TRANSIENT ALTERATIONS IN THALAMO-CEREBELLAR FUNCTIONAL CONNECTIVITY IN PREMANIFEST HUNTINGTON'S DISEASE.

Background: There are no disease modifying therapies for Huntington's 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.

Purpose: To evaluate the relationship between thalamo-cerebellar connectivity and HD progression.

Study type: Prospective and retrospective.

Population: Patients with HD and healthy controls from a single-center dataset (n=34), and patients from the public TRACK-HD dataset (n=91).

Field strength/sequence: 3T and 7T.

Assessment: Thalamo-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 tests: Kruskal-Wallis with post hoc Dunn's tests and Pearson correlations (p _significant <0.05).

Results: In the 7T cohort, significant premanifest and control group differences in thalamo-dentate connectivity were observed (p _Dunn <0.05, η 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 (p _Den =0.06, r=0.42, p _Ant <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, r _Den =-0.17, r _Ant =-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 conclusion: Transient changes in thalamo-cerebellar connectivity are seen in premanifest HD with increasing progression. More studies are needed to validate this potentially useful biomarker.