Perilesional neurodegenerative injury in multiple sclerosis: Relation to focal lesions and impact on disability

Abstract

Background: Axonal injury is the primary source of irreversible neurological decline in persons with multiple sclerosis (pwMS). Identifying and quantifying myelin and axonal loss in lesional and perilesional tissue in vivo is fundamental for a better understanding of multiple sclerosis (MS) outcomes and patient impairment. Using advanced magnetic resonance imaging (MRI) methods, consisting of selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and multi-compartment diffusion MRI with the spherical mean technique (SMT), we conducted a cross-sectional pilot study to assess myelin and axonal damage in the normal appearing white matter (NAWM) surrounding chronic black holes (cBHs) and how this pathology correlates with disability in vivo. We hypothesized that lesional axonal transection propagates tissue injury in the surrounding NAWM and that the degree of this injury is related to patient disability.

Methods: Eighteen pwMS underwent a 3.0 Tesla conventional clinical MRI, inclusive of T1 and T2 weighted protocols, as well as SIR-qMT and SMT. Regions of interests (ROIs) were manually delineated in cBHs, NAWM neighboring cBHs (perilesional NAWM), distant ipsilateral NAWM and contra-lateral distant NAWM. SIR-qMT-derived macromolecular-to-free pool size ratio (PSR) and SMT-derived apparent axonal volume fraction (V_ax) were extracted to infer on myelin and axonal content, respectively. Group differences were assessed using mixed-effects regression models and correlation analyses were obtained by bootstrapping 95% confidence interval.

Results: In comparison to perilesional NAWM, both PSR and V_ax values were reduced in cBHs (p < 0.0001) and increased in distant contra-lateral NAWM ROIs (p < 0.001 for PSR and p < 0.0001 for V_ax) but not ipsilateral NAWM (p = 0.176 for PSR and p = 0.549 for V_ax). V_ax values measured in cBHs correlated with those in perilesional NAWM (Pearson rho = 0.63, p < 0.001). No statistically relevant associations were seen between PSR/V_ax values and clinical and/or MRI metrics of the disease with the exception of cBH PSR values, which correlated with the Expanded Disability Status Scale (Pearson rho = -0.63, p = 0.03).

Conclusions: Our results show that myelin and axonal content, detected by PSR and V_ax, are reduced in perilesional NAWM, as a function of the degree of focal cBH axonal injury. This finding is indicative of an ongoing anterograde/retrograde degeneration and suggests that treatment prevention of cBH development is a key factor for preserving NAWM integrity in surrounding tissue. It also suggests that measuring changes in perilesional areas over time may be a useful measure of outcome for proof-of-concept clinical trials on neuroprotection and repair. PSR and V_ax largely failed to capture associations with clinical and MRI characteristics, likely as a result of the small sample size and cross-sectional design, however, longitudinal assessment of a larger cohort may unravel the impact of this pathology on disease progression.

Keywords: Magnetic resonance imaging; Multiple sclerosis; Myelin; Neurodegeneration; White matter.

Fig. 1.. Region of interest (ROI) placement.

ROIs were drawn around cBHs (red), perilesional NAWM (blue), ipsilateral NAWM (orange) and distant NAWM (green) on (A) T1-weighted, (B) T2-weighted FLAIR, (C) V_ax and (D) PSR parametric maps. The corresponding V_ax and PSR signal intensity values are visible on the left (V_ax) and right (PSR). The size of each of the corresponding perilesional, ipsilateral and distant NAWM ROIs were identical. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2.. PSR and V_ax values in the four tissues studied: cBHs, perilesional (reference group), ipsilateral NAWM and distant NAWM.

(A) PSR values in cBH, perilesional, ipsilateral and distant NAWM; (B) V_ax values in cBH, perilesional, ipsilateral and distant. Box plots represent mean and interquartile range, whiskers represent 95% confidence interval. Asterisks over each bar represent significance level (** = p < 0.01, *** = p < 0.001).

Fig. 3.. Association between cBHs and perilesional V_ax..

V_ax values measured in cBH correlated with those in perilesional NAWM (Pearson rho = 0.63 and 95% CI = 0.29 – 0.9, p < 0.001).

Fig. 4.. Distribution of PSR values in distant NAWM in patients with different disease durations.

Patients were split into two groups based on the median disease duration: ≤12 years (n = 6) and >12 years (n = 7). Y-axis represents PSR values derived from distant NAWM. Box plot represents mean and interquartile range, whiskers represent 95% confidence intervals.