Imaging to evaluate remyelination and neuroprotection

The treatment goals of remyelination and neuroprotection in multiple sclerosis (MS) present new challenges to treatments, and also in finding ways to evaluate these outcome measures. Dr Benedetta Bodini (Sorbonne University, France) discussed the potential of MRI and PET techniques in evaluating myelin repair and neuroprotection in clinical treatment trials [1].

MRI offers very high sensitivity to tissue microstructural damage and generally has a high resolution; PET has the highest possible specificity for single cellular, myelin, or neuronal targets, but at the expense of resolution, which is generally very low.

Dr Bodini gave an overview of MRI techniques that are sensitive to myelin content changes. Magnetisation transfer ratio (MTR) is very sensitive to myelin and has very reasonable acquisition times. However, the signal is affected by oedema and axonal density, as well as by microglia. MTR captures changes in myelin content in single lesions. Dr Bodini said MTR has already been shown to be sensitive to the effects of remyelinating treatment in clinical trials and that sample sizes are very reasonable. She added that inhomogeneous magnetisation transfer (ihMT) can improve MTR because of a higher myelin specificity. Other valuable techniques that can measure myelin changes include diffusion-weighted imaging (DWI), myelin water fraction imaging (MWI), and quantitative susceptibility-weighed imaging (SWI) to measure myelin and iron. As MRI techniques have a suboptimal specificity for myelin in vivo, PET holds a special place in imaging de-/remyelination. PET captures clinically relevant remyelination, which is critical to determine disease evolution and disability (see Table 1).

Table 1. Imaging techniques for de- and remyelination: a summary [1].

Dr Bodini went on to discuss imaging techniques to measure potential neuroprotection. The most widely used is whole brain atrophy, which is easy to implement and correlates with clinical and cognitive scores. Thalamic atrophy may be a promising primary MRI endpoint for phase 2 trials. Early markers of neuronal damage are N-acetyl-aspartate ¹H-MRS (NAA-¹H-MRS), advanced DWI, ¹¹C-FMZ, and synaptic vesicle protein.

“A turning point in the search for effective imaging measures of neuroprotection will be the development of imaging strategies to evaluate the key mechanisms leading to neurodegeneration”, Dr Bodini argued. One of these mechanisms is energy dysregulation. Different techniques have been developed to investigate different aspects of energy dysregulation, notably ²³Na-MRI, ³¹P-MRS, and diffusion-weighted (DW)-MRS (see Table 2).

Table 2. Imaging techniques for neuroprotection: a summary [1].

Dr Bodini concluded with the following take-home messages:

• MRI and PET should be deployed as outcome measures in future clinical phase 2 trials testing pro-myelinating and neuroprotective MS treatments.
• Future outcome measures will include imaging techniques of mechanisms leading to neurodegeneration.
• PET should be used in the future to validate single MRI sequences or a combination of multiple MRI measurements to improve MRI specificity for myelin and neurons.

1. Bodini B. Symposium SYMP04, EAN 2020.

 

Posted on 10 September, 202023 February, 2021