Chronic black holes (cBHs), characterized by severe myelin and axonal loss, are associated with higher disability levels in patients with multiple sclerosis (MS). However, whether cBHs impact perilesional tissue via retrograde and/or antegrade degeneration and how this remote pathology affects patient disability has not been investigated in vivo. Novel MRI techniques, such as selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and multi-compartment microscopic diffusion MRI spherical mean technique (SMT) have the potential to more accurately assess myelin and axonal injury in vivo, thus allowing us to measure remote tissue injury and its impact on patient clinical disability.
To compare the macromolecular-to-free pool size ratio (PSR), derived from SIR-qMT, and apparent axonal volume fraction (Vax), from SMT, values among cBHs, perilesional normal-appearing white matter (NAWM) and contra-lateral (distant) NAWM and test associations of these measures with disability in vivo.
Eighteen MS patients underwent 3T MRI consisting of clinical protocols, SIR-qMT and SMT. Regions of interest (ROIs) were manually placed on CBHs, perilesional NAWM and distant NAWM areas; PSR/Vaxwere calculated and compared using a mixed effects model. Pearson correlation analyses tested the associations between PSR/Vax values and patient clinical and MRI metrics.
Compared to perilesional NAWM, both PSR (-43.3%, p<0.001) and Vax (-29.7%, p<0.001) values were reduced in cBHs and increased in distant NAWM (10.2%, p<0.001 for PSR and 20%, p<0.001 for Vax). A strong correlation was seen for cBH and perilesional NAWM Vaxvalues (rho=0.63 p<0.001). No significant associations were seen between PSR/Vaxvalues and other clinical or MRI metrics of disease apart from cBHs PSR, which correlated with the EDSS score (rho=-0.63, p=0.03). There was a trend for decreasing PSR and Vaxvalues in all regions with worsening disease phenotype.
Our results show that myelin and axonal integrity, detected by PSR and Vax, are reduced in perilesional NAWM, as a function of the degree of focal cBH axonal injury. This is indicative of an ongoing anterograde and retrograde degeneration and suggests that preventing cBH development is a key factor for preserving NAWM integrity in surrounding tissue. PSR and Vaxlargely failed to capture associations with clinical and MRI characteristics. However, the trends observed with disease phenotypes suggest that longitudinal assessment of a larger cohort may indeed unravel the impact of this pathology on disease progression.