Identification of the first biomarkers of primary tauopathies

Identification of the first biomarkers of primary tauopathies

The first tau biomarkers that have the potential to identify types of frontotemporal lobar degeneration (FTLD) in living patients and facilitate the design of clinical trials to evaluate prospective therapies have been identified.

The new results show that fluid biomarkers identified certain tauopathies, which are neurodegenerative diseases involving tau proteins, with an accuracy rate of more than 80%.

Doctor Chihiro Sato

“This is the first biomarker for primary tauopathies, and it will enable clinical trials that clinicians dreamed of but did not happen due to lack of biomarkers,” said study researcher Chihiro Sato, PhD. assistant professor of neurology at the University of Washington. School of Medicine in St. Louis, Missouri, said Medscape Medical News.

The results were published online November 24 in Natural medicine.

Necessary diagnostic markers

The symptomatic phases of these life-threatening diseases involve neurological damage that typically evolves over years or even decades.

Disorders such as FTLD are characterized as primary tauopathies because tau accumulation is the main pathological finding. In contrast, Alzheimer’s disease (AD) is considered a secondary tauopathy because tau is deposited after the deposition of beta-amyloid (Aβ).

For years, cerebrospinal fluid (CSF) biomarkers Aβ and total and phosphorylated tau (p tau) have aided in the diagnosis of AD and the evaluation of therapy outcomes in clinical trials. Positron emission tomography can measure aggregated Aβ and tau in the brains of living patients with AD.

Plasma biomarkers can now help in the early diagnosis and monitoring of AD progression.

However, this is not the case for other tauopathies including FTLD, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, and Pick’s disease. Most tauopathies can only be definitively diagnosed by brain autopsy.

“It is therefore very important” to have ante-mortem fluid biomarkers to improve diagnostic accuracy and facilitate clinical trials for tauopathy therapeutics, Sato said.

Find a Tau CSF signature

Tau comes in different lengths, depending on the number of repeats (Rs). Previous research suggests that tauopathies can be classified into 3R, 4R, and 3R/4R mixed tauopathies based on the dominant isoforms found in tau aggregates.

Researchers recently used biochemical extraction and mass spectrometry methods to show that truncated tau protein could be detected and quantified in CSF. “Tau is very long in the brain, but when it’s secreted or released into CSF ​​in a soluble form, it gets truncated or cut,” Sato said.

“We wanted to see if we could find a signature of tau in cerebrospinal fluid that reflected changes in the brain,” she added.

The researchers focused on the tau species 4R isoform of the tau microtubule-binding region (MTBR-tau), which constitute the central regions of tau aggregates in the brain and exist in the CSF as truncated fragments of tau. C-terminal. They identified two tau markers that seemed promising: MTBR-tau 275 and MTBR-tau 282.

To assess biomarker accuracy, they used a cohort of patients with autopsy-confirmed primary tauopathy. This included corticobasal degeneration, progressive supranuclear palsy, FTLD with DNA binding protein TAR (FTLD-TDP), FTLD mutations in microtubule association protein tau (FTLD-MAPT), argyrophilic grains and Pick’s disease.

“This is a pathologically confirmed cohort, which means we know what disorder they had in the end,” Sato said.

The different tauopathies have a variable and sometimes overlapping spectrum of symptoms. For example, progressive supranuclear palsy is more associated with motor or gait-related problems, whereas corticobasal degeneration may involve more cognitive impairment.

The researchers also had data on patients with Alzheimer’s disease and on people who formed a healthy control group.

High diagnostic accuracy

Results showed that biomarkers increase in corticobasal degeneration, progressive supranuclear palsy, FTLD-MAPT and AD but decrease in CSF of corticobasal degeneration, FTLD-MAPT and AD compared to control participants and participants with other FTLD-tau, such as Pick’s disease.

Sato noted that patients with FTD-MAPT carry a mutation implicated in the disorder and can be diagnosed with genetic testing. “But it’s nice to have a biomarker to track the disease or help stage it,” she said.

The researchers showed that these biomarkers could identify people with corticobasal degeneration with up to 83% accuracy. “We found that regardless of the clinical syndromes presented by the patients, if they were found to have [corticobasal degeneration] in the end, then this biomarker is very highly specific,” Sato said.

She noted that the diagnostic accuracy of biomarkers is “much better” than diagnosis without a biomarker, for which the accuracy is only 25% to 50%.

The researchers also confirmed that CSF MTBR-tau/t-tau measurements are reproducible and stable over 4 months, “which will reliably provide biomarker values ​​in clinical or clinical trial settings.”

Sato reiterated that the new findings are “exciting” as the biomarker can be used to screen patients eligible for inclusion in clinical trials for corticobasal degeneration.

“If we have biomarkers, we can zero in on people with the same disorder and we can start developing therapies with these clinical trials,” she said.

Dr. Song Horie

Various pharmaceutical companies are already developing anti-tau therapies, said lead author Kanta Horie, PhD, volunteer research associate professor of neurology, Washington University School of Medicine in St. Louis. Medscape Medical News.

Having biomarkers will allow these potential drug candidates to be tested moving forward, Horie added.

Sato said this development, while promising, is at a nascent stage.

Impressive but modest achievement

Commenting for Medscape Medical News, David Knopman, MD, professor of neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, said the research is “significant” because it shows, for the first time, that it is possible to identify a subset of individuals with primary tauopathies.

“Any success in detecting non-AD tauopathy is a great achievement,” said Knopman, who was not involved in the research.

However, from a clinician’s perspective, the advances “are rather modest,” he added.

Knopman noted that the only sporadic tauopathy in which the ratios of MTBR-tau275 or MTBR-tau282 to total tau showed reductions was in patients with autopsy-proven corticobasal degeneration compared to healthy control participants and those with FTLD- PDT.

The fact that the levels declined “highlights a potential disease mechanism, namely aggregation in the brain leading to lower levels of the particular tau isoform in the CSF,” he said.

However, he said it was “disappointing” that the tests failed to identify patients with progressive supranuclear palsy.

While testing has shown that MTBr-tau/total-tau ratios are lower in carriers of FTLD-tau mutations, genetic testing is “the diagnostic tool of choice” for these patients, so the biomarker “has rather limited clinical utility,” Knopman said. .

Moreover, since the ratios were also low with pathology-proven Alzheimer’s disease, “MTBR-tau testing would not help” distinguish corticobasal degenerative tauopathy from Alzheimer’s disease, he said. added.

The study was funded by the Rainwater Charitable Foundation, the NIH/NIA and the Barnes Jewish Hospital Foundation. Horie is an Eisai-sponsored volunteer research associate professor at Washington University in St. Louis and received a salary from Eisai. He and Sato may receive income based on the methods used in the study to detect MTBR tau isoforms, and a patent for this technology has been filed. Knopman did not disclose any financial relationship relevant to the discovery of biomarkers in AD or non-AD degenerative diseases. He is a Site Principal Investigator for Lilly and Biogen, both for AD therapeutics, but receives no personal compensation, and is part of a DSMB for the Dominantly Inherited Alzheimer Network trial unit, which is testing anti-AD therapies.

Night with. Published on November 24, 2022. Full article

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