Abstract
Huntington’s disease (HD) leads to white matter (WM) degeneration that may be due to an early breakdown in axon myelination but in vivo imaging correlates of demyelination remain relatively unexplored in HD compared to other neurodegenerative diseases. This study investigated HD-related effects on a putative marker of myelin, the macromolecular proton fraction (MMPF) from quantitative magnetization transfer and on fractional anisotropy, axial and radial diffusivity from diffusion tensor MR-imaging. Microstructural differences were studied in WM pathways of the basal ganglia and motor systems known to be impaired in HD: the corpus callosum, the cortico-spinal tract, the anterior thalamic radiation, fibers between prefrontal cortex and caudate and between supplementary motor area and putamen. Principal component analysis was employed for dimensionality reduction. Patients showed reductions in a component with high loadings on MMPF in all WM pathways and a trend for increases in a component loading on axial and radial diffusivities but no differences in a component loading on fractional anisotropy. While patients’ performance in executive functioning was impaired, their working memory span was preserved. Inter-individual differences in the diffusivity component correlated with patients’ performance in clinical measures of the United Huntington Disease Rating Scale. In summary, HD-related reductions in MMPF suggest that myelin breakdown contributes to WM impairment in human HD and emphasize the potential of quantitative MRI metrics to inform about disease pathogenesis. Disease severity in manifest HD, however, was best captured by non-specific diffusivity metrics sensitive to multiple disease and age-related changes.
Highlights
Huntington’s disease (HD) is a progressive neurodegenerative disease caused by an expansion and instability of the cytosine-adenine-guanine triplet repeat (CAG repeat) in the Huntingtin gene
The present study investigated HD-related differences in white matter (WM) microstructure by utilizing both high angular resolution diffusion imaging (HARDI) (Tuch et al, 2002) and quantitative magnetization transfer imaging (Henkelman et al, 1993, 2001) which provides improved myelin specificity compared to diffusion MRI. qMT estimates the liquid and semisolid constituents of tissue by applying an off-resonance radiofrequency pulse with time-varying amplitude to selectively saturate the macromolecular magnetization
Based on i. evidence indicating that myelin breakdown underpins WM damage in HD (Bartzokis et al, 2007; Ernst et al, 2014; Huang et al, 2015; Teo et al, 2016) and ii. histology evidence demonstrating that macromolecular proton fraction (MMPF) is highly sensitive to the myelin content of WM (Schmierer et al, 2007; Ou et al, 2009; Liu et al, 2015), the aim of this study was to investigate whether MMPF was a sensitive in vivo measure of WM degeneration in HD
Summary
Huntington’s disease (HD) is a progressive neurodegenerative disease caused by an expansion and instability of the cytosine-adenine-guanine triplet repeat (CAG repeat) in the Huntingtin gene. Mutation carriers show gray matter atrophy in the basal ganglia (BG) and subtle and progressive white matter (WM) impairment many years before the onset of any clinical symptoms (Dayalu and Albin, 2015). Microstructural impairments at prodromal disease stages have been identified for major WM bundles including the corpus callosum, the anterior thalamic radiation and the cortico-spinal tract (Matsui et al, 2015; Novak et al, 2014, 2015; Phillips et al, 2014, 2015; Odish et al, 2015; Poudel et al, 2015; Steventon et al, 2015).
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