Striatal connectivity in pre-manifest Huntington's disease is differentially affected by disease burden

Background and purpose Different amounts of cumulative exposure to the toxic mutant form of the huntingtin protein might underlie the distinctive pattern of striatal connectivity in pre-manifest Huntington's disease (pre-HD). The aim of this study was to investigate disease-burden-dependent cortical-striatal and subcortical-striatal loops at different pre-HD stages. Methods A total of 16 participants with pre-HD and 25 controls underwent magnetic resonance imaging to investigate striatal structural and functional connectivity (FC). Individuals with pre-HD were stratified into far-from-onset and close-to-onset disease groups according to the disease-burden score. Cortical-striatal and subcortical-striatal FC was investigated through seed-region of interest (ROI) and ROI-to-ROI approaches, respectively. The integrity of white-matter pathways originating from striatal seeds was investigated through probabilistic tractography. Results In far-from-onset pre-HD, the left caudate nucleus showed cortical increased FC in brain regions overlapping with the default mode network and increased coupling connectivity with the bilateral thalamus. By contrast, close-to-onset individuals showed increased fractional anisotropy (and mean diffusivity) in the right caudate nucleus and widespread striatal atrophy. Finally, we reported an association between cortical-caudate FC and caudate structural connectivity, although this did not survive multiple comparison correction. Conclusions Functional reorganization of the caudate nucleus might underlie plasticity compensatory mechanisms that recede as individuals with pre-HD approach clinical symptom onset and neurodegeneration.