HIGH RESOLUTION MAGNETIC RESONANCE IMAGING TO ASSESS AXONAL DAMAGE IN NEUROPATHY MODELS

Peripheral neuropathies are common conditions whose treatment, in most cases, is still lacking due to an incomplete pathogenetic knowledge; therefore, preclinical in vivo models are crucial, but highly translational outcome measures are still needed in this field. High resolution diffusion MRI could be a surrogate, translational, biomarker to characterise early morphological changes as neuropathy ensues, creating a virtuous link between bench and bedside. We tested this approach in a proof-of-concept and a feasibility setting. We aimed at characterising MRI changes in a robust model of axonopathy that ensues after repetitive administration of paclitaxel (PTX). We compared 2 groups (n=12 each) of female Wistar rats: control (CTRL, vehicle treated, iv) and PTX (10mg/kg, 1qwx4, iv). At the end of treatment, neuropathy development was verified via Dynamic test, nerve conduction studies (NCS) and light microscopy of the caudal nerve. 7T MRI was performed on whole rat tails (collected after sacrifice and formalin-fixed, n=3/group) to study caudal nerves and the anatomical relationship with surrounding structures. High resolution anatomical images were acquired by means of a T1w sequence with a voxel size of 50x50x50 μm3. Diffusion weighted images were acquired in five b-shells: b of 500, 2000, 4500, 6000, 8000 sec*mm-2 with 15, 24, 33, 42, 51 isotropically distributed gradient directions and a voxel size of 125x125x125 μm3. Diffusion data were fitted with the Diffusion Tensor Imaging (DTI) classical model and Fractional Anisotropy (FA), Axial, Radial and Mean Diffusitìvity (AD, RD and MD) were computed. All selected outcome measures (dynamic test, NCS and morphological assessment of caudal nerves) demonstrated that nerve damage induction was satisfactory and consistent with a moderate-severe axonal polyneuropathy, making our cohort ideal to test 7T MRI implementation. Neuroimaging showed a decrease of FA (by 5%) and an increase of diffusivity, being the more relevant variation in RD (by 15%), in the PTX group if compared to control. These preliminary results may sustain the hypothesis of axonal damage leading to an increased water diffusivity in the PTX tissue microstructure. In summary, we provided preliminary promising data of the 7T MRI exploitation to study axonal damage in the preclinical setting.