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

Abstract 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.