Following the impressive progress in the treatment of relapsing-remitting multiple sclerosis (MS), the major challenge ahead is the development of treatments to prevent or delay the irreversible accumulation of clinical disability in progressive forms of the disease. The substrate of clinical progression is neuro-axonal degeneration, and a deep understanding of the mechanisms that underlie this process is a precondition for the development of therapies for progressive MS. PET imaging involves the use of radiolabelled compounds that bind to specific cellular and metabolic targets, thereby enabling direct in vivo measurement of several pathological processes. This approach can provide key insights into the clinical relevance of these processes and their chronological sequence during the disease course. In this Review, we focus on the contribution that PET is making to our understanding of extraneuronal and intraneuronal mechanisms that are involved in the pathogenesis of irreversible neuro-axonal damage in MS. We consider the major challenges with the use of PET in MS and the steps necessary to realize clinical benefits of the technique. In addition, we discuss the potential of emerging PET tracers and future applications of existing compounds to facilitate the identification of effective neuroprotective treatments for patients with MS.
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