Exploring the heterogeneity of MS lesions using positron emission tomography: a reappraisal of their contribution to disability

The biological mechanisms driving disability worsening in multiple sclerosis (MS) are only partly understood. Monitoring changes in lesion load on MRI has a limited predictive value on the progression of clinical disability, and there is an essential need for novel imaging markers specific for the main candidate mechanisms underlying neurodegeneration which include failing myelin repair, innate immune cell activation and gray matter neuronal damage. Positron Emission Tomography (PET) is an imaging technology based on the injection of radiotracers directed against specific molecular targets, which has recently allowed the selective quantification in-vivo of the key biological mechanisms relevant to MS pathophysiology. Pilot PET studies performed in patients with all forms of MS allowed to revisit the contribution of MS lesions to disability worsening and showed that the evolution of lesions toward chronic activation, together with their remyelination profile were relevant predictors of disability worsening. PET offers the opportunity to bridge a critical gap between neuropathology and in-vivo imaging. This technique provides an original approach to disentangle some of the most relevant pathological components driving MS progression, to follow-up their temporal evolution, to investigate their clinical relevance and to evaluate novel therapeutics aimed to prevent disease progression.