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01-01-2020 | Progressive Supranuclear Palsy | Original Paper

4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration

Authors: Eri Saijo, Michael A. Metrick II, Shunsuke Koga, Piero Parchi, Irene Litvan, Salvatore Spina, Adam Boxer, Julio C. Rojas, Douglas Galasko, Allison Kraus, Marcello Rossi, Kathy Newell, Gianluigi Zanusso, Lea T. Grinberg, William W. Seeley, Bernardino Ghetti, Dennis W. Dickson, Byron Caughey

Published in: Acta Neuropathologica | Issue 1/2020

Abstract

To address the need for more meaningful biomarkers of tauopathies, we have developed an ultrasensitive tau seed amplification assay (4R RT-QuIC) for the 4-repeat (4R) tau aggregates of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other diseases with 4R tauopathy. The assay detected seeds in 10⁶–10⁹-fold dilutions of 4R tauopathy brain tissue but was orders of magnitude less responsive to brain with other types of tauopathy, such as from Alzheimer’s disease cases. The analytical sensitivity for synthetic 4R tau fibrils was ~ 50 fM or 2 fg/sample. A novel dimension of this tau RT-QuIC testing was the identification of three disease-associated classes of 4R tau seeds; these classes were revealed by conformational variations in the in vitro amplified tau fibrils as detected by thioflavin T fluorescence amplitudes and FTIR spectroscopy. Tau seeds were detected in postmortem cerebrospinal fluid (CSF) from all neuropathologically confirmed PSP and CBD cases but not in controls. CSF from living subjects had weaker seeding activities; however, mean assay responses for cases clinically diagnosed as PSP and CBD/corticobasal syndrome were significantly higher than those from control cases. Altogether, 4R RT-QuIC provides a practical cell-free method of detecting and subtyping pathologic 4R tau aggregates as biomarkers.

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Title: 4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration
Authors: Eri Saijo
Michael A. Metrick II
Shunsuke Koga
Piero Parchi
Irene Litvan
Salvatore Spina
Adam Boxer
Julio C. Rojas
Douglas Galasko
Allison Kraus
Marcello Rossi
Kathy Newell
Gianluigi Zanusso
Lea T. Grinberg
William W. Seeley
Bernardino Ghetti
Dennis W. Dickson
Byron Caughey
Publication date: 01-01-2020
Publisher: Springer Berlin Heidelberg
Keywords: Progressive Supranuclear Palsy
Biomarkers
Published in: Acta Neuropathologica / Issue 1/2020
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02080-2

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4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration

Abstract

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