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18F-florzolotau positron emission tomography (PET) assists in the in vivo diagnosis of progressive supranuclear palsy (PSP).We aimed to investigate the relationship between 18F-florzolotau uptake and clinical severity, structural volume changes, and plasma markers in four-repeat tauopathies.A total of 80 participants were recruited: 35 with PSP (11 with PSP-Richardson syndrome and 24 with PSP non-Richardson syndrome), 9 with corticobasal syndrome (CBS), 10 with Alzheimer's disease (AD), 8 with Parkinson's disease, and 18 controls. All participants underwent 18F-florzolotau PET, brain magnetic resonance imaging (MRI), and plasma biomarker investigation (total and phosphorylated tau [pTau181], neurofilament light chain, and glial fibrillary acidic protein [GFAP]).18F-Florzolotau uptake was significantly higher in the subcortical regions of the pallidum, subthalamic nucleus (STN), midbrain, red nucleus, and raphe nucleus in PSP patients compared to the other groups (all p < 0.01). Subcortical tau tracer retention assisted in distinguishing PSP and CBS from controls (AUC = 0.836, p < 0.001). Tau tracer retention could differentiate PSP and CBS from AD in cortical (p < 0.001) and subcortical regions (p = 0.028). The motor severity of PSP positively correlated with tau burden in STN (p = 0.044) and substantia nigra (p = 0.035). Tau tracer uptake was associated with cortical volume changes in CBS (p = 0.031), PSP non-Richardson syndrome (p = 0.003), and AD (p = 0.044). Cortical tau retention correlated with plasma levels of GFAP (p = 0.001) and pTau181 (p = 0.036).Subcortical 18F-Florzolotau uptake assist the diagnosis of 4R tauopathy parkinsonism. Additionally, regional tau burden contributes to structural brain volume changes and correlates with plasma levels of GFAP and pTau181. [ABSTRACT FROM AUTHOR]