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

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-11-24 DOI:10.1007/s00401-024-02834-7
Luna Slemann, Johannes Gnörich, Selina Hummel, Laura M. Bartos, Carolin Klaus, Agnes Kling, Julia Kusche-Palenga, Sebastian T. Kunte, Lea H. Kunze, Amelie L. Englert, Yunlei Li, Letizia Vogler, Sabrina Katzdobler, Carla Palleis, Alexander Bernhardt, Alexander Jäck, Andreas Zwergal, Franziska Hopfner, Sebastian N. Roemer-Cassiano, Gloria Biechele, Sophia Stöcklein, Gerard Bischof, Thilo van Eimeren, Alexander Drzezga, Osama Sabri, Henryk Barthel, Gesine Respondek, Timo Grimmer, Johannes Levin, Jochen Herms, Lars Paeger, Marie Willroider, Leonie Beyer, Günter U. Höglinger, Sigrun Roeber, Nicolai Franzmeier, Matthias Brendel
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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 [18F]PI-2620 tau PET signals in individuals with 4R-tauopathies, including a pilot PET autopsy study in patients. First, we conducted a longitudinal [18F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and detected elevated [18F]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 [18F]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 [18F]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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神经元和少突胶质细胞(而非星形胶质细胞)的tau可转化为原发性tau病患者体内的tau PET信号
Tau PET作为4-repeat(4R)-tau病进行性核上性麻痹(PSP)的成像生物标记物引起了越来越多的关注。然而,体外 4R-tau 结合到体内 tau PET 信号的转化仍不清楚。因此,我们进行了一项转化研究,采用多种先进的方法来研究4R-tau病患者体内[18F]PI-2620 tau PET信号的来源,包括对患者进行试验性PET尸检研究。首先,我们在4-repeat-tau小鼠模型(PS19)中进行了纵向[18F]PI-2620 PET/MRI研究,发现在神经元tau水平较高的情况下,[18F]PI-2620 PET信号升高。在体内注射放射性示踪剂后进行细胞分拣的创新方法显示,PS19 小鼠单个神经元的示踪剂摄取量高于星形胶质细胞。PSP 患者和疾病对照组在进行 tau PET 治疗 2-63 个月后进行尸检,其在生期间的区域性 [18F]PI-2620 tau PET 信号与纤维状 tau 的丰度和自体放射成像信号强度相关。在PSP患者的自显影中,AT8密度高的tau阳性神经元和少突胶质细胞(而非tau阳性星形胶质细胞)是[18F]PI-2620自显影信号的驱动因素。灰质和白质交界处的少突胶质细胞中tau丰度较高,这有助于确定一个优化的额叶靶区,以检测PSP患者的tau负荷。总之,神经元和少突胶质细胞的tau构成了4-重复tau病中tau PET放射性示踪剂结合的主要来源,并转化为体内信号。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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