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CSF Test Developed for Uncommon Brain Diseases

By Labmedica International staff writers
Posted on 30 Oct 2019
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Image: Representative negative-stained transmission electron microscopy images of 4R RT-QuIC products seeded with brain homogenates from individuals with the designated diseases – frontotemporal dementia and Parkinsonism linked to chromosome 17; corticobasal degeneration; and progressive supranuclear palsy (Photo courtesy of National Institute of Allergy and Infectious Diseases).
Image: Representative negative-stained transmission electron microscopy images of 4R RT-QuIC products seeded with brain homogenates from individuals with the designated diseases – frontotemporal dementia and Parkinsonism linked to chromosome 17; corticobasal degeneration; and progressive supranuclear palsy (Photo courtesy of National Institute of Allergy and Infectious Diseases).
Scientific studies have linked the abnormal deposition of tau in the brain to at least 25 different neurodegenerative diseases. However, to accurately diagnose these diseases, brain tissue often must be analyzed after the patient has died.

Scientists have developed an ultrasensitive new test to detect abnormal forms of the protein tau associated with uncommon types of neurodegenerative diseases called tauopathies. This advance gives them hope of using cerebrospinal fluid, or CSF, an accessible patient sample, to diagnose these and perhaps other, more common neurological diseases, such as Alzheimer's disease.

Scientists from the National Institutes of Health (Hamilton, MT, USA) and their colleagues used the same test concept they developed when using post-mortem brain tissue samples to detect the abnormal tau types associated with Pick disease, Alzheimer's disease and chronic traumatic encephalopathy (CTE). To address the need for more meaningful biomarkers of tauopathies, they 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. 4R RT-QuIC stands for 4-repeat tau protein amplified in a real-time, quaking-induced conversion process.

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 ~ 50fM or 2fg/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 Fourier-transform infrared (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. The authors concluded that 4R RT-QuIC provides a practical cell-free method of detecting and subtyping pathologic 4R tau aggregates as biomarkers. The study was published on October 16, 2019, in the journal Acta Neuropathologica.

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