Wang Zexi, Solomon Alexia, Lupo Janine M, Yao Jingwen
Department of Radiological Sciences, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Department of Neurobiology & Behavior, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, California, USA.
Hum Brain Mapp. 2025 Aug 1;46(11):e70305. doi: 10.1002/hbm.70305.
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.
亨廷顿舞蹈症（HD）是一种进行性神经退行性疾病，由亨廷顿蛋白（HTT）基因中的胞嘧啶 - 腺嘌呤 - 鸟嘌呤重复序列扩增引起，导致广泛的脑萎缩和白质变性。尽管皮质 - 纹状体通路已得到广泛研究，但齿状核 - 红核 - 丘脑束（DRTT）作为整合运动和认知功能的关键小脑传出通路，尽管越来越多的证据表明小脑参与这些功能，但在很大程度上仍未被探索。通过研究DRTT沿线的微观结构改变，我们旨在阐明其在HD进展中的作用及其与运动和认知障碍的关联，从而深入了解DRTT对疾病严重程度和临床结果的潜在贡献。我们回顾性分析了来自三个跨国HD队列（TRACK - HD/ON、PREDICT - HD和IMAGE - HD）的638名参与者的1392次扫描，这些扫描符合标准化纳入标准，并应用HD - ISS对疾病阶段进行分类。对扩散MRI数据进行概率纤维束成像，以重建终止于运动或前额叶皮质的同侧和交叉DRTT通路，并沿每条纤维束的100个节点提取分数各向异性（FA）和平均扩散率（MD）值。使用线性混合效应模型进行纤维束沿线分析，以评估组间差异以及与运动和认知评分的相关性，同时控制协变量。与健康对照（HC）相比，在症状前HD（PM，HD - ISS 0期和1期）和症状性HD（HD，HD - ISS 2期和3期）组中以及随时间推移，沿DRTT的多个区域观察到FA显著降低和MD增加，特别是在齿状核区域和齿状核 - 红核投射中。这些微观结构变化与更严重的运动和认知障碍相关。相反，DRTT丘脑 - 皮质投射呈现相反的模式，PM和HD中的FA高于HC。在该节段内，FA和MD也与运动评分呈正相关。纤维束沿线分析揭示了症状前和症状性HD个体的DRTT均存在微观结构破坏，表明DRTT在HD进展中起作用。我们的研究结果还突出了评估纤维束沿线区域变化的价值。这些特定节段的白质改变为HD病理学提供了更多见解，并可能作为HD中运动和认知障碍的生物标志物。
