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

Abstract

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.

Keywords: clinical progression; disability worsening; innate immune cell; microglia; multiple sclerosis; positron emission tomography; remyelination; white matter lesions.

Conflict of interest statement

We have no conflict of interest related to this article.

B. Stankoff received honoraria from Biogen, Teva, Novartis, Genzyme, Roche and research support from Genzyme, Merck‐Serono and Roche.

B. Bodini receives rese arch support from ARSEP. She has received funding for traveling and/or speaker's honoraria from Novartis, Genzyme, Roche and Merck Serono.

M Tonietto and E Poirion have nothing to disclose.

© 2018 International Society of Neuropathology.

Figures

Figure 1

Three single‐patient maps of lesional myelin content changes showing demyelinating (in red) and remyelinating (in blue) voxels derived from longitudinal [11C]PIB PET, localized inside white matter (WM) lesions (in white), overlaid onto the corresponding MPRAGE scans. A. Map of lesional myelin content changes of a 20‐year‐old woman with a disease duration of 3 years, where a clear prevalence of demyelination over remyelination is visible. B. The map of myelin content changes of this 27‐year‐old man with a 10‐year history of MS shows active demyelination together with moderate remyelination in all visible WM lesions. C. An extensive process of remyelination characterizes the map of myelin content changes of this 32‐year‐old woman with a disease duration of 3 years. Of note, the extensive lesion visible in the left‐hemispheric WM corresponds to a recent lesional area, characterized by large gadolinium‐enhancing regions on the corresponding T1 spin‐echo scans.

Figure 2

A. Map of activated innate immune cells in a single patient with secondary progressive multiple sclerosis, measured with [18F]DPA‐714 PET, overlaid onto the corresponding MPRAGE. White matter (WM) lesions are displayed in white. Voxels characterized by activated innate immune cells are displayed in dark red if localized inside lesions, in purple if localized in the perilesional area, and in aquamarine if localized in normal‐appearing tissues. B. Example of a WM lesion classified as “active,” characterized by an extensive activation of innate immune cells inside and around the lesion edge. C. Example of a lesion characterized by a lack of innate immune cell activation, defined as “inactive.” D. Single lesion with no activation of innate immune cells inside its border, but with an extensive activation in the perilesional area. Lesions characterized by this profile of innate immune cell activation are suggestive of “smoldering plaques.”