Uncovering distinct progression patterns of tau deposition in progressive supranuclear palsy using [(18)F]Florzolotau PET imaging and subtype/stage inference algorithm

BACKGROUND: Progressive supranuclear palsy (PSP) is a primary 4-repeat tauopathy with diverse clinical phenotypes. Previous post-mortem studies examined tau deposition sequences in PSP, but in vivo scrutiny is lacking. METHODS: We conducted [(18)F]Florzolotau tau positron emission tomography (PET) scans on 148 patients who were clinically diagnosed with PSP and 20 healthy controls. We employed the Subtype and Stage Inference (SuStaIn) algorithm to identify PSP subtype/stage and related tau patterns, comparing clinical features across subtypes and assessing PSP stage-clinical severity association. We also evaluated functional connectivity differences among subtypes through resting-state functional magnetic resonance imaging. FINDINGS: We identified two distinct subtypes of PSP: Subtype1 and Subtype2. Subtype1 typically exhibits a sequential progression of the disease, starting from subcortical and gradually moving to cortical regions. Conversely, Subtype2 is characterized by an early, simultaneous onset in both regions. Interestingly, once the disease is initiated, Subtype1 tends to spread more rapidly within each region compared to Subtype2. Individuals categorized as Subtype2 are generally older and exhibit less severe dysfunctions in areas such as cognition, bulbar, limb motor, and general motor functions compared to those with Subtype1. Moreover, they have a more favorable prognosis in terms of limb motor function. We found significant correlations between several clinical variables and the identified PSP SuStaIn stages. Furthermore, Subtype2 displayed a remarkable reduction in functional connectivity compared to Subtype1. INTERPRETATION: We present the evidence of distinct in vivo spatiotemporal tau trajectories in PSP. Our findings can contribute to precision medicine advancements for PSP. FUNDING: This work was supported by grants from the 10.13039/501100001809National Natural Science Foundation of China (number 82272039, 81971641, 82021002, and 92249302); 10.13039/100000001Swiss National Science Foundation (number 188350); the STI2030-Major Project of China (number 2022ZD0211600); the Clinical Research Plan of Shanghai Hospital Development Center of China (number SHDC2020CR1038B); and the 10.13039/501100012166National Key R&D Program of China (number 2022YFC2009902, 2022YFC2009900), the 10.13039/501100004543China Scholarship Council (number 202006100181); the 10.13039/501100001659Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198).