Objective: To test the hypothesis that the trajectory of functional connections over time of the striatum and the cerebellum differs between pre-symptomatic patients with the HD gene expansion (GE) and patients with a family history of HD but without the gene-expansion (GNE), we evaluated function MRI data from the Kids-HD study. 

Methods: We utilized resting-state, functional MRI data from participants in the Kids-HD study between 6 to 18 years old.  Participants were divided into the GE (CAG 36-59) and GNE (CAG <36) groups.  Seed to seed correlations were calculated between four regions that provide input signals to the anterior cerebellum: 1) dorsocaudal putamen; 2) globus pallidus externa; 3) subthalamic nucleus, and 4) pontine nuclei and two regions that represented output from the cerebellum, the dentate nucleus to the: 1) ventrolateral thalamus and 2) dorsocaudal putamen. Linear mixed effects regression models evaluated differences in developmental trajectories of these connections over time between groups.

Results: Four of the six striatal-cerebellum correlations showed significantly different trajectories between groups.  All showed a pattern where in the early age ranges (6-12 years), there was hyperconnectivity in the GE compared to the GNE with those trajectories showing linear decline in the latter half of the age range.

Conclusion: These results parallel previous findings showing striatal hypertrophy in GE children as early as age 6.  These findings support the notion of developmentally higher connectivity between the striatum and cerebellum early in the life of the child with the HD gene expansion, possibly setting the stage for cerebellar compensatory mechanisms.

Supplemental Figure 1: Overview of how long participants were followed during the Kids-HD study.  Single data points represent participants who were only seen once.  

Supplemental Figure 2: This figure represents the cross-sectional sex by group interaction (does not account for longitudinal changes by age).  Panel A outlines the differences in functional connectivity of the globus pallidus externa (GPE) to the anterior cerebellum (aCB) between the gene expanded (GE) and gene non-expanded (GNE) groups by sex.  Panel B shows similar results for functional connectivity between the subthalamic nucleus (STN) and the aCB.  Most notably in each panel, functional connectivity seems to be higher in GE boys relative to GNE boys.

Supplemental Figure 3: This figure represents the triple interaction of age*group*sex, which allows us to investigate the differences in trajectory of functional connectivity strength between groups by sex.  This represents functional connectivity changes between the aCB to the GPE.  In both boys and girls, functional connectivity strength is higher earlier in life in the GE group with a steeper decline over time relative to the GNE group.

Supplemental Figure 4: This figure represents the triple interaction of age*group*sex, which allows us to investigate the differences in trajectory of functional connectivity strength between groups by sex.  This represents functional connectivity changes between the aCB to the STN.  Again, in both boys and girls, functional connectivity strength is higher earlier in life in the GE group with a steeper decline over time relative to the GNE group.