 7 Tesla magnetic resonance imaging, we aimed at characterizing cortical microstructural abnormalities related to myelin content in cortical lesions and normal-appearing cortex, to assess their evolution at 1-year follow-up and to relate cortical myelin changes to clinical and radiological disease burden. Data obtained from 25 patients with early MS and 19 healthy volunteers showed overall abnormally low myelin content in cortical lesions and several areas of normal-appearing cortex. Myelin content along the cortex correlated with neurological impairment. Individual cortical lesion analysis revealed heterogenous patterns, ranging from extensive to partial demyelination, or even measurements comparable to the healthy group. At 1-year follow-up, cortical myelin was overall decreased in cortical lesions and scattered areas in the normal-appearing cortex. Diffusion metrics obtained in the same regions did not show the presence of cortical neural loss accompanying early demyelination. The second section reports results from a study in which we combined 11C-PBR28 positron-emission tomography, marking activated microglia, with the more recently validated synthetic magnetic resonance imaging for myelin content assessment, aiming at researching the presence of correlates of pathology in the white matter of patients with multiple sclerosis at different disease stages, and assessing the interplay between neuroinflammation and demyelination. We found abnormal increase of microglia activation in MS patients compared to healthy volunteers in several areas across the white matter, correlating with clinical and radiological disease burden. An individual analysis of white matter lesions showed the presence of active lesions in the early phases of the disease, evolving in inactive or peripherally active lesions in the late disease phases, the latter correlating with clinical disability. Myelin content in the normal-appearing white matter of MS patients correlated with neurological impairment and lesion load. Higher microglia activation in the white matter lesions was related to lower myelin content in the non-lesioned white matter.