Neuronal and oligodendroglial, but not astroglial, tau translates to in vivo tau PET signals in individuals with primary tauopathies

Tau PET has attracted increasing interest as an imaging biomarker for 4-repeat (4R)-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 performed a translational study using a broad spectrum of advanced methodologies to investigate the sources of [<sup>18</sup>F]PI-2620 tau PET signals in individuals with 4R-tauopathies, including a pilot PET autopsy study in patients. First, we conducted a longitudinal [<sup>18</sup>F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and detected elevated [<sup>18</sup>F]PI-2620 PET signals in the presence of high levels of neuronal tau. An innovative approach involving cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons than in the astrocytes of PS19 mice. Regional [<sup>18</sup>F]PI-2620 tau PET signals during the lifetime correlated with the abundance of fibrillary tau and with autoradiography signal intensity in PSP patients and disease controls who underwent autopsy 2-63 months after tau PET. In autoradiography, tau-positive neurons and oligodendrocytes with a high AT8 density, but not tau-positive astrocytes, were the drivers of [<sup>18</sup>F]PI-2620 autoradiography signals in individuals with PSP. The high tau abundance in oligodendrocytes at the boundary of gray and white matter facilitated the identification of an optimized frontal lobe target region to detect the tau burden in patients with PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau PET radiotracer binding in 4-repeat-tauopathies, translating to an in vivo signal.

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Publication Details

Journal
Acta Neuropathologica
Published
2024-11-24
DOI
https://doi.org/10.1007/s00401-024-02834-7
Citations
13
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
4.80

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article

Neuronal and oligodendroglial, but not astroglial, tau translates to in vivo tau PET signals in individuals with primary tauopathies

Alexander Jäck, Lars Paeger, Gérard N. Bischof, Marie Willroider et al.
13 citations
Acta Neuropathologica
Parkinson's Disease Mechanisms and Treatments
4.80
article

Neuronal and oligodendroglial, but not astroglial, tau translates to in vivo tau PET signals in individuals with primary tauopathies

Alexander Jäck, Lars Paeger, Gérard N. Bischof, Marie Willroider, Alexander Bernhardt, Osama Sabri, Luna Slemann, Letizia Vogler, Franziska Hopfner, Timo Grimmer, Sophia Stoecklein, Henryk Barthel, Johannes Levin, Carla Palleis, Gesine Respondek, Gloria Biechele, Amelie L. Englert, Matthias Brendel, Johannes Gnörich, Sabrina Katzdobler, Sigrun Roeber, Günter U. Höglinger, Jochen Herms, Lea H. Kunze, Carolin Klaus, Thilo van Eimeren, Leonie Beyer, Andreas Zwergal, Alexander Drzezga, Selina Hummel, Nicolai Franzmeier, Laura M. Bartos, Julia Kusche‐Palenga, Yunlei Li, A. Kling, Sebastian T. Kunte, Sebastian N. Roemer‐Cassiano
article en
13 citations

Abstract

Tau PET has attracted increasing interest as an imaging biomarker for 4-repeat (4R)-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 performed a translational study using a broad spectrum of advanced methodologies to investigate the sources of [<sup>18</sup>F]PI-2620 tau PET signals in individuals with 4R-tauopathies, including a pilot PET autopsy study in patients. First, we conducted a longitudinal [<sup>18</sup>F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and detected elevated [<sup>18</sup>F]PI-2620 PET signals in the presence of high levels of neuronal tau. An innovative approach involving cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons than in the astrocytes of PS19 mice. Regional [<sup>18</sup>F]PI-2620 tau PET signals during the lifetime correlated with the abundance of fibrillary tau and with autoradiography signal intensity in PSP patients and disease controls who underwent autopsy 2-63 months after tau PET. In autoradiography, tau-positive neurons and oligodendrocytes with a high AT8 density, but not tau-positive astrocytes, were the drivers of [<sup>18</sup>F]PI-2620 autoradiography signals in individuals with PSP. The high tau abundance in oligodendrocytes at the boundary of gray and white matter facilitated the identification of an optimized frontal lobe target region to detect the tau burden in patients with PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau PET radiotracer binding in 4-repeat-tauopathies, translating to an in vivo signal.

Acta NeuropathologicaVol. 148(1)
Forschungszentrum Jülich (DE), German Center for Neurodegenerative Diseases (DE), TUM Klinikum (DE), LMU Klinikum (DE), Medizinische Hochschule Hannover (DE), Munich Cluster for Systems Neurology (DE), University Hospital Leipzig (DE), German Center for Lung Research (DE), University Hospital Cologne (DE), Technical University of Munich (DE), Ludwig-Maximilians-Universität München (DE), University of Gothenburg (SE)
Deutsche Forschungsgemeinschaft
Good health and well-being
Openalex Percentile: Top 4%
Parkinson's Disease Mechanisms and Treatments
4.80
DOIOpen Access PDFOpenAlex
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