Moving beyond the tensor:
Advanced characterisation of white matter microstructure
in Huntington’s Disease using translational neuroimaging
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Abstract
Huntington’s disease (HD) is a genetic neurodegenerative disorder leading to
devastating cognitive, psychiatric and motor symptoms. Currently, this disease cannot be
cured, and a research priority is to increase the understanding of its pathogenesis and to provide
biomarkers for evaluating the efficacy of targeted therapies.
Subtle and progressive white matter (WM) alterations have been observed early in HD
progression, before clinical onset of the disease. However the aetiology of WM degeneration
and its role in disease pathogenesis remain unclear. The assessment of early WM
microstructural changes in the HD brain is therefore of fundamental importance, as this might
prove useful for the identification of disease-related biomarkers and for measuring
responsiveness to pharmaceutical and other therapeutic approaches.
The primary aim of this work was to exploit both ultra-strong gradients (300 mT/m)
and ultra-high field (7 Tesla, 9.4 Tesla) to assess WM microstructure in HD, using a variety of
MRI techniques in premanifest and manifest patients, as well as in a mouse model of the
disease. Specifically, this Thesis moved beyond the diffusion tensor framework, with the
application of advanced WM microstructural imaging.
Using these advanced MR techniques I was able to provide a comprehensive and
detailed characterisation of WM microstructural alterations in the HD brain, and to better tease
apart changes in apparent myelin from alterations in axon microstructure. Assessing both
human patients and a mouse model of HD allowed for direct cross-species comparisons and
bi-directional translation of results.
Additionally, I was able to exploit the improved compartmental specificity obtained by
complementing standard DTI metrics with advanced MRI measurements, to study the effects
of two months of a novel drumming training on WM plasticity in patients with manifest HD