Striatal Connectivity in Premanifest Huntington Disease Is Differentially Affected by Disease Burden

Background: Different amount of cumulative exposure to the toxic mutant form of the huntingtin protein might underlie distinctive pattern of striatal connectivity in premanifest Huntington's disease (pre-HD). Aim of this study is to investigate disease burden-dependent cortical- and subcortical-striatal loops in different pre-HD stages. Methods: Sixteen pre-HD participants and 25 controls underwent magnetic resonance exam to investigate striatal structural and functional connectivity. Pre-HD individuals were stratified into far and close to disease onset groups according to the disease-burden score. Cortical-striatal and subcortical-striatal functional connectivity was investigated through seed-ROI and ROI-to-ROI approaches, respectively. Integrity of white matter pathways originating from striatal seeds was investigated through probabilistic tractography. Results: In far-to-onset pre-HD, the left caudate nucleus showed cortical increased functional connectivity 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 functional connectivity and caudate structural connectivity, although not surviving multiple comparison correction. Conclusions: Functional reorganization of the caudate nucleus might underlie plasticity compensatory mechanisms which recede as premanifest individuals approach clinical symptoms onset and neurodegeneration.