Along-Tract Diffusion Alterations in the Dentato-Rubro-Thalamic Tract Correlate With Motor and Cognitive Decline in Huntington's Disease

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by cytosine-adenine-guanine repeat expansion in the huntingtin (HTT) gene, leading to widespread brain atrophy and white matter degeneration. Although cortico-striatal pathways have been extensively studied, the dentato-rubro-thalamic 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-HD/ON, PREDICT-HD, and IMAGE-HD) with standardized inclusion criteria, and applied the HD-ISS 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-frontal cortices, with fractional anisotropy (FA) and mean diffusivity (MD) values extracted along 100 nodes per tract. Along-tract analyses were conducted using linear mixed-effects 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-ISS Stage 0 and 1) and manifest HD (HD, HD-ISS 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-red nucleus projection. These microstructural changes were correlated to the greater motor and cognitive impairments. Conversely, the DRTT thalamo-cortical 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-tract 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-specific white matter alterations provide additional insights into HD pathology and may serve as biomarkers for motor and cognitive impairments in HD.

Keywords: Huntington's disease; cognitive impairment; dentato‐rubro‐thalamic‐tract; diffusion MRI; motor decline; tractography; white matter alterations.

FIGURE 1

Imaging analysis pipeline. (A) Examples of diffusion‐weighted imaging (DWI) preprocessing and diffusion tensor imaging (DTI) fitting; (B) examples of subcortical and cortical regions of interest (ROIs) in Montreal Neurological Institute (MNI) space, along with T1‐weighted (T1w) segmentation; (C) examples of decussating dentato‐rubro‐thalamic tract (DRTT) connecting to motor and prefrontal cortices.

FIGURE 2

Group comparisons of fractional anisotropy (FA) values along the right‐decussating dentato‐rubro‐thalamic tract (DRTT). (A) Motor‐DRTT and (B) Prefrontal‐DRTT display mean FA values for healthy controls (HC), premanifest (PM), and manifested Huntington's disease (HD) groups, with shaded areas representing standard deviations. Heatmap illustrates the significance of group differences and interaction term at each node, where red and blue denote positive and negative z values from the linear mixed‐effects (LME) model. The brain illustration highlights anatomical regions where significant group differences were identified. In (A), two arrows highlight regions with significant FA differences: (1) dentate nucleus (DN) and dentate‐red nucleus (DN–RN) projection, and (2) thalamo‐cortical projection. In (B), four arrows mark distinct regions: (1) DN and DN–RN, (2) thalamus, (3) thalamo‐cortical projection, and (4) cortex.

FIGURE 3

Group comparisons of mean diffusivity (MD) values along the right‐decussating dentato‐rubro‐thalamic tract (DRTT). (A) Motor‐DRTT and (B) Prefrontal‐DRTT display mean MD values for healthy controls (HC), premanifest (PM), and manifested Huntington's disease (HD) groups, with shaded areas representing standard deviations. Heatmap illustrates the significance of group differences and interaction term at each node, where red and blue denote positive and negative z values from the linear mixed‐effects (LME) model. The brain illustrations indicate anatomical regions with significant MD differences using arrows. In (A), two arrows highlight: (1) the dentate‐red nucleus (DN–RN) projection and (2) post‐thalamic regions including the thalamo‐cortical projection and cortex. In (B), two arrows indicate: (1) the DN and DN–RN projection, and (2) the regions from thalamus to cortex.

FIGURE 4

Node‐wise and segmental correlations between log‐transformed total motor score (TMS) and fractional anisotropy/mean diffusivity (FA/MD) values along right decussating motor dentato‐rubro‐thalamic tract (DRTT). (A) Z values (coefficient/standard error) and significant nodes were reported. Dots represent nodes have significant correlations before false discovery rate Benjamini‐Hochberg (FDR‐BH) correction (p < 0.05), and stars indicate significant nodes after FDR‐BH correction. Blue indicates FA, and red indicates MD. (B) Significant correlations within each segment were highlighted. Regressions were performed using the averages of FA of significant nodes in each segment.

FIGURE 5

Node‐wise and segmental correlations between Symbol Digit Modalities Test (SDMT)/Stroop Word Test (SWT) and fractional anisotropy/mean diffusivity (FA/MD) values along right decussating prefrontal dentato‐rubro‐thalamic tract (DRTT). (A) Z‐values (coefficient/standard error) and significant nodes were reported. Dots represent nodes have significant correlations before false discovery rate Benjamini‐Hochberg (FDR‐BH) correction (p < 0.05), and stars indicate significant nodes after FDR‐BH correction. Blue indicates FA, and red indicates MD. (B) Significant correlations within each segment were highlighted. Regressions were performed using the averages of FA/MD of significant nodes in each segment.

FIGURE 6

Schematic representation of cortico‐striatal‐thalamo‐cortical (CSTC) and dentato‐rubro‐thalamic tract (DRTT) circuitry in Huntington's disease (HD), highlighting our findings of microstructural disruption in the DRTT alongside previously reported alterations in CSTC pathways.