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.

Promoting remyelination in multiple sclerosis

“…From the imaging perspective, standard MRI measures (such as T2-weighted and gadolinium-enhanced T1-weighted sequences) correlate only modestly with disability and lack the ability to differentiate between pathological correlates of MS: namely inflammation, oedema, axonal loss, demyelination, remyelination and gliosis [131]. As a result, advanced MRI techniques including myelin water fraction (MWF) [132,133], diffusion tensor imaging (DTI) [134,135] and magnetisation transfer ratio (MTR) [136,137], as well as positron emission tomography (PET) [43,138], have been variably used to measure myelin dynamics.…”

Identifying Progression in Multiple Sclerosis: New Perspectives

“…70 A large proportion of lesions considered inactive on MRI were very active on PET, indicating subacute or chronic active lesions. 66 The number of these active lesions was correlated with individual disability trajectories, suggesting that they may be major players in MS progression. 66 TSPO PET also revealed a diffuse brain inflammatory component that is higher in PMS, predominates in areas close to the cerebrospinal fluid, and correlates with microstructural damage.…”

“…66 The number of these active lesions was correlated with individual disability trajectories, suggesting that they may be major players in MS progression. 66 TSPO PET also revealed a diffuse brain inflammatory component that is higher in PMS, predominates in areas close to the cerebrospinal fluid, and correlates with microstructural damage. 69 Using myelin radiotracers, 65 it has been shown that MS patients have heterogeneous individual remyelination profiles, which are critical in determining disability accrual.…”

“…Positron Emission Tomographic Imaging Positron emission tomography (PET) has recently been used to investigate in vivo several key biological mechanisms involved in MS progression, including innate immune cell activation and myelin loss and repair. 65,66 Until now, translocator protein (TSPO) tracers have been chosen to image the innate component of inflammation, 65 but their specificity is still limited, because some expression has been detected in astrocytes and endothelial cells. Using the first generation TSPO tracer 11 C-PK11195, an increased uptake was seen in all MS phenotypes, especially in PMS.…”

PET is necessary to make the next step forward in understanding MS pathophysiology – Yes

“…A second key application of PET in MS research is the quantification of demyelination and remyelination, which is now possible using benzothiazole-and stilbene-derived radiotracers. 5 We now know that each patient with MS is characterized by a specific remyelination profile, which reflects the individual level of spontaneous myelin repair in response to a demyelinating insult and is critical to determine disease evolution and disability. 8 In the next future, the application of myelin-specific fluorinated compounds will allow a wider use of PET in the context of clinical trials evaluating the efficacy of drugs designed to promote myelin repair.…”