Myelin Breakdown in Human Huntington’s Disease: Multi-Modal Evidence from Diffusion MRI and Quantitative Magnetization Transfer

AbstractWhite 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.

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Drumming Motor Sequence Training Induces Apparent Myelin Remodelling in Huntington’s Disease: A Longitudinal Diffusion MRI and Quantitative Magnetization Transfer Study

Journal of Huntington s Disease ◽

10.3233/jhd-200424 ◽

2020 ◽

Vol 9 (3) ◽

pp. 303-320

Author(s):

Chiara Casella ◽

Jose Bourbon-Teles ◽

Sonya Bells ◽

Elizabeth Coulthard ◽

Greg D. Parker ◽

...

Keyword(s):

Executive Function ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Diffusion Tensor ◽

Small Sample Size ◽

Magnetization Transfer ◽

Small Sample ◽

Motor Sequence ◽

Longitudinal Diffusion ◽

Microstructural Changes

Background: Impaired myelination may contribute to Huntington’s disease (HD) pathogenesis. Objective: This study assessed differences in white matter (WM) microstructure between HD patients and controls, and tested whether drumming training stimulates WM remodelling in HD. Furthermore, it examined whether training-induced microstructural changes are related to improvements in motor and cognitive function. Methods: Participants undertook two months of drumming exercises. Working memory and executive function were assessed before and post-training. Changes in WM microstructure were investigated with diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics, the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model of diffusion (CHARMED) and the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) imaging. WM pathways linking putamen and supplementary motor areas (SMA-Putamen), and three segments of the corpus callosum (CCI, CCII, CCIII) were studied using deterministic tractography. Baseline MPF differences between patients and controls were assessed with tract-based spatial statistics. Results: MPF was reduced in the mid-section of the CC in HD subjects at baseline, while a significantly greater change in MPF was detected in HD patients relative to controls in the CCII, CCIII, and the right SMA-putamen post-training. Further, although patients improved their drumming and executive function performance, such improvements did not correlate with microstructural changes. Increased MPF suggests training-induced myelin changes in HD. Conclusion: Though only preliminary and based on a small sample size, these results suggest that tailored behavioural stimulation may lead to neural benefits in early HD, that could be exploited for delaying disease progression.

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Dynamics of the connectome in Huntington's disease: A longitudinal diffusion MRI study

NeuroImage Clinical ◽

10.1016/j.nicl.2015.07.003 ◽

2015 ◽

Vol 9 ◽

pp. 32-43 ◽

Cited By ~ 18

Author(s):

Omar F.F. Odish ◽

Karen Caeyenberghs ◽

Hadi Hosseini ◽

Simon J.A. van den Bogaard ◽

Raymund A.C. Roos ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Diffusion Mri ◽

Longitudinal Diffusion ◽

Mri Study

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Drumming motor sequence training induces apparent myelin remodelling in Huntington’s disease: a longitudinal diffusion MRI and quantitative magnetization transfer study

10.1101/2019.12.24.887406 ◽

2019 ◽

Author(s):

Chiara Casella ◽

Jose Bourbon-Teles ◽

Sonya Bells ◽

Elizabeth Coulthard ◽

Greg D. Parker ◽

...

Keyword(s):

Executive Function ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Diffusion Tensor ◽

Magnetization Transfer ◽

Motor Sequence ◽

Longitudinal Diffusion ◽

Microstructural Changes ◽

Before And After ◽

The Right

1.AbstractBackgroundImpaired myelination may contribute to Huntington’s disease (HD) pathogenesis. This study assessed differences in white matter (WM) microstructure between HD patients and controls, and tested whether drumming training stimulates WM remodelling in HD. Furthermore, it examined whether training-induced microstructural changes are related to improvements in motor and cognitive function.MethodsParticipants undertook two months of drumming exercises. Working memory and executive function were assessed before and after training. Changes in WM microstructure were investigated with diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics, the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model of diffusion (CHARMED) and the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) imaging. WM pathways linking the putamen and the supplementary motor area (SMA-Putamen), and three segments of the corpus callosum (CCI, CCII, CCIII) were studied using deterministic tractography. Baseline MPF differences between patients and controls were assessed with tract-based spatial statistics (TBSS).ResultsMPF was reduced in HD patients compared to controls in the mid-section of the CC in HD subjects at baseline, while a significantly greater change in MPF was detected in HD patients relative to controls in the CCII, CCIII, and the right SMA-putamen post-training. Further, although patients improved their drumming and executive function performance, such improvements did not correlate with microstructural changes.ConclusionsIncreased MPF suggests training-induced myelin changes in HD. Tailored behavioural stimulation may lead to neural benefits in early HD that could be exploited for delaying disease progression.

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