Improving the assessment of axonal injury in early multiple sclerosis.

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.