Refinement of Morphological Analysis of the Caudal Nerve in a Rodent Model of Axonal Damage with 7T MRI

Peripheral neuropathies are common conditions whose treatment, in most cases, is still lacking. Preclinical animal models are crucial to solve this unmet need, but highly translational outcome measures are needed to promptly translate data from bench to bedside. 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 well-characterised animal model of axonopathy. We aimed at characterising MRI changes in a consistent model of axonopathy. We relied on paclitaxel (PTX) as a neurotoxic agent, given the expected relevant axonal damage (Pozzi et al., IJMS 2023). 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. In a proof-of-concept and a feasibility setting, 7T MRI was performed on 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 ?m3. 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 ?m3. 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. Dynamic test confirmed allodynia development in PTX group, and NCS showed a moderate-severe axonal polyneuropathy, confirmed by histopathological observations. Therefore, we confirmed PTX group had a relevant neuropathy to be used as a test bench for 7T MRI acquisitions. DTI 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 in the murine model leading to an increased water diffusivity in the PTX tissue microstructure. We provided preliminary promising evidence of the 7T MRI exploitation in the preclinical setting. This technique has a high translational potential and, if confirmed as valuable, may have clinical relevance.