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

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.

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

“…Here, the combination of standard DTI metrics with MTR and FR afforded a more biologically meaningful interpretation of microstructural changes. These results replicate evidence from a previous study carried out by our group at 7 Tesla 7 and are in accord with the Demyelination Hypothesis, which argues that early myelinated fibres are more susceptible to myelin disorder in the disease 21 .…”

“…Huntington's disease (HD), a neurodegenerative disorder leading to devastating cognitive, psychiatric and motor symptoms, cannot currently be cured, and a research priority is to increase understanding of its pathogenesis. Subtle and progressive white matter (WM) alterations have been observed early in HD progression [1][2][3][4][5][6][7] , but their aetiology and role remain unclear. Therefore, with the present study we aimed to disentangle the contribution of changes in axon microstructure versus changes in myelin to WM pathology in premanifest HD.…”

“…Thus, characterising WM microstructure across this tract might provide insight into regional differences in the impact of HD on WM, and elucidate disease-related pathological processes in the context of the Demyelination Hypothesis 21 . This suggests that mutant huntingtin (mHTT) leads to premature myelin breakdown and has been given support by several studies demonstrating alteration in myelin-associated biological processes at the cellular and molecular level in the HD brain 7,[22][23][24][25][26][27][28] . Specifically, the Demyelination Hypothesis proposes myelin impairment to begin from early-myelinating caudate and putamen striatum structures and then spread in a bilateral and symmetric pattern to other early-myelinating regions.…”

Mutation‐related magnetization‐transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra‐strong gradient MRI

“…Huntington disease (HD), a neurodegenerative disorder leading to devastating cognitive, psychiatric, and motor symptoms, cannot currently be cured, and a research priority is to increase understanding of its pathogenesis. Subtle and progressive white matter (WM) alterations have been observed early in HD progression (Casella et al, 2021; Gregory et al, 2019; McColgan et al, 2015; McColgan et al, 2017; McColgan et al, 2018; Paulsen et al, 2008; Scahill et al, 2020), but their etiology and role remain unclear. Therefore, the present study aimed to disentangle the contribution of changes in axon microstructure versus changes in magnetization transfer as a proxy measure of myelin and/or iron, to WM pathology in premanifest HD.…”

“…Both explanations fit within the demyelination hypothesis as they implicate an increasingly unsuccessful compensation for the disease‐related myelin loss. For a critical review of human and animal studies lending support to the demyelination hypothesis (see Casella et al, 2021).…”