Fluorine-18 labeled PI-2620 tau positron emission tomography and quantitative susceptibility mapping reveal spatiotemporal interactions between tau deposition and iron accumulation in progressive supranuclear palsy

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disease with four-repeat (4R)-tau pathology. Recent studies suggest tau deposition overlaps with iron dysregulation in vulnerable brain regions. We used second-generation fluorine-18 labeled PI-2620 tau positron emission tomography (18F-PI-2620 tau PET) imaging and quantitative susceptibility mapping (QSM) to explore intrinsic interactions during neurodegeneration in the PSP brain. Methods: Seventeen patients with PSP (including 11 PSP-Richardson’s syndrome [PSP-RS] subtype) and eight healthy controls underwent 18F-PI-2620 PET and 3.0 T brain magnetic resonance imaging (MRI) scans. Whole-brain tau uptake was analyzed using standardized uptake value ratio (SUVR) with cerebellum as the reference. Iron content in subcortical regions was quantified using mean susceptibility values (MSV). The effect of QSM on the association between tau uptake and brain volume was tested using mediation analysis. Results: PSP and PSP-RS patients showed increased tau uptake in bilateral globus pallidus (GP) and right subthalamic nucleus (STN), and reduced uptake in left caudate nucleus (CN) (all P <0.05). Tau uptake in STN, red nucleus (RN), and dentate nucleus (DN) in PSP yielded a unique internal correlation network (all P <0.05) and correlated with severity of patients’ non-motor symptoms (all P <0.01). Greater susceptibility was observed in bilateral CN, putamen (PUT), GP, STN, RN, and substantia nigra (SN) (all P <0.05). Structural atrophy of brain regions, including basal ganglia (all P <0.01), was found in brain volume analysis in both PSP and PSP-RS groups. Regional analysis revealed associations between tau-SUVR, QSM-MSV, and volume in multiple vulnerable regions. Mediation analysis showed that effects of tau burden on structural atrophy in left CN and right PUT could be partially or fully explained by iron accumulation. Conclusions: These findings show the strong relationships among 4R tauopathy, iron dysregulation, and structural atrophy in vivo. Advanced neurodegeneration may be explained by tau-dependent, iron-dependent, or synergistic mechanisms, providing insights into PSP pathogenesis.