# Developing a novel reference region for [18F]PI-2620-PET imaging to facilitate the assessment of 4-repeat tauopathies

## TL;DR

This study develops a new reference region for PET imaging to better assess 4R tauopathies like PSP, improving diagnosis and monitoring.

## Contribution

A data-driven temporo-orbital white matter reference region is proposed for [18F]PI-2620 PET imaging in 4R tauopathies.

## Key findings

- The temporo-orbital white matter reference outperformed cerebellar references in diagnosing PSP.
- PSP patients showed significantly higher [18F]PI-2620 signal in basal ganglia using the new reference.
- The novel reference showed stronger associations between PET signal and clinical disease severity.

## Abstract

Progressive supranuclear palsy (PSP) is a fatal 4-repeat (4R) tauopathy with progressive movement phenotypes. In-vivo 4R tau biomarkers are therefore crucial for PSP diagnosis, monitoring, and treatment evaluation. The tau-PET tracer [18F]PI-2620 binds to 4R tau and shows increased uptake in PSP-associated regions (e.g., globus pallidus), and is therefore a candidate 4R tau biomarker. However, commonly used cerebellar tau-PET reference regions show regional proximity to cerebellar 4R tau deposits in PSP, confounding semiquantitative [18F]PI-2620 assessments. Therefore, we employed bias-free image-derived input function (IDIF) PET quantification to identify an optimized data-driven reference region for assessing 4R tau in PSP.

Dynamic [18F]PI-2620 PET (60 min) was acquired in 58 PSP-Richardson Syndrome (PSP-RS) and 18 healthy controls (HC). IDIF-modelling with carotid timeseries derived total distribution volume (VT). Iteratively normalizing VT images to atlas-based white matter (WM), we identified reference candidates maximizing PSP-RS vs. HC pallidum differences. The best-performing WM references were combined to a temporo-orbital WM reference, validated in PSP-nonRS (n = 54), HC (n = 18), and disease controls (α-synucleinopathies, n = 21; Alzheimer’s disease (AD, n = 22) using VT-ratios (VTr) and 20-40min static standardized uptake value ratios (SUVr).

Using the data-driven temporo-orbital WM reference, PSP patients showed significantly higher basal ganglia [18F]PI-2620 signal vs. HC compared to cerebellar normalization. Receiver operating curve (ROC) analysis confirmed higher diagnostic accuracy using the temporo-orbital WM reference. Pallidum [18F]PI-2620 showed significant associations with clinical disease severity exclusively when using the novel temporo-orbital WM reference.

A data-driven temporo-orbital WM reference optimizes [18F]PI-2620 PET assessment for PSP diagnosis, outperforming conventional cerebellar references used in tau-PET imaging.

The online version contains supplementary material available at 10.1007/s00259-025-07396-8.