In Vivo Mapping of Catecholaminergic Loss and Iron Deposition in Huntington's Disease

BACKGROUND: The pathophysiology of Huntington's disease (HD) remains obscure. Magnetic resonance imaging (MRI) can reveal in vivo molecular changes related to disease pathology. OBJECTIVES: To investigate catecholaminergic neuronal integrity and subcortical brain iron accumulation in HD employing neuromelanin-sensitive MRI, and quantitative susceptibility mapping (QSM-MRI). METHODS: Twenty-five HD gene expansion carriers (HDGECs; 11 premanifest, mean predicted phenoconversion time 21.25 ± 8.28 years) and 25 healthy controls (HC) underwent clinical investigation, measurement of plasma neurofilament light chain (NfL) levels, neuromelanin-sensitive, and QSM-MRI on a 3 T scanner. For neuromelanin analysis, the substantia nigra (SN) and locus coeruleus (LC) areas and contrast-to-noise ratio (CNR) were computed. Regions of interest from the MuSus100 atlas were segmented for QSM-MRI analysis, and susceptibility values extracted using the whole brain mask as reference. RESULTS: Manifest HDGECs showed, on neuromelanin-sensitive MRI analysis, reduced LC and SN areas, and LC CNR compared with HC (P < 0.001). QSM analysis demonstrated increased susceptibility values in caudate, putamen, external and internal pallidum, and the subthalamic nucleus of manifest HGDECs (P < 0.001). Higher susceptibility values in these regions correlated with clinical markers of disease burden, higher plasma NfL, and poorer neuropsychological outcomes in multiple domains (P < 0.05). Smaller LC area correlated with higher plasma NfL (P = 0.029). Higher susceptibility values in the caudate and putamen correlated with lower SN CNR (P < 0.05). CONCLUSIONS: Our findings confirm widespread iron subcortical accumulation in HD, reveal significant noradrenergic neuronal loss, and describe dopaminergic alteration which may reflect ongoing pathology along the nigrostriatal pathway. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.