Abstract
White matter (WM) alterations have been identified as a relevant pathological feature of Huntington’s disease (HD). Increasing evidence suggests that WM changes in this disorder are due to alterations in myelin‐associated biological processes. Multi-compartmental analysis of the complex gradient-echo MRI signal evolution in WM has been shown to quantify myelin in vivo, therefore pointing to the potential of this technique for the study of WM myelin changes in health and disease. This study first characterized the reproducibility of metrics derived from the complex multi-echo gradient-recalled echo (mGRE) signal across the corpus callosum in healthy participants, finding highest reproducibility in the posterior callosal segment. Subsequently, the same analysis pipeline was applied in this callosal region in a sample of premanifest HD patients (n = 19) and age, sex and education matched healthy controls (n = 21). In particular, we focused on two myelin-associated derivatives: i. the myelin water signal fraction (fm), a parameter dependent on myelin content; and ii. The difference in frequency between myelin and intra-axonal water pools (Δω), a parameter dependent on the ratio between the inner and the outer axonal radii. fm was found to be lower in HD patients (β = −0.13, p = 0.03), while Δω did not show a group effect. Performance in tests of working memory, executive function, social cognition and movement was also assessed, and a greater age-related decline in executive function was detected in HD patients (β = −0.06, p = 0.006), replicating previous evidence of executive dysfunction in HD. Finally, the correlation between fm, executive function, and proximity to disease onset was explored in patients, and a positive correlation between executive function and fm was detected (r = 0.542; p = 0.02). This study emphasises the potential of complex mGRE signal analysis for aiding understanding of HD pathogenesis and progression. Moreover, expanding on evidence from pathology and animal studies, it provides novel in vivo evidence supporting myelin breakdown as an early feature of HD.
Highlights
The reproducibility of frequency difference mapping (FDM) evolution and 3-pool model derivatives in the corpus cal losum (CC) was found vary according to anatomical location, with more precise fitting parameters in the posterior portion of the callosum
Lower reproducibility of the data in the anterior portions of the CC could be attributed to in-flow artifacts from the anterior cerebral artery (Nam et al, 2015a; Tendler and Bowtell, 2019)
The relative signal fraction between intra- and extraaxonal compartments was lower than in other studies (Tendler and Bowtell, 2019). This could be attributed to the constraint we placed on the intra-axonal water R*2 when modelling the data, which we intro duced in order to reduce the effect of the limited number of long TEs on the value estimation uncertainty
Summary
Why study myelin changes in Huntington’s disease?. An increasing body of research suggests that WM changes in HD are due to changes in myelin-associated biological processes at the cellular and molecular level (Bardile et al, 2019; Gomez-Tortosa et al, 2001; Huang et al, 2015; Jin et al, 2015; Myers et al, 1991; Radulescu et al, 2018; Teo et al, 2016; Yin et al, 2020) – for a critical review of such changes see Casella et al, (2020). In HD, myelin changes are suggested to follow both a topologically selective and temporally specific degenera tion, with early myelinated fibres being the most susceptible to, and the first to be affected by, myelin breakdown (Bartzokis et al, 1999, 2007; Dumas et al, 2012; Faria et al, 2016; Phillips et al, 2013; Tabrizi et al, 2011)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
