Stage-dependent tau-PET signatures in Huntington’s disease revealed by [¹⁸F]PI-2620

PURPOSE: Neuropathological and biomarker evidence implicates tau dysregulation as a downstream component of Huntington's disease (HD) pathobiology, yet its in vivo distribution has not been characterised using second-generation tau-PET tracers. We aimed to define the regional organisation, stage dependence and clinical relevance of tau-sensitive PET signal across the HD disease spectrum. METHODS: Fifty-four participants (13 healthy controls, 9 premanifest mutation carriers and 32 manifest carriers) underwent 60-minute dynamic [¹⁸F]PI-2620 PET imaging. Tau-PET signal was quantified using distribution volume ratios (DVR) derived from reference-tissue kinetic modelling. Analyses combined region-of-interest and whole-brain mapping with threshold-based positivity profiling, modelling of cumulative genetic disease burden (CAP), and clinico-anatomical association analyses. RESULTS: Tau-PET abnormalities showed a spatially ordered pattern dominated by subcortical involvement. The globus pallidus exhibited the strongest effect, with marked DVR increases and high positivity rates emerging in premanifest carriers and approaching saturation in manifest HD. Additional subcortical changes involved the putamen, whereas caudate DVR decreased in manifest disease. Cortical effects were more modest and selectively involved posterior associative regions. CAP modelling supported predominantly monotonic subcortical stage-related profiles, while limbic and cortical regions showed heterogeneous cross-sectional patterns. Clinico-anatomical analyses linked subcortical tau-PET signal with genetic burden and motor severity and limbic signal with psychiatric symptoms. CONCLUSION: Tau-sensitive PET signal represents a spatially ordered and stage-dependent feature of HD and identifies a reproducible pallidal signature linked to disease burden, supporting its potential as a biomarker for patient stratification and mechanistic monitoring in therapeutic studies targeting downstream pathological processes. TRIAL REGISTRATION NUMBER: NCT07503743.