Multi-compartment analysis of the complex gradient-echo signal quantifies myelin breakdown in premanifest Huntington's disease

Chiara Casella, Elena Kleban, Anne E Rosser, Elizabeth Coulthard, Hugh Rickards, Fabrizio Fasano, Claudia Metzler-Baddeley, Derek K Jones

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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.

Original languageEnglish
Article number102658
Pages (from-to)102658
JournalNeuroImage: Clinical
Volume30
Early online date5 Apr 2021
DOIs
Publication statusE-pub ahead of print - 5 Apr 2021

Bibliographical note

Funding Information:
The present research was funded by a Wellcome Trust PhD studentship to CC (ref: 204005/Z/16/Z); DKJ and EK were supported by a New Investigator Award (to DKJ) from the Wellcome Trust (ref: 096646/Z/11/Z) and a Strategic Award from the Wellcome Trust (ref: 104943/Z/14/Z). We thank Dr Slawomir Kusmia and Dr Mark Drakesmith for their support with the project.

Publisher Copyright:
© 2021 The Authors

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