Neuronal and oligodendroglial but not astroglial tau translates to in vivo tau-PET signals in primary tauopathies

Tau-PET receives growing interest as an imaging biomarker for the 4-repeat tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau-PET signals is still unclear. Therefore, we conducted a longitudinal [18F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and found elevated [18F]PI-2620 PET signal in the presence of high neuronal tau. Cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons compared to astrocytes of PS19 mice. Regional [18F]PI-2620 tau-PET signals during lifetime correlated with abundance of fibrillary tau in subsequent autopsy samples of PSP patients and disease controls. In autoradiography, tau-positive neurons and oligodendrocytes with high AT8 density but not tau-positive astrocytes were the driver of [18F]PI-2620 autoradiography signals in PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau-PET radiotracer binding in 4-repeat-tauopathies, yielding the capacity to translate to an in vivo signal. ### Competing Interest Statement MB is a member of the Neuroimaging Committee of the EANM. MB received speaker honoraria from Roche, GE healthcare and Life Molecular Imaging and is an advisor of Life Molecular Imaging. NF received speaker honoraria from Eisai and Life Molecular Imaging and consulting honoraria by MSD. CP and JL are inventor in a patent Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies (EP 23 156 122.6) filed by LMU Munich. JL reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers, non-financial support from Abbvie and compensation for duty as part-time CMO from MODAG, all outside the submitted work. TvE reports speaker/consultant fees from Eli Lilly, Shire, H. Lundbeck A/S, Orion Corporation, and author fees from Thieme medical publishers, all without conflict of interest with regard to the submitted work. Gesine Respondek is a full-time employee at Roche Pharmaceuticals since July 2021 and has consulted for UCB, all outside of the submitted work. AZ reports speaker fees and research support from Dr. Willmar Schwabe GmbH and author fees from Thieme medical publishers, Springer medical publishers and W. Kohlhammer GmbH medical publishers. Outside the submitted work, TG received consulting fees from AbbVie, Alector, Anavex, Biogen, BMS; Cogthera, Eli Lilly, Functional Neuromodulation, Grifols, Iqvia, Janssen, Noselab, Novo Nordisk, NuiCare, Orphanzyme, Roche Diagnostics, Roche Pharma, UCB, and Vivoryon; lecture fees from Biogen, Eisai, Grifols, Medical Tribune, Novo Nordisk, Roche Pharma, Schwabe, and Synlab; and has received grants to his institution from Biogen, Eisai, and Roche Diagnostics. LB is a Novartis Pharma GmbH employee, unrelated to this work. All other authors have declared that no conflict of interest exists.