Background

Following demyelination, remyelination may take place in multiple sclerosis (MS) lesions, but this process is heterogeneous and often fails. Brain perfusion was shown to impact remyelination in rodents, but this relationship has never been assessed in patients with MS. Positron emission tomography (PET) with 11C-PiB allows to simultaneously map demyelination and remyelination in vivo, and to generate quantitative maps of brain perfusion.

Objectives

To analyse the relationship between baseline perfusion and subsequent myelin content changes in white matter (WM) lesions.

Methods

11C-PIB PET and 3T MRI were acquired in 15 patients with relapsing-remitting MS at baseline and after 2-4 months. Nine hundred and four lesions were identified at baseline on T2-weighted scans with the exclusion of gadolinium-enhancing lesions to avoid artefacts in perfusion quantification. Logan reference graphical analysis and simplified reference tissue model were used to generate voxelwise maps of distribution volume ratio (DVR) and relative delivery (R1) from 11C-PiB images, respectively. Perfusion at baseline, as measured by R1, and the percentage of demyelinating and remyelinating voxels over the follow-up, derived from DVR maps, were calculated for each lesion.

Mixed-effect models were employed to evaluate the association between perfusion at baseline and the percentage of demyelinating and remyelinating voxels over the follow-up in WM lesions. A logistic regression was employed to determine the impact of perfusion on the probability of lesions to successfully repair, I.e. to remyelinate at least 50% of their demyelinated voxels at baseline and to undergo demyelination over the follow-up in less than 25% of voxels classified as normally myelinated at study entry.

Results

WM lesions showed lower perfusion compared to normal-appearing WM (0.43±0.08 vs 0.49±0.03, p<0.001), although single-lesion R1 values were remarkably heterogeneous (range: [0.08-2.5]). At the single lesion level, a higher perfusion at baseline was associated with a more extensive remyelination (β=0.32, p<0.001) and a reduced demyelination (β=-0.28, p<0.001) over the follow-up. Lesion-specific perfusion at baseline was an independent predictor of successful myelin repair over the follow-up (OR=8.4, p<0.001).

Conclusions

The level of perfusion of single MS lesions is critical for myelin repair and may be one key factor underlying the heterogeneous levels of remyelination across patients with MS.