The first tau biomarkers that have the potential to identify types of frontotemporal lobar degeneration (FTLD) in living patients and facilitate 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 that involve tau proteins, with an accuracy rate of more than 80%.
“This is the first biomarker for primary tauopathies, and it will enable clinical trials that clinicians have been dreaming of but that didn’t happen because of the lack of biomarkers,” study investigator Chihiro Sato, PhD, assistant professor of neurology at Washington University School of Medicine in St. Louis, in Missouri, told Medscape Medical News.
The findings were published online November 24 in Nature Medicine.
Diagnostic Markers Needed
The symptomatic phases of these fatal illnesses involve neurologic impairment that typically progresses over years, and often decades.
Disorders such as FTLD are characterized as primary tauopathies because tau accumulation is the major pathologic finding. In contrast, Alzheimer’s disease (AD) is considered a secondary tauopathy because tau is deposited after amyloid beta (Aβ) deposition.
For years, the cerebrospinal fluid (CSF) biomarkers Aβ and total and phosphorylated tau (p tau) have aided in the diagnosis of AD and in the assessment of outcomes of therapies in clinical trials. Positron-emission tomography enables measurement of aggregated Aβ and tau in the brains of living AD patients.
Plasma-based biomarkers may now aid 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 disease. Most tauopathies can only be definitively diagnosed by brain autopsy.
“So, it’s very important” to have antemortem fluid biomarkers to improve diagnostic accuracy and facilitate clinical trials for tauopathy therapeutics, Sato said.
Finding a Tau CSF Signature
Tau comes in different lengths, depending on the number of repetitions (Rs). Previous research suggests that tauopathies can be classified into 3R, 4R, and 3R/4R mixed tauopathies on the basis of dominant isoforms found in tau aggregates.
The investigators recently used biochemical extraction and mass spectrometry methods to show that truncated tau could be detected and quantified in CSF. “Tau protein is very long in the brain, but when it’s secreted or released into the CSF in soluble form, it’s truncated, or cut,” Sato said.
“We wanted to see if we could find a signature of tau in the cerebrospinal fluid that would reflect changes in the brain,” she added.
The researchers focused on 4R isoform tau species from microtubule binding region tau (MTBR-tau), which constitutes the core regions of tau aggregates in the brain and exists in CSF as truncated C-terminal tau fragments. They identified two tau markers that looked promising: MTBR-tau 275 and MTBR-tau 282.
To evaluate the accuracy of the biomarkers, they used a cohort of patients with an autopsy-confirmed primary tauopathy. This included corticobasal degeneration, progressive supranuclear palsy, FTLD with TAR DNA-binding protein (FTLD-TDP), FTLD microtubule association protein tau mutations (FTLD-MAPT), argyrophilic grain disease, and Pick disease.
“This is a pathologically confirmed cohort, meaning that we know what disorder they had in the end,” said Sato.
The different tauopathies have a varying and sometimes overlapping spectrum of symptoms. For example, progressive supranuclear palsy is associated more with motor or gait-related problems, whereas corticobasal degeneration may involve more cognitive impairment.
Researchers also had data on patients with AD and on persons who functioned as a healthy control group.
High Diagnostic Accuracy
Results showed that the biomarkers increase in corticobasal degeneration, progressive supranuclear palsy, FTLD-MAPT and AD but decrease in the CSF of corticobasal degeneration, FTLD-MAPT, and AD in comparison with the control participants and the participants with other FTLD-tau, such as Pick disease.
Sato noted that patients with FTD-MAPT carry a mutation that is 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.
Investigators showed that these biomarkers may identify individuals with corticobasal degeneration with an accuracy as high as 83%. “We found that regardless of the clinical syndromes patients presented with, if they turned out to have [corticobasal degeneration] at the end, then this biomarker is very highly specific,” said Sato.
She noted that the diagnostic accuracy of the 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 measures are reproducible and stable over 4 months, “which will reliably provide biomarker values in clinic or clinical trial settings.”
Sato reiterated that the new findings are “exciting” in that the biomarker can be used to screen for eligible patients for inclusion in corticobasal degeneration clinical trials.
“If we have biomarkers, we can concentrate those people who have the same disorder, and we can start to develop therapeutics with those clinical trials,” she said.
Various pharmaceutical companies are already developing anti-tau therapies, lead author Kanta Horie, PhD, voluntary research associate professor of neurology, Washington University School of Medicine in St. Louis, told Medscape Medical News.
Having biomarkers will allow testing of these potential drug candidates to move 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 “important” 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 with the research.
However, from the perspective of a clinician, the advances “are rather modest,” he added.
Knopman noted that the one sporadic tauopathy in which ratios of MTBR-tau275 or MTBR-tau282 to total tau showed reductions was in patients with autopsy-proven corticobasal degeneration compared with healthy control participants and those with FTLD-TDP.
The fact that levels declined “highlights a potential disease mechanism, namely, aggregation within the brain leading to lower levels of the particular tau isoform in CSF,” he said.
However, said it was “disappointing” that the assays did not identify patients with progressive supranuclear palsy.
While the assays showed that MTBr-tau/total-tau ratios were 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,” said Knopman.
Also, because ratios were also low with pathology-proven AD, “the MTBR-tau assays would not help” to distinguish corticobasal degeneration tauopathy from AD, he added.
The study was funded by the Rainwater Charitable Foundation, NIH/NIA, and the Barnes Jewish Hospital Foundation. Horie is an Eisai-sponsored voluntary research associate professor at Washington University in St. Louis and has received salary from Eisai. He and Sato may receive income based on methods used in the study to detect MTBR tau isoforms, and a patent for this technology has been submitted. Knopman has disclosed no financial relationships relevant to biomarker discovery in AD or non-AD degenerative diseases. He is a site PI for Lilly and Biogen, both for AD therapeutics, but receives no personal compensation, and he is on a DSMB for the Dominantly Inherited Alzheimer Network Trial Unit, which is testing anti-AD therapeutics.
Nat Med. Published November 24, 2022. Full article