18F-PI-2620 Tau PET Improves the Imaging Diagnosis of Progressive Supranuclear Palsy

Abstract

Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy movement disorder that can be imaged by the ¹⁸F-labeled tau PET tracer 2-(2-([¹⁸F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine (¹⁸F-PI-2620). The in vivo diagnosis is currently established on clinical grounds and supported by midbrain atrophy estimation in structural MRI. Here, we investigate whether ¹⁸F-PI-2620 tau PET has the potential to improve the imaging diagnosis of PSP. Methods: In this multicenter observational study, dynamic (0-60 min after injection) ¹⁸F-PI-2620 PET and structural MRI data for 36 patients with PSP, 22 with PSP-Richardson syndrome, and 14 with a clinical phenotype other than Richardson syndrome (i.e., variant PSP) were analyzed along with data for 10 age-matched healthy controls (HCs). The PET data underwent kinetic modeling, which resulted in distribution volume ratio (DVR) images. These and the MR images were visually assessed by 3 masked experts for typical PSP signs. Furthermore, established midbrain atrophy parameters were measured in structural MR images, and regional DVRs were measured in typical tau-in-PSP target regions in the PET data. Results: Visual assessments discriminated PSP patients and HCs with an accuracy of 63% for MRI and 80% for the combination of MRI and ¹⁸F-PI-2620 PET. As compared with patients of the PSP-Richardson syndrome subgroup, those of the variant PSP subgroup profited more in terms of sensitivity from the addition of the visual ¹⁸F-PI-2620 PET to the visual MRI information (35% vs. 22%). In quantitative image evaluation, midbrain-to-pons area ratio and globus pallidus DVRs discriminated best between the PSP patients and HCs, with sensitivities and specificities of 83% and 90%, respectively, for MRI and 94% and 100%, respectively, for the combination of MRI and ¹⁸F-PI-2620 PET. The gain of sensitivity by adding ¹⁸F-PI-2620 PET to MRI data was more marked in clinically less affected patients than in more affected patients (37% vs. 19% for visual, and 16% vs. 12% for quantitative image evaluation). Conclusion: These results provide evidence for an improved imaging-based PSP diagnosis by adding ¹⁸F-PI-2620 tau PET to structural MRI. This approach seems to be particularly promising at earlier disease stages and could be of value both for improving early clinical PSP diagnosis and for enriching PSP cohorts for trials of disease-modifying drugs.

Keywords: 18F-PI-2620; 4R-tauopathy; midbrain atrophy; progressive supranuclear palsy; tau PET.

Graphical abstract

FIGURE 1.

Axial ¹⁸F-PI-2620 tau PET and sagittal T1-weighted 3-dimensional magnetization-prepared 2 rapid-acquisition gradient-echo structural MR images of PSP patient and of HC. Pathologic ¹⁸F-PI-2620 binding is seen in globus pallidus (white arrow), in striatum, and in subthalamic nucleus of PSP patient. Hummingbird sign (yellow arrow) due to atrophy of rostral midbrain is seen in structural MR image of PSP patient. No pathologic ¹⁸F-PI-2620 binding is present in HC, and midbrain appears normal.

FIGURE 2.

Scatterplots for MRI (midbrain-to-pons area ratio) parameter that discriminated best between patients with PSP and HCs, and for tau-PET/MRI-in-PSP index.

FIGURE 3.

Receiver-operator-characteristic curves for MRI (midbrain-to-pons area ratio) and ¹⁸F-PI-2620 PET (globus pallidus DVR) parameters that discriminated best for each technique between patients with PSP and HCs, and for tau-PET/MRI-in-PSP index.

FIGURE 4.

Association between age, disease duration, disease severity, structural MRI, and ¹⁸F-PI-2620 tau PET parameters in patients with PSP. Values are correlation coefficients. Significant correlations (P < 0.05 after false-discovery-rate correction) are colorized according to scale on right. DN = dentate nucleus; GP = globus pallidus; GPE = globus pallidus externus; GPI = globus pallidus internus; MB = midbrain; MRPI = MR parkinsonism index; PSPRS = PSP rating scale; PUT = putamen; SEADL = Schwab and England activities-of-daily-living scale; SN = substantia nigra; STN = subthalamic nucleus.

FIGURE 5.

Sensitivities and specificities for discrimination between PSP patients and HCs by means of MRI, ¹⁸F-PI-2620 PET, and combination of both techniques for 2 disease-severity subgroups of PSP patients separated by PSP rating score of 31 (mean value of entire PSP population). Results are shown for visual and quantitative image analyses. For combination of both modalities (¹⁸F-PI-2620 PET + MRI), ≥1 abnormal parameter that was positive made brain positive for PSP. Gain of sensitivity was most pronounced by addition of ¹⁸F-PI-2620 PET to MRI information for subgroup with visual image analysis of PSP rating score of <31.