期刊
ACTA NEUROPATHOLOGICA
卷 139, 期 1, 页码 63-77出版社
SPRINGER
DOI: 10.1007/s00401-019-02080-2
关键词
Tau; Progressive supranuclear palsy; Corticobasal degeneration; Strain; Diagnosis; Biomarker
资金
- Intramural Research Program of the NIAID
- NIH/Cambridge Scholars program
- US National Institutes of Health [P30AG010133]
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine
- NIH [K08 AG052648, AGO5131, AG023501, AG019724, K24053435]
- Shiley-Marcos Alzheimer's Disease Research Center at UCSD
- CBD Solutions
- Massachusetts Alzheimer's Disease Research Center [P50 AG005134]
- Tau Consortium
- Blue-field Project to Cure FTD
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases [ZIA AI001086-08]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI001086] Funding Source: NIH RePORTER
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 10(6)-10(9)-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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