Ono Maiko, Sahara Naruhiko, Kumata Katsushi, Ji Bin, Ni Ruiqing, Koga Shunsuke, Dickson Dennis W, Trojanowski John Q, Lee Virginia M-Y, Yoshida Mari, Hozumi Isao, Yoshiyama Yasumasa, van Swieten John C, Nordberg Agneta, Suhara Tetsuya, Zhang Ming-Rong, Higuchi Makoto
National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Brain. 2017 Mar 1;140(3):764-780. doi: 10.1093/brain/aww339.
Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer's disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer's disease slices with 11C-PBB3 and 18F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick's disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate 11C-PBB3 versus faint 18F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for 11C-PBB3 and 18F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for 11C-PBB3 than 18F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies.
多种神经退行性疾病的特征是由每种疾病特有的构象异构体（即毒株）组成的tau原纤维沉积。tau成像剂的开发使tau蛋白病患者的tau病变可视化，但它们与不同tau毒株的结合模式仍不清楚。在这里，我们使用tau蛋白病脑样本，通过荧光、放射自显影和匀浆结合试验，并采用同源和异源阻断，比较了tau正电子发射断层扫描配体PBB3和AV-1451的结合情况。荧光显微镜显示，PBB3和AV-1451对非幽灵缠结和幽灵缠结有强烈标记，而在阿尔茨海默病脑和伴有钙化的弥漫性神经原纤维缠结（其特征为所有六种tau异构体的积累）中，PBB3能更清晰地检测到营养不良性神经突。相应地，注意到用11C-PBB3和18F-AV-1451对阿尔茨海默病切片进行放射自显影标记的分布部分不同。与非常微弱的AV-1451信号相比，PBB3荧光能灵敏地检测到进行性核上性麻痹、皮质基底节变性和因N279K tau突变导致的家族性tau蛋白病脑内由4重复异构体组成的神经元和胶质tau病变，以及皮克病和因G272V tau突变导致的家族性tau蛋白病脑内由3重复异构体组成的病变。这与这些组织中11C-PBB3的适度放射自显影标记与18F-AV-1451的微弱标记一致。放射性配体与脑匀浆的结合显示出对11C-PBB3和18F-AV-1451具有不同亲和力的多个结合成分，并且进行性核上性麻痹tau沉积物上11C-PBB3的结合位点可用性高于18F-AV-1451。我们的数据表明，与AV-1451相比，PBB3对多种tau原纤维毒株具有明显的选择性。这突出了PBB3捕获广泛tau病变的更强能力。
