Early tau detection in flortaucipir images: validation in autopsy-confirmed data and implications for disease progression
Authors: Kotari Vikas , Southekal Sudeepti , Navitsky Michael , Kennedy Ian A. , Lu Ming , Morris Amanda , Zimmer Jennifer Ann , Fleisher Adam S. , Mintun Mark A. , Devous Michael D. , Pontecorvo Michael J. 
Published: March 2023

Abstract
Background
There is an increasing interest in utilizing tau PET to identify patients early in Alzheimer’s disease (AD). In this work, a temporal lobe composite (Eτ) volume of interest (VOI) was evaluated in a longitudinal flortaucipir cohort and compared to a previously described global neocortical VOI. In a separate autopsy-confirmed study, the sensitivity of the Eτ VOI for identifying intermediate (B2) neurofibrillary tangle (NFT) pathology was evaluated.

Methods
A total of 427 subjects received flortaucipir, florbetapir, MRI, and cognitive evaluation at baseline and 18 months. In a separate autopsy study, 67 subjects received ante-mortem flortaucipir scans, and neuropathological findings were recorded according to NIA-AA recommendations by two experts. Two VOIs: Eτ comprising FreeSurfer volumes (bilateral entorhinal cortex, fusiform, parahippocampal, and inferior temporal gyri) transformed to MNI space and a previously published global AD signature-weighted neocortical VOI (ADsignature) (Devous et al., J Nucl Med 59:937–43, 2018), were used to calculate SUVr relative to a white matter reference region (PERSI) (Southekal et al., J Nucl Med Off Publ Soc Nucl Med 59:944–51, 2018). SUVr cutoffs for positivity were determined based on a cohort of young, cognitively normal subjects. Subjects were grouped based on positivity on both VOIs (Eτ+/ADsignature+; Eτ+/ADsignature–; Eτ−/ADsignature−). Groupwise comparisons were performed for baseline SUVr, 18-month changes in SUVr, neurodegeneration, and cognition. For the autopsy study, the sensitivity of Eτ in identifying intermediate Braak pathology (B2) subjects was compared to that of AD signature-weighted neocortical VOI. The average surface maps of subjects in the Eτ+/ADsignature− group and B2 NFT scores were created for visual evaluation of uptake.

Results
Sixty-four out of 390 analyzable subjects were identified as Eτ+/ADsignature–: 84% were Aβ+, 100% were diagnosed as MCI or AD, and 59% were APOE ε4 carriers. Consistent with the hypothesis that Eτ+/ADsignature– status reflects an early stage of AD, Eτ+/ADsignature– subjects deteriorated significantly faster than Eτ–/ADsignature– subjects, but significantly slower than Eτ+/ADsignature+ subjects, on most measures (i.e., change in ADsignature SUVr, Eτ ROI cortical thickness, and MMSE). The ADsignature VOI was selective for subjects who came to autopsy with a B3 NFT score. In the autopsy study, 12/15 B2 subjects (including 10/11 Braak IV) were Eτ+/ADsignature–. Surface maps showed that flortaucipir uptake was largely captured by the Eτ VOI regions in B2 subjects.

Conclusion
The Eτ VOI identified subjects with elevated temporal but not global tau (Eτ+/ADsignature–) that were primarily Aβ+, APOE ε4 carriers, and diagnosed as MCI or AD. Eτ+/ADsignature– subjects had greater accumulation of tau, greater atrophy, and higher decline on MMSE in 18 months compared to Eτ−/ADsignature− subjects. Finally, the Eτ VOI identified the majority of the intermediate NFT score subjects in an autopsy-confirmed study. As far as we know, this is the first study that presents a visualization of ante-mortem FTP retention patterns that at a group level agree with the neurofibrillary tangle staging scheme proposed by Braak. These findings suggest that the Eτ VOI may be sensitive for detecting impaired subjects early in the course of Alzheimer’s disease.