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