White matter loss can be seen many years before disease onset in the brains of premanifest HD (preHD) gene expansion carriers. The earliest white matter changes are seen around the striatum, within the corpus callosum and in the posterior white matter tracts.

By constructing white matter networks, using diffusion MRI, I reveal how specific white matter connections are affected in preHD. I demonstrate the selective vulnerability of cortical-striatal white matter connections to highly connected hub regions in the cerebral cortex, showing loss of these white matter connections correlate with symptoms in the premanifest stage.

Over time a hierarchy of white matter vulnerability is observed in preHD, where cortico-striatal connections are affected first followed by inter-hemispheric and intra-hemispheric connections. Change over 2 years is predominantly seen in posterior cortico-striatal connections.

I link these system level white matter changes to HD related abnormalities at the cellular level by investigating the relationship between regional gene expression and regional loss of white matter connections in preHD. I demonstrate how cortico-striatal and inter-hemispheric white matter loss is associated with the expression of synaptic genes, particularly those showing abnormal transcription in HD.

Having established cortico-striatal selective vulnerability I show how we can define sub-regions of the striatum based on white matter connectivity in healthy brains. This enables investigation of white matter loss to specific striatal sub-regions in preHD. Using longitudinal data from the Track-On HD study I show wide spread changes across the white matter of striatal sub-regions at baseline, with only motor-striatal sub-regions showing white matter loss over 2 years.

Finally, I outline the CLEAR-HD study where I will use ultra-high field 7T MRI to link white matter loss in preHD with markers of neuronal loss in the deep and superficial layers of the cerebral cortex. In a cohort of healthy participants, I demonstrate strong relationships between quantitative 7T MRI contrasts, layer specific cell count and gene expression. These contrasts are particularly sensitive to cortical genes showing abnormal transcription in HD.