{"doi":"10.1101/2025.01.15.25320232","title":"TRANSIENT ALTERATIONS IN THALAMO-CEREBELLAR FUNCTIONAL CONNECTIVITY IN PREMANIFEST HUNTINGTON’S DISEASE","abstract":"Abstract 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.","journal":"medRxiv","year":2025,"id":560405,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":396762,"name":"Jingwen Yao","orcid":"0000-0002-8828-1841","position":1,"is_corresponding":false},{"id":1160750,"name":"Radhika Bhalerao","orcid":null,"position":2,"is_corresponding":false},{"id":920861,"name":"Angela Jakary","orcid":"0000-0002-2759-684X","position":3,"is_corresponding":false},{"id":920864,"name":"Julia Glueck","orcid":"0009-0000-4196-5931","position":4,"is_corresponding":false},{"id":921320,"name":"Theresa Driscoll","orcid":null,"position":5,"is_corresponding":false},{"id":347892,"name":"Michael D. Geschwind","orcid":"0000-0003-2861-3776","position":6,"is_corresponding":false},{"id":672823,"name":"Alexandra Nelson","orcid":"0000-0002-9305-5662","position":7,"is_corresponding":false},{"id":465961,"name":"Katherine L. Possin","orcid":"0000-0002-6623-3793","position":8,"is_corresponding":false},{"id":536256,"name":"Christopher P. Hess","orcid":"0000-0002-5132-5302","position":9,"is_corresponding":false},{"id":345506,"name":"Janine Lupo","orcid":"0000-0002-0051-6387","position":10,"is_corresponding":false},{"id":523726,"name":"Melanie A. Morrison","orcid":"0000-0002-5993-0515","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:55:42.883572Z","pmid":"39867412","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}