Mutation-related apparent myelin, not axon density, drives white matter differences in premanifest Huntington's disease: Evidence from in vivo ultra-strong gradient MRI

White matter (WM) alterations have been observed early in Huntington's disease (HD) progression but their role in the disease-pathophysiology remains unknown. We exploited ultra-strong-gradient MRI to tease apart contributions of myelin (with the magnetization transfer ratio), and axon density (with the restricted volume fraction from the Composite Hindered and Restricted Model of Diffusion) to WM differences between premanifest HD patients and age- and sex-matched controls. Diffusion tensor MRI (DT-MRI) measures were also assessed. We used tractometry to investigate region-specific changes across callosal segments with well-characterized early- and late-myelinating axonal populations, while brain-wise alterations were explored with tract-based cluster analysis (TBCA). Behavioural measures were included to explore disease-associated brain-function relationships. We detected lower myelin in the rostrum of patients (tractometry: p = 0.0343; TBCA: p = 0.030), but higher myelin in their splenium (p = 0.016). Importantly, patients' myelin and mutation size were positively associated (all p-values < 0.01), indicating that increased myelination might be a direct result of the mutation. Finally, myelin was higher than controls in younger patients but lower in older patients (p = 0.003), suggesting detrimental effects of increased myelination later in the course of the disease. Higher FR in patients' left cortico-spinal tract (CST) (p = 0.03) was detected, and was found to be positively associated with MTR in the posterior callosum (p = 0.033), possibly suggesting compensation to myelin alterations. This comprehensive, ultra-strong gradient MRI investigation provides novel evidence of CAG-driven myelin alterations in premanifest HD which may reflect neurodevelopmental, rather than neurodegenerative disease-associated changes.