@article{e20da9d0c5de4aadb21c4f5a9eb598c8,
title = "4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration",
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{\textquoteright}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.",
keywords = "Biomarker, Corticobasal degeneration, Diagnosis, Progressive supranuclear palsy, Strain, Tau",
author = "Eri Saijo and Metrick, {Michael A.} and Shunsuke Koga and Piero Parchi and Irene Litvan and Salvatore Spina and Adam Boxer and Rojas, {Julio C.} and Douglas Galasko and Allison Kraus and Marcello Rossi and Kathy Newell and Gianluigi Zanusso and Grinberg, {Lea T.} and Seeley, {William W.} and Bernardino Ghetti and Dickson, {Dennis W.} and Byron Caughey",
note = "Funding Information: We thank David Dorward and Cindi Schwartz of the NIAID Research Technology Branch for help with electron microscopy. We thank Drs. Suzette Priola, Ankit Srivastava, and Bradley Groveman for helpful internal review of the initial manuscript. This work was supported in part by the Intramural Research Program of the NIAID. MM is supported by the NIH/Cambridge Scholars program. B. G. was supported by a grant of the US National Institutes of Health (P30AG010133) and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine. D. G. is supported by NIH grant AGO5131 and the Shiley-Marcos Alzheimer{\textquoteright}s Disease Research Center at UCSD. S. K. was supported by a research grant from the CBD Solutions. Some of the tissue specimens were obtained with support of the Massachusetts Alzheimer{\textquoteright}s Disease Research Center (P50 AG005134). We also acknowledge the Department of Pathology and Laboratory Medicine, University of Kansas School of Medicine. Human tissue was obtained from the NIH NeuroBioBank. The UCSF Neurodegenerative Disease Brain Bank is supported by NIH Grants AG023501 and AG019724, the Tau Consortium, and the Bluefield Project to Cure FTD. LTG is funded by NIH K24053435. This study is also supported by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Grant No. ZIA AI001086-08). SS is funded by NIH K08 AG052648. Funding Information: We thank David Dorward and Cindi Schwartz of the NIAID Research Technology Branch for help with electron microscopy. We thank Drs. Suzette Priola, Ankit Srivastava, and Bradley Groveman for helpful internal review of the initial manuscript. This work was supported in part by the Intramural Research Program of the NIAID. MM is supported by the NIH/Cambridge Scholars program. B. G. was supported by a grant of the US National Institutes of Health (P30AG010133) and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine. D. G. is supported by NIH grant AGO5131 and the Shiley-Marcos Alzheimer{\textquoteright}s Disease Research Center at UCSD. S. K. was supported by a research grant from the CBD Solutions. Some of the tissue specimens were obtained with support of the Massachusetts Alzheimer{\textquoteright}s Disease Research Center (P50 AG005134). We also acknowledge the Department of Pathology and Laboratory Medicine, University of Kansas School of Medicine. Human tissue was obtained from the NIH NeuroBioBank. The UCSF Neurodegenerative Disease Brain Bank is supported by NIH Grants AG023501 and AG019724, the Tau Consortium, and the Bluefield Project to Cure FTD. LTG is funded by NIH K24053435. This study is also supported by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Grant No. ZIA AI001086-08). SS is funded by NIH K08 AG052648. Publisher Copyright: {\textcopyright} 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",
year = "2020",
month = jan,
day = "1",
doi = "10.1007/s00401-019-02080-2",
language = "English (US)",
volume = "139",
pages = "63--77",
journal = "Acta neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "1",
}