Dynamics of cortical degeneration over a decade in Huntington’s disease

Abstract Background Characterizing changing brain structure in neurodegeneration is fundamental to understanding long-term effects of pathology and ultimately providing therapeutic targets. It is well-established that Huntington’s disease (HD) gene-carriers undergo progressive brain changes during the course of disease, yet the long-term trajectory of cortical atrophy is not well-defined. Given that genetic therapies currently tested in HD are primarily expected to target the cortex, understanding atrophy across this region is essential. Methods Capitalizing on a unique longitudinal dataset with a minimum of three and maximum of seven brain scans from 49 HD gene-carriers and 49 age-matched controls, we implemented a novel dynamical systems approach to infer patterns of regional neurodegeneration over ten years. We use Bayesian hierarchical modelling to map participant- and group-level trajectories of atrophy spatially and temporally, additionally relating atrophy to the genetic marker of HD (CAG-repeat length) and motor and cognitive symptoms. Results We show, for the first time, that neurodegenerative changes exhibit complex temporal dynamics with substantial regional variation around the point of clinical diagnosis. Although widespread group differences were seen across the cortex, occipital and parietal regions undergo the greatest rate of cortical atrophy. We have established links between atrophy and genetic markers of HD, while demonstrating that specific cortical changes predict decline in motor and cognitive performance. Conclusions HD gene-carriers display regional variability in the spatial pattern of cortical atrophy, which relates to genetic factors and motor and cognitive symptoms. Our findings indicate a complex pattern of neuronal loss, which enables greater characterization of HD progression.