Transient Alterations In Thalamo-Cerebellar Functional Connectivity In Premanifest Huntington'S Disease

BackgroundThere are no disease modifying therapies for Huntingtons disease (HD), a rare but fatal genetic neurodegenerative condition. To develop and test new management strategies, a better understanding of the mechanisms underlying HD progression is needed. Aberrant changes in thalamo-cortical and striato-cerebellar circuitry have been observed in asymptomatic HD, along with transient enlargement of the dentate nucleus. PurposeTo evaluate the relationship between thalamo-cerebellar connectivity and HD progression. Study TypeProspective and retrospective. PopulationPatients with HD and healthy controls from a single-center dataset (n=34), and patients from the public TRACK-HD dataset (n=91). Field strength/Sequence3T and 7T. AssessmentThalamo-cerebellar connectivity was compared across patients and controls and related to motor scores and predicted years to symptom onset. Cross-sectional findings were validated within-patient by mapping changes in individual connectivity over time. HD effects on cognitive performance were also explored and related to connectivity. Statistical TestsKruskal-Wallis with post hoc Dunns tests and Pearson correlations (psignificant<0.05). ResultsIn the 7T cohort, significant premanifest and control group differences in thalamo-dentate connectivity were observed (pDunn<0.05, 2=.19-.22), with manifest HD connectivity approaching normative values. Thalamic connectivity with the dentate nucleus and anterior cerebellum also correlated with years to onset (pDen=0.06, r=0.42, pAnt<0.05, r=-0.45), together indicating potential transient functional alterations in premanifest HD. Similar patterns were observed between connectivity (thalamus to dentate nucleus and anterior lobe) and cognitive performance scores across all subjects (p<0.05, rDen=-0.17, rAnt=-0.18). In the premanifest TRACK-HD cohort, connectivity of multiple thalamo-cerebellar connections correlated with years to onset, revealing distinct patterns for patients with low versus high motor scores, again indicative of potential transient alterations. Exploratory non-parametric regression of serial imaging data further supported these findings. Data conclusionTransient changes in thalamo-cerebellar connectivity are seen in premanifest HD with increasing progression. More studies are needed to validate this potentially useful biomarker.