Subtracting First Principal Component May Improve 4R Tau Detectability on [¹⁸F]Flortaucipir Tau PET

[¹⁸F]flortaucipir PET imaging has shown relatively low sensitivity for detecting four-repeat (4R) tau, which limits its utility in 4R tauopathies such as progressive supranuclear palsy (PSP). Previous studies have suggested that the first component of principal-component analysis includes non-disease-related uptake in non-Alzheimer tauopathies. In this study, we tested the hypothesis that subtracting this component could increase sensitivity to 4R tau using a large PSP cohort. Methods: Prospectively recruited patients with PSP (n = 141; 80 Richardson syndrome, 44 PSP-subcortical, and 17 PSP-cortical variants) and controls (n = 102) underwent [¹⁸F]flortaucipir PET. The first principal component (PC1) was extracted from the SUV ratio (SUVR) images of 62 controls and then subtracted from the remaining controls (n = 40) and all PSP patients. We compared the diagnostic performance before and after PC1 subtraction by evaluating SUVR differences between PSP and controls, as well as across PSP clinical variants, and by calculating correlation coefficients between SUVR and the severity of tau pathology. Results: Area under the receiver operating characteristic curves differentiating PSP and controls were improved by PC1 subtraction in the frontal white matter (0.54 to 0.67; P = 0.002) and subcortical (0.69 to 0.87; P < 0.001) regions. In the frontal regions, no differences were observed across PSP clinical variants before PC1 subtraction, whereas the PSP-cortical variant showed an SUVR higher than that of the PSP Richardson syndrome and PSP-subcortical variants after PC1 subtraction (adjusted P < 0.05). A correlation with the severity of tau pathology was observed only in the red nucleus before PC1 subtraction, whereas correlations were observed in the precentral, superior frontal gyrus, and red nucleus after PC1 subtraction (adjusted P < 0.05). Conclusion: Our approach enhanced the diagnostic performance of [¹⁸F]flortaucipir PET in PSP and increased sensitivity to 4R tau, suggesting that subtracting the first principal component improves the detectability of subtle 4R tau uptake and the potential utility of [¹⁸F]flortaucipir PET imaging for non-Alzheimer tauopathies.