Background -- Neuropathological Advances in Multiple Sclerosis -- Neurophysiology -- MRI Techniques to Assess Neurodegeneration -- Atrophy -- T1 Black Holes and Gray Matter Damage -- Magnetization Transfer Imaging -- Perfusion MR I -- Diffusion-Weighted Imaging -- Proton MR Spectroscopy -- Functional MRI -- Evaluation of MRI Outcomes -- Validation of MRI Surrogates -- Defining Responders and Non-responders -- Predictive Models in Multimodal Imaging -- Lessons from Other Neurodegenerative Diseases -- Alzheimer's Disease -- Other Neurodegenerative Conditions -- Incorporation of Other Biomarkers -- Designing MS Trials for Neurodegeneration -- Critical Review of Existing Trials -- Design for the Next Trials of Neurodegeneration.