Background White matter (WM) impairments precede striatal atrophy and motor symptoms in Huntington’s disease (HD) but their aetiology remains unknown.
Aims We exploited ultra-strong gradient MRI to disentangle the contribution of changes in axon microstructure versus changes in myelin to WM pathology in HD.
Methods We assessed apparent myelin [with the magnetization transfer ratio (MTR)], and axon density [with the restricted volume fraction (FR) from the Composite Hindered and Restricted Model of Diffusion (CHARMED)] in premanifest HD patients and age- and sex-matched controls. Group differences in diffusion tensor MRI measures were also assessed. We investigated region-specific changes across the corpus callosum (CC) with tractometry and brain-wise WM microstructure abnormalities with tract-based cluster analysis (TBCA). Behavioural measures were included to explore disease-associated brain-function relationships.
Results We detected lower apparent myelin in the posterior CC of patients (tractometry: p = 0.0343; TBCA: p = 0.030), and higher apparent myelin in the anterior CC (tractometry: p = 0.016). A positive association between apparent myelin and mutation size in patients (all p-values < 0.01) suggested a direct link between myelin alterations and disease mutation. Higher FR in the cortico-spinal tract (CST) (TBCA: p = 0.03) was detected in patients, demonstrating that WM changes in premanifest HD extend beyond the CC. FR in the CST was associated with MTR in the posterior CC (p = 0.033) and a trend was present for a positive association with cognitive performance (p = 0.057), suggesting compensation to myelin loss.
Conclusions We provide novel in vivo evidence for myelin-based WM alterations as an early feature of human HD. Critical pathogenic events were present in mutation carriers prior to clinical onset, emphasising the importance of understanding the mechanisms underlying early WM abnormalities for the discovery of new therapeutic approaches.
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