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

Eri Saijo, Michael A. Metrick, 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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
JournalActa neuropathologica
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Frontotemporal Lobar Degeneration
Tauopathies
Progressive Supranuclear Palsy
Cerebrospinal Fluid
Seeds
Biomarkers
Brain
Fourier Transform Infrared Spectroscopy
Spectrum Analysis
Alzheimer Disease
Fluorescence

Keywords

  • Biomarker
  • Corticobasal degeneration
  • Diagnosis
  • Progressive supranuclear palsy
  • Strain
  • Tau

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration. / Saijo, Eri; Metrick, Michael A.; Koga, Shunsuke; Parchi, Piero; Litvan, Irene; Spina, Salvatore; Boxer, Adam; Rojas, Julio C.; Galasko, Douglas; Kraus, Allison; Rossi, Marcello; Newell, Kathy; Zanusso, Gianluigi; Grinberg, Lea T.; Seeley, William W.; Ghetti, Bernardino; Dickson, Dennis W.; Caughey, Byron.

In: Acta neuropathologica, 01.01.2019.

Research output: Contribution to journalArticle

Saijo, E, Metrick, MA, Koga, S, Parchi, P, Litvan, I, Spina, S, Boxer, A, Rojas, JC, Galasko, D, Kraus, A, Rossi, M, Newell, K, Zanusso, G, Grinberg, LT, Seeley, WW, Ghetti, B, Dickson, DW & Caughey, B 2019, '4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration', Acta neuropathologica. https://doi.org/10.1007/s00401-019-02080-2
Saijo, Eri ; Metrick, Michael A. ; Koga, Shunsuke ; Parchi, Piero ; Litvan, Irene ; Spina, Salvatore ; Boxer, Adam ; Rojas, Julio C. ; Galasko, Douglas ; Kraus, Allison ; Rossi, Marcello ; Newell, Kathy ; Zanusso, Gianluigi ; Grinberg, Lea T. ; Seeley, William W. ; Ghetti, Bernardino ; Dickson, Dennis W. ; Caughey, Byron. / 4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration. In: Acta neuropathologica. 2019.
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AU - Saijo, Eri

AU - Metrick, Michael A.

AU - Koga, Shunsuke

AU - Parchi, Piero

AU - Litvan, Irene

AU - Spina, Salvatore

AU - Boxer, Adam

AU - Rojas, Julio C.

AU - Galasko, Douglas

AU - Kraus, Allison

AU - Rossi, Marcello

AU - Newell, Kathy

AU - Zanusso, Gianluigi

AU - Grinberg, Lea T.

AU - Seeley, William W.

AU - Ghetti, Bernardino

AU - Dickson, Dennis W.

AU - Caughey, Byron

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N2 - 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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