Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies
Maiko Ono,Maiko Ono,Naruhiko Sahara,Katsushi Kumata,Bin Ji,Ruiqing Ni,Shunsuke Koga,Dennis W. Dickson,John Q. Trojanowski,Virginia M.-Y. Lee,Mari Yoshida,Isao Hozumi,Yasumasa Yoshiyama,John C. van Swieten,Agneta Nordberg,Tetsuya Suhara,Ming-Rong Zhang,Makoto Higuchi +17 more
TLDR
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 indicate distinct selectivity of P BB3 compared to AV- 1451 for diverse tau fibril strains.Abstract:
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.read more
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Tau PET imaging in neurodegenerative tauopathies—still a challenge
Antoine Leuzy,Konstantinos Chiotis,Konstantinos Chiotis,Laetitia Lemoine,Per-Göran Gillberg,Ove Almkvist,Ove Almkvist,Elena Rodriguez-Vieitez,Agneta Nordberg,Agneta Nordberg +9 more
TL;DR: Findings from in vitro and in vivo studies using both initial and new tau ligands are described and discussed, including their relation to biomarkers for amyloid-β and neurodegeneration, and cognitive findings.
Journal ArticleDOI
Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches.
Adam L. Boxer,Jin-Tai Yu,Lawrence I. Golbe,Irene Litvan,Anthony E. Lang,Günter U. Höglinger,Günter U. Höglinger +6 more
TL;DR: Progressive supranuclear palsy (PSP), previously believed to be a common cause of atypical parkinsonism, is now recognised as a range of motor and behavioural syndromes that are associated with a characteristic 4-repeat tau neuropathology.
Journal ArticleDOI
Tau PET imaging: present and future directions.
Laure Saint-Aubert,Laetitia Lemoine,Konstantinos Chiotis,Antoine Leuzy,Elena Rodriguez-Vieitez,Agneta Nordberg,Agneta Nordberg +6 more
TL;DR: Recent findings on the most promising tau PET tracers to date are summarized, what has been learnt is discussed, and some suggestions for the next steps that need to be achieved in a near future are offered.
Journal ArticleDOI
Radiological biomarkers for diagnosis in PSP: Where are we and where do we need to be?
Jennifer L. Whitwell,Günter U. Höglinger,Günter U. Höglinger,Angelo Antonini,Yvette Bordelon,Adam L. Boxer,Carlo Colosimo,Thilo van Eimeren,Thilo van Eimeren,Lawrence I. Golbe,Jan Kassubek,Carolin Kurz,Irene Litvan,Alexander Pantelyat,Gil D. Rabinovici,Gesine Respondek,Gesine Respondek,Axel Rominger,James B. Rowe,Maria Stamelou,Keith A. Josephs +20 more
TL;DR: The degree to which structural and molecular neuroimaging metrics fulfill criteria for diagnostic biomarkers of PSP is critically evaluated to discuss the role of biomarkers in the diagnosis of Richardson's syndrome, variant PSP syndromes and autopsy confirmed PSP, and emphasize current shortfalls in the field.
Journal ArticleDOI
The complexity of tau in Alzheimer's disease.
TL;DR: This review will primarily focus on recent advances in understanding the contributions of tau to AD, as well as new approaches to uncover novel roles of pathological tau during disease progression.
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