# Developing a Novel Reference Region for PI‐2620‐PET Imaging to Facilitate Assessment of 4‐Repeat Tauopathies

## TL;DR

This study identifies a new reference region for PI-2620-PET imaging to better detect 4R tauopathies like progressive supranuclear palsy.

## Contribution

The study introduces a novel temporo-orbital white-matter reference region for improved quantification of 4R tau in PET imaging.

## Key findings

- The temporo-orbital white-matter reference region showed strong sensitivity for detecting PSP-RS vs. healthy controls.
- Using the new reference region, minimal differences were found in non-tau diseases like Alzheimer's and alpha-synucleinopathies.
- Conventional cerebellar reference regions showed minimal group differences compared to the new method.

## Abstract

Neurodegenerative 4‐repeat (4R) tauopathies commonly manifest as progressive supranuclear palsy (PSP). PSP patients show elevated PI‐2620‐PET in subcortical 4R tau predilection sites (e.g., globus pallidus), suggesting PI‐2620‐PET as a promising 4R tau neuroimaging candidate. However, optimal quantification of PI‐2620‐PET in 4R tauopathies remains challenging, as conventional cerebellar tau‐PET reference regions also accumulate 4R tau. We aimed to use unbiased image‐derived input function (IDIF) PET data to determine an optimized PET reference region for in vivo quantification of 4R tau.

We obtained 60‐minute dynamic PI‐2620‐PET in 54 PSP Richardson Syndrome (PSP‐RS) patients and 19 healthy controls (HC), applying IDIF‐modeling using carotid timeseries to assess unbiased PI‐2620‐PET binding and determine total distribution volume (VT). Through an iterative approach, we intensity‐normalized VT‐images against white‐matter regions in the Hammers brain atlas, identifying regions where intensity‐normalized pallidum PET values showed the largest PSP‐RS vs. HC differences. White‐matter regions with strongest PSP‐RS vs. HC differences surviving multiple‐comparison correction were summarized into a single reference region spanning bilateral temporo‐orbital white‐matter. This ROI was then used to determine SUVRs using conventional 20‐40 minute PI‐2620‐PET data in PSP‐RS, a PSP‐non‐RS validation sample (n = 63), as well as non‐tau disease controls (i.e., alpha‐synucleinopathies, n = 20; Alzheimer's disease, n = 23).

Using PI‐2620 SUVRs obtained with the temporo‐orbital white‐matter reference, we detected strong PSP‐RS vs. HC group differences in basal ganglia SUVRs using voxel‐wise comparisons (p <0.001, FWE‐cluster corrected). Similar basal ganglia differences were detected for PSP‐non‐RS vs. HC, but not for alpha‐syn (no group differences) or AD vs. HC (cortical AD‐like group differences). In contrast, minimal group differences were found using a conventional inferior cerebellar grey matter reference region.

Our findings strongly suggest temporo‐orbital white‐matter is superior to inferior cerebellum as a reference region for PI‐2620‐PET imaging in 4R tauopathies, due to increased sensitivity and purported specificity for 4R tau.