Network spread determines severity of degeneration and disconnection in Huntington's disease

Trans‐neuronal propagation of mutant huntingtin protein contributes to the organised spread of cortico‐striatal degeneration and disconnection in Huntington's disease (HD). We investigated whether the network diffusion model, which models transneuronal spread as diffusion of pathological proteins via the brain connectome, can determine the severity of neural degeneration and disconnection in HD. We used structural magnetic resonance imaging (MRI) and high‐angular resolution diffusion weighted imaging (DWI) data from symptomatic Huntington's disease (HD) (N = 26) and age‐matched healthy controls (N = 26) to measure neural degeneration and disconnection in HD. The network diffusion model was used to test whether disease spread, via the human brain connectome, is a viable mechanism to explain the distribution of pathology across the brain. We found that an eigenmode identified in the healthy human brain connectome Laplacian matrix, accurately predicts the cortico‐striatal spatial pattern of degeneration in HD. Furthermore, the spread of neural degeneration from sub‐cortical brain regions, including the accumbens and thalamus, generates a spatial pattern which represents the typical neurodegenerative characteristics in HD. The white matter connections connecting the nodes with the highest amount of disease factors, when diffusion based disease spread is initiated from the striatum, were found to be most vulnerable to disconnection in HD. These findings suggest that trans‐neuronal diffusion of mutant huntingtin protein across the human brain connectome may explain the pattern of gray matter degeneration and white matter disconnection that are hallmarks of HD.