Evaluation of [18F]PI-2620, a second-generation selective tau tracer, for assessing four-repeat tauopathies

Abstract

Tau aggregates represent a key pathologic feature of Alzheimer's disease and other neurodegenerative diseases. Recently, PET probes have been developed for in vivo detection of tau accumulation; however, they are limited because of off-target binding and a reduced ability to detect tau in non-Alzheimer's disease tauopathies. The novel tau PET tracer, [¹⁸F]PI-2620, has a high binding affinity and specificity for aggregated tau; therefore, it was hypothesized to have desirable properties for the visualization of tau accumulation in Alzheimer's disease and non-Alzheimer's disease tauopathies. To assess the ability of [¹⁸F]PI-2620 to detect regional tau burden in non-Alzheimer's disease tauopathies compared with Alzheimer's disease, patients with progressive supranuclear palsy (n = 3), corticobasal syndrome (n = 2), corticobasal degeneration (n = 1) or Alzheimer's disease (n = 8), and healthy controls (n = 7) were recruited. All participants underwent MRI, amyloid β assessment and [¹⁸F]PI-2620 PET (Image acquisition at 60-90 min post-injection). Cortical and subcortical tau accumulations were assessed by calculating standardized uptake value ratios using [¹⁸F]PI-2620 PET. For pathologic validation, tau pathology was assessed using tau immunohistochemistry and compared with [¹⁸F]PI-2620 retention in an autopsied case of corticobasal degeneration. In Alzheimer's disease, focal retention of [¹⁸F]PI-2620 was evident in the temporal and parietal lobes, precuneus, and cingulate cortex. Standardized uptake value ratio analyses revealed that patients with non-Alzheimer's disease tauopathies had elevated [¹⁸F]PI-2620 uptake only in the globus pallidus, as compared to patients with Alzheimer's disease, but not healthy controls. A head-to-head comparison of [¹⁸F]PI-2620 and [¹⁸F]PM-PBB3, another tau PET probe for possibly visualizing the four-repeat tau pathogenesis in non-Alzheimer's disease, revealed different retention patterns in one subject with progressive supranuclear palsy. Imaging-pathology correlation analysis of the autopsied patient with corticobasal degeneration revealed no significant correlation between [¹⁸F]PI-2620 retention in vivo. High [¹⁸F]PI-2620 uptake at 60-90 min post-injection in the globus pallidus may be a sign of neurodegeneration in four-repeat tauopathy, but not necessarily practical for diagnosis of non-Alzheimer's disease tauopathies. Collectively, this tracer is a promising tool to detect Alzheimer's disease-tau aggregation. However, late acquisition PET images of [¹⁸F]PI-2620 may have limited utility for reliable detection of four-repeat tauopathy because of lack of correlation between post-mortem tau pathology and different retention pattern than the non-Alzheimer's disease-detectable tau radiotracer, [¹⁸F]PM-PBB3. A recent study reported that [¹⁸F]PI-2620 tracer kinetics curves in four-repeat tauopathies peak earlier (within 30 min) than Alzheimer's disease; therefore, further studies are needed to determine appropriate PET acquisition times that depend on the respective interest regions and diseases.

Keywords: Alzheimer’s disease; Tau imaging; corticobasal degeneration; progressive supranuclear palsy; tauopathy.

Graphical Abstract

Figure 1

Representative images of [¹⁸F]PI-2620 tau PET images. Individual tau PET images for patients with PSP, CBS, CBD, Alzheimer’s disease and HC. All images are based on the same color scale (SUVR values ranging from 1 to 2.5). Cerebellar grey matter is used as the reference region for quantification. SUVRs, standardized uptake value ratios

Figure 2

[¹⁸F]PI-2620 standardized uptake value ratios in regions of interest. Graphs showing the distribution of [¹⁸F]PI-2620 SUVRs in eight ROIs for patients with HC (red), PSP (blue) + CBD (green) + CBS (purple), and Alzheimer’s disease (yellow). Dots represent individual subject SUVRs for each ROI. Significant pairwise Wilcoxon tests with a Bonferroni correction between diagnostic groups (n = 3) are indicated at the top: *P < 0.05

Figure 3

Neuropathological assessment of tau pathology and correlations with [¹⁸F]PI-2620 uptake in autopsied CBD. (A–D) Immunohistochemistry [AT8 (A), RD3 (C) and RD4 (D)] and Gallyas silver staining (B) in case #18. Scale bars indicate 50 μm (A and B) and 100 μm (C and D). (A) Caudate nucleus, (B) Straight gyrus, (C and D) Substantia nigra. Representative astrocytic plaque was detected in caudate nucleus (A). (E) Staging of AT8 staining [Stage 0 (Occipital lobe): absent, Stage 1 (Occipital lobe): sparse, Stage 2 (Precentral gyrus): moderate, Stage 3 (Superior colliculus): numerous] Scale bars indicate 100 μm. (F–H) Correlation analysis between in vivo [¹⁸F]PI-2620 SUVR and tau staging (F), %area (G) or particles (H) of AT8 staining in matching ROIs. P-values for Spearman correlation test.

Figure 4

Head-to-head comparison of [¹⁸F]PI-2620 and [¹⁸F]PM-PBB3 in patients with PSP-CBS (#52). (A) [¹⁸F]PI-2620 and [¹⁸F]PM-PBB3 imaging in subject #52 representative of range of tracer binding. Transaxial and coronal [¹⁸F]PI-2620 images adjacent to same-slice [¹⁸F]PM-PBB3 images are shown. Red arrowheads indicate positive retention of both [¹⁸F]PI-2620 and [¹⁸F]PM-PBB3 (globus pallidus and substantia nigra). Blue arrowheads indicate positive [¹⁸F]PM-PBB3 retention, but weak [¹⁸F]PI-2620 (thalamus, frontal gyrus and subthalamic nucleus). (B) Plot of SUVR for [¹⁸F]PI-2620 and [¹⁸F]PM-PBB3 in matching ROIs. P-values for Spearman correlation test.