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Although cortico\u2010striatal pathways have been extensively studied, the dentato\u2010rubro\u2010thalamic tract (DRTT), a key cerebellar efferent pathway integrating motor and cognitive functions, remains largely unexplored, despite increasing evidence of cerebellar involvement in these functions. By investigating microstructural alterations along the DRTT, we aim to elucidate its role in HD progression and its association with motor and cognitive impairments, providing insights into the potential contribution of the DRTT to disease severity and clinical outcomes. We retrospectively analyzed 1392 scans from 638 participants across three multinational HD cohorts (TRACK\u2010HD\/ON, PREDICT\u2010HD, and IMAGE\u2010HD) with standardized inclusion criteria, and applied the HD\u2010ISS to categorize disease stages. Probabilistic tractography was performed on diffusion MRI data to reconstruct ipsilateral and decussating DRTT pathways ending in the motor or pre\u2010frontal cortices, with fractional anisotropy (FA) and mean diffusivity (MD) values extracted along 100 nodes per tract. Along\u2010tract analyses were conducted using linear mixed\u2010effects models to assess group differences and correlations with motor and cognitive scores, while controlling for covariates. Significantly decreased FA and increased MD were observed in premanifest HD (PM, HD\u2010ISS Stage 0 and 1) and manifest HD (HD, HD\u2010ISS Stage 2 and 3) groups and over time compared to healthy controls (HC) across multiple regions along the DRTT, particularly in the dentate nucleus region and dentate nucleus\u2010red nucleus projection. These microstructural changes were correlated to the greater motor and cognitive impairments. Conversely, the DRTT thalamo\u2010cortical projection exhibited an opposite pattern, with higher FA in PM and HD than in HC. Both FA and MD were also positively correlated with motor score within this segment. Along\u2010tract analysis revealed microstructural disruptions across DRTT in both premanifest and manifest HD individuals, suggesting that the DRTT plays a role in HD progression. Our findings also highlight the value of assessing regional changes along the tract. These segment\u2010specific white matter alterations provide additional insights into HD pathology and may serve as biomarkers for motor and cognitive impairments in HD.<\/jats:p>","DOI":"10.1002\/hbm.70305","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T13:14:06Z","timestamp":1754054046000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Along\u2010Tract Diffusion Alterations in the Dentato\u2010Rubro\u2010Thalamic Tract Correlate With Motor and Cognitive Decline in Huntington's Disease"],"prefix":"10.1002","volume":"46","author":[{"given":"Zexi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Radiological Sciences David Geffen School of Medicine, UCLA  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexia","family":"Solomon","sequence":"additional","affiliation":[{"name":"Department of Radiological 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