Synopsis

Keywords: Multiple Sclerosis, PET/MR, Prelesions, lesion formation

Introduction

Methods

• We took advantage of the cohort described in (5), with 19 persons with active relapsing–remitting MS (pwMS) and 8 age-and sex-matched Healthy Controls (HC), who underwent a longitudinal [11C]PiB-PET and MRI protocol with one acquisition at baseline and another after 72.7 ± 27.9 days.

• T1, T2, FLAIR, FA, MD, RD, AD, and Magnetization Transfer Ratio (MTR), were obtained from 3T MRI as described in (5). We normalized T1 and T2 (6) and computed T1/T2 ratio (7).
• [11C]-PiB PET was acquired on HRRT and reconstructed as described in (8). We extracted distribution volume ratio (DVR) and demyelination maps (used to compute demyelinated voxel density) for pwMS compared to HC using the methods described in (5). We applied the SRTM2 to native images to extract the R1 parameter that estimates the CBF, according to (3-4).
  

• Lesions were manually segmented on T2 with respect to FLAIR. White Matter (WM) was segmented using FreeSurfer5.3 after a lesion filling procedure. Normal Appearing WM (NAWM) was defined as the supratentorial WM after taking off the T2 lesions from the first visit, and a 2mm erosion to decrease partial volume effect.

• Prelesions were defined as non lesional areas on first visit in which a new lesion appeared at the second visit. We manually segmented them on the second visit T2 in a half way space between the two visits obtained by rigid registration, and multiplied them by the NAWM. To study their characteristics, as NAWM perfusion of pwMS is spatially heterogeneous (9), for each prelesion we defined a controlateral reference region in the NAWM that we called the mirror. This mirror was the controlateral symetric of the prelesion, after multiplication by the NAWM without prelesions, and successive dilatations until it reached at least the volume of its matched prelesion as shown in Figure 1.
  

• All MRI sequences and PET derived metrics for myelin and perfusion, as well as previously defined Regions of Interest (ROIs) were non linearly registered to the MNI152 atlas to allow intersubject comparison. We also created an HC perfusion atlas in MNI152 space by averaging all HC R1 value for each voxel.
• For each prelesion, to assess its perfusion status, we compared the observed relative difference in R1 between the prelesion and mirror couple to a theoretical value. This theoretical value was the R1 interhemispheric variability for the volume of the ROI described by (4). If the observed R1 relative difference was smaller on absolute value than the expected controlateral variability for this volume, we defined this prelesion as isoperfused. Otherwise, if the relative difference was positive it was hyperperfused compared to its matched mirror and if it was negative it was hypoperfused.
• Statistical tests were paired between prelesions and their matched mirrors (paired T-test at the whole cohort level, and wilcoxon rank sum test in perfusion subgroups in which normality couldn't be verified), alpha was set to 0.05, divided by two for unilateral tests, and corrected for multiple comparisons.
  
  
  

Results

• We identified 69 analyzable prelesions on 17 subjects of our cohort. At the global level, we found significant differences in MRI signal between prelesions and mirrors (lower T1, higher T2, lower T1/T2 ratio and lower MTR) but no differences in PET assessed myelin content nor perfusion (Figure 4).
• Prelesions were heterogeneous regarding their perfusion : 56.5% were isoperfused compared to their mirrors, 18.8% hypoperfused and 24.6% hyperperfused. This heterogeneity was not explained by size, distance to lateral ventricles (Figure 2) nor anatomical physiological regional differences of perfusion due to their position (Figure 3).
• Those different groups of perfusion corresponded to different stages of demyelination. Hyperperfused prelesions displayed no evidence of demyelination regarding MTR, [11C]-PIB DVR or demyelinated voxels density, but only displayed diffusion diffrerences when compared to their mirrors (higher MD and RD) (Figure 5A). On the contrary, hypoperfused prelesions had a significantly lower MTR and [11C]-PIB assessed DVR and higher demyelinated voxel density when compared to their mirrors (Figure 5B).
  

Discussion

Acknowledgements

References

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