Mapping iron content and white matter integrity in the anterior thalamic radiations across Huntington's disease stages

Abstract

Huntington’s disease (HD) is characterized by progressive neurodegeneration, often accompanied by disrupted iron regulation and altered white matter (WM) integrity. This study investigates iron content and microstructural changes in the anterior thalamic radiations (ATR) across different HD stages. Thirty-one gene carriers and twenty-four controls underwent neuropsychological assessment and 3 T-MRI scanning, including relaxometry and diffusion tensor imaging (DTI) sequences to assess iron content and WM microstructure. ATR changes were examined using average and along-the-tract analyses, with ANOVA and post-hoc Tukey tests to identify group differences and Spearman correlations to evaluate clinical associations. Machine-learning models were applied to assess the potential of MRI metrics as diagnostic biomarkers for HD, focusing on disease stage differentiation and presymptomatic detection. Premanifest individuals exhibited increased iron content and enhanced WM integrity bilaterally, while manifest patients maintained elevated left ATR iron levels alongside bilateral WM degeneration. Both ATRs contribute to the clinical manifestations of HD, including cognitive impairment and neuropsychiatric disturbances. Both along-the-tract relaxometry and DTI metrics emerged as promising biomarkers for distinguishing HD subgroups and identifying presymptomatic individuals. These findings highlight the interplay between iron dysregulation and WM disruption in HD, offering potential pathways for early diagnosis and targeted therapeutic strategies.