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'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.

• Authors: Eri Saijo, Michael A Metrick 2nd, 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
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 139 Issue 1 Pg. 63-77 (01 2020) ISSN: 1432-0533 [Electronic] Germany
• PMID: 31616982 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• MAPT protein, human
• Protein Isoforms
• tau Proteins

Topics

• Biomarkers (cerebrospinal fluid)
• Fluoroimmunoassay (methods)
• Frontotemporal Lobar Degeneration (cerebrospinal fluid)
• Humans
• Protein Isoforms (cerebrospinal fluid)
• Sensitivity and Specificity
• tau Proteins (cerebrospinal fluid)