Disentangling pontine fiber geometry and microstructure in ARSACS using advanced MRI

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a genetic disease characterized by spasticity and ataxia which reflects involvement of the corticospinal tracts (CST) and cerebellum. The primary involvement of the middle cerebellar peduncles (MCP) and transverse pontine fibers (TPF) at the crossing with the CST, and their role in the pathophysiology of the disease, is currently debated.

Advanced MRI techniques capable of isolating sub-voxel microstructural parameters can test the hypothesis that the MCP and TPF are abnormally large, compressing the CST at their crossing, and potentially impairing CST development.

Tract macro- and micro-structural properties, including axon and tract caliber, axon density and geometry, and myelin content were estimated from diffusion-relaxometry (using the standard model for diffusion) and magnetization transfer imaging. These features were analyzed using tractometry profiles of the CST, MCP, and TPF in a pilot study of 9 patients and 9 age-matched controls.

While the CST showed significant decreases in tract size, axon caliber, and myelination throughout its length compared to controls (p < 0.01), the MCP and TPF were relatively unaffected. In our cohort, neither the MCP nor the pons were enlarged. The proximal MCP showed an increase in axon caliber.

The increase in fractional anisotropy and axon density towards the center of the TPF could be driven by geometric confounds related to differences in the relative sizes of the CST and TPF compared to controls. This highlights the importance of investigating tract-specific microstructural profiles, particularly in regions of geometric complexity. The findings confirm the involvement of the CST, with a relatively limited involvement of the MCP and TPF.