Improving the Assessment of Axonal Injury in Early Multiple Sclerosis

Abstract

Rationale and Objectives

Several quantitative magnetic resonance imaging (MRI) methods are available to measure tissue injury in multiple sclerosis (MS), but their pathological specificity remains limited. The multi-compartment diffusion imaging using the spherical mean technique (SMT) overcomes several technical limitations of the diffusion-weighted image signal, thus delivering metrics with increased pathological specificity. Given these premises, here we assess whether the SMT-derived apparent axonal volume (V_ax) provides a better tissue classifier than the diffusion tensor imaging (DTI)-derived axial diffusivity (AD) in the white matter (WM) of MS brains.

Methods

Forty-three treatment-naïve people with newly diagnosed MS, clinically isolated syndrome, or radiologically isolated syndrome and 18 healthy controls (HCs) underwent a 3.0 Tesla MRI inclusive of T₁-weighted (T₁-w) and T₂-w fluid-attenuated inversion recovery (FLAIR) sequences, and multi-b shell diffusion-weighted imaging. In patients only, pre- and post-gadolinium diethylenetriamine penta-acetic acid T₁-w sequences were obtained for the evaluation of contrast-active lesions (CELs). V_ax and AD were calculated in T₂-lesions, chronic black holes (cBHs), and normal appearing (NAWM) in patients and normal WM (NWM) in HCs. V_ax and AD values were compared across all the possible combinations of these regions. CELs were excluded from the analyses.

Results

V_ax differed in all comparisons (p ≤ 0.047 by paired t-test); AD differed in most comparisons (p < 0.001) except between NAWM and NWM, and between cBHs and T₂-lesions. V_ax had higher accuracy (p ≤ 0.029 by DeLong test) and larger effect size (p ≤ 0.038 by paired t-test) than AD in differentiating areas with even minimal tissue injury.

Conclusions

V_ax provides a better radiological quantitative discriminator of different degrees of axonal-mediated tissue injury even between areas with expected minimal pathology. Our data support further studies to assess the readiness of V_ax as a measure of outcome for clinical trials on neuroprotection in MS.