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.

Background

Microstructural alterations in the Normal-Appearing White Matter (NAWM) preceeding the onset of a new lesion have been described using advanced MRI in patients with MS. However, the biological substrate of these alterations remains poorly understood due to the lack of specificity of the MRI signal. We have previously shown that Positron Emission Tomography (PET) with 11C-PIB has the potential to quantify myelin content changes in WM lesions. Interestingly, dynamic 11C-PIB PET acquisitions, including early frames, enable the estimation of regional brain perfusion too.

Objectives

To characterize whether perfusion changes, microstructural damage and demyelination could precede lesion appearance on T2-weighted (T2-w) MRI images.

Methods

Longitudinal dynamic 11C-PIB PET and 3T MRI, including diffusion weighted and magnetization transfer imaging, were acquired in 19 active patients with relapsing-remitting MS. Following baseline scans, patients underwent a second evaluation after 1-2 month (n= 10) or after 3-4 months (n=9). Prelesional areas were defined as the baseline NAWM areas which became hyperintensities on the second T2-w image. Logan reference graphical analysis and simplified reference tissue model were respectiveley used to generate voxelwise maps of Distribution Volume Ratio (DVR), and relative delivery (R1) from 11C-PIB images. Myelin content, reflected by DVR, and perfusion, measured by R1, were extracted for each prelesional area and the corresonding contralateral area in the NAWM. Magnetization transfer ratio (MTR), fractional anisotropy (FA), radial and axial diffusivity (RD and AD) were calculated in the same areas. Paired t-test were used to test differences in DVR, R1, MTR, FA, RD and AD between the prelesional and its contralateral areas.

Results

We identified 77 prelesional areas. In the subgroup of patients with a 1-2 months follow-up, prelesional areas (45 out of 77) showed a higher perfusion (8.5%, p=0.03), increased RD (4.2%, p=0.003), lower MTR (-1.2%, p=0.008) and reduced FA (-6.2%, p=0.008), compared to contralateral NAWM areas, while no difference was detected in DVR (p=0.4). No statistical differences were found in the subgroup of patients with a follow-up of 3-4 months.

Conclusions

One-two months before becoming hyperintense on T2-w MRI, prelesional areas are characterized by an increased perfusion associated with microstructural changes, but not by demyelination.

Background

In multiple sclerosis (MS), pathological changes are not limited to lesions, but extensively involve normal-appearing tissues, being more pronounced in perilesions. Histological studies have shown that the pathological changes affecting perilesions mainly result from the ongoing damage in demyelinating lesions. Similarly, the structural integrity of perilesions could depend on the extent of myelin repair at the lesional level, which can be explored in vivo by positron emission tomography (PET) with 11C-PiB.

Objectives

To assess in a longitudinal study whether myelin content changes in white matter lesions, measured with 11C-PiB PET, influence the microstructural integrity of the surrounding perilesions over time, explored by diffusion tensor imaging and magnetization transfer (MT)-derived metrics.

Methods

Nineteen patients with MS underwent a longitudinal PET/MRI study. Voxel-wise maps of 11C-PiB distribution volume ratio, reflecting myelin content, were used to calculate for each patient in each non-enhancing lesion 3 indices of myelin content change: the percentage of demyelinated voxels at baseline, and the percentage of demyelinating and remyelinating voxels over the follow-up. From each 3 mm-thick perilesional area surrounding lesions, the change over time (delta) of fractional anisotropy (FA), mean diffusivity (MD) and MT ratio (MTR), reflecting microstructural damage, was calculated. Associations between the indices of myelin content change and the delta FA, MD, and MTR in perilesions were assessed using multivariate linear regressions. Perilesions were classified in “improving” or “worsening” according to the sign of the change of the microstructural parameters and a multivariate logistic regression was used to test which PET-derived index was independently associated with perilesion class.

Results

A higher percentage of demyelinated voxels at baseline and of demyelinating voxels over the follow-up inside lesions were associated with a more severe microstructural damage developing over time in perilesions (p<0.001). Conversely, a higher percentage of remyelinating lesional voxels correlated with a more preserved perilesional microstructure at the follow-up (p<0.001). The percentage of remyelinating voxels inside lesions was the only independent predictor of perilesion improvement (p=0.001). We found that at least 43% of the demyelinated volume had to remyelinate to predict a favorable evolution of the microstructure of perilesional tissue (AUC=0.8).

Conclusions

Lesional remyelination effectively protects the integrity of surrounding tissues over time, possibly by reducing the extent of Wallerian degeneration and rescuing damaged axons.

Background

In multiple sclerosis (MS), pathological changes are not limited to lesions, but extensively involve normal-appearing tissues, being more pronounced in perilesions. Histological studies have shown that the pathological changes affecting perilesions mainly result from the ongoing damage in demyelinating lesions. Similarly, the structural integrity of perilesions could depend on the extent of myelin repair at the lesional level, which can be explored in vivo by positron emission tomography (PET) with 11C-PiB.

Objectives

To assess in a longitudinal study whether myelin content changes in white matter lesions, measured with 11C-PiB PET, influence the microstructural integrity of the surrounding perilesions over time, explored by diffusion tensor imaging and magnetization transfer (MT)-derived metrics.

Methods

Nineteen patients with MS underwent a longitudinal PET/MRI study. Voxel-wise maps of 11C-PiB distribution volume ratio, reflecting myelin content, were used to calculate for each patient in each non-enhancing lesion 3 indices of myelin content change: the percentage of demyelinated voxels at baseline, and the percentage of demyelinating and remyelinating voxels over the follow-up. From each 3 mm-thick perilesional area surrounding lesions, the change over time (delta) of fractional anisotropy (FA), mean diffusivity (MD) and MT ratio (MTR), reflecting microstructural damage, was calculated. Associations between the indices of myelin content change and the delta FA, MD, and MTR in perilesions were assessed using multivariate linear regressions. Perilesions were classified in “improving” or “worsening” according to the sign of the change of the microstructural parameters and a multivariate logistic regression was used to test which PET-derived index was independently associated with perilesion class.

Results

A higher percentage of demyelinated voxels at baseline and of demyelinating voxels over the follow-up inside lesions were associated with a more severe microstructural damage developing over time in perilesions (p<0.001). Conversely, a higher percentage of remyelinating lesional voxels correlated with a more preserved perilesional microstructure at the follow-up (p<0.001). The percentage of remyelinating voxels inside lesions was the only independent predictor of perilesion improvement (p=0.001). We found that at least 43% of the demyelinated volume had to remyelinate to predict a favorable evolution of the microstructure of perilesional tissue (AUC=0.8).

Conclusions

Lesional remyelination effectively protects the integrity of surrounding tissues over time, possibly by reducing the extent of Wallerian degeneration and rescuing damaged axons.