Zooming in on a single disease and studying it intensely is often the most productive path to finding treatments. But there is no easy way to distinguish between people living with any of the primary tauopathies -; a group of rare brain disorders characterized by rapidly worsening problems with thinking and movement -; because the symptoms are too similar. As a result, most studies of primary tauopathies have included a mixture of such diseases, even though researchers know that the diseases differ in important ways and likely require different treatments.
Now researchers at the Washington University School of Medicine in St. Louis, however, found a biomarker that, with up to 89% accuracy, identifies people with a primary tauopathy called corticobasal degeneration (CBD). Traditional diagnostic methods for CBD are only 25% to 50% accurate, the researchers said.
The biomarker could be developed into a tool to screen potential volunteers for CBD-specific research studies and clinical trials, and ultimately to identify individuals who could benefit from CBD-specific treatments, the researchers said.
The survey was published on 24 November i Natural medicine.
Before, the only way to find out which primary tauopathy a person had was to wait until they died and then examine the person’s brain under a microscope. A patient comes in with stiffness, balance problems, slurred speech and memory problems, and it could be CBD, but it could also be progressive supranuclear palsy (PSP) or Alzheimer’s or other diseases. This biomarker can reliably identify people with CBD, which means we can use it to enroll people in clinical trials. And down the road, that may be the key to starting therapies.”
Chihiro Sato, PhD, co-senior author, assistant professor of neurology
CBD is one of about two dozen brain diseases that are considered tauopathies because they share one critical characteristic: toxic tau aggregates in the brain. Individual tauopathies involve different subtypes of tau and exhibit different patterns of damage to brain cells and tissues. The sets of symptoms of the different tauopathies overlap, making it difficult for doctors to tell them apart. This complicates efforts to study them and find treatments.
Tauopathies are classified as either primary or secondary, depending on when tau tangles occur in the course of the disease. In primary tauopathies, tau tangles form initially, apparently by themselves. In secondary tauopathies, tangles only form after other changes have taken place in the brain. For example, in Alzheimer’s disease, the most common secondary tauopathy, the brain protein amyloid beta builds up for years before tau tangles appear.
In 2020, Kanta Horie, PhD, a research associate professor of neurology and first author on the current paper, developed a highly sensitive technique to detect specific fragments of tau in the cerebrospinal fluid that surrounds the brain and spinal cord. Horie and colleagues used the technique to identify a new form of tau in Alzheimer’s patients and showed that the level of the new tau in the cerebrospinal fluid indicates the stage of the disease and follows the amount of tau tangles in the brain.
As part of this study, Horie, Sato and colleagues -; including co-senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology -; used the technique to search for characteristic forms of tau linked to primary tauopathies. To ensure the subjects were classified accurately, Horie, Sato and Bateman collaborated with co-authors Adam Boxer, MD, PhD, Salvatore Spina, MD, PhD, and Lawren VandeVrede, MD, PhD, all in the Department of Neurology at the University of California , San Francisco. The team examined brain tissue and cerebrospinal fluid from people who had died with dementia and movement disorders and whose specific diseases had been confirmed at autopsy. The study population included individuals with one of five primary tauopathies -; CBD; PSP; frontotemporal lobar degeneration with microtubule association protein tau mutations (FTLD-MAPT); agyrophilic grain disease; and Pick’s disease -; as well as Alzheimer’s and dementia unrelated to tau. For comparison, they also examined samples from people without dementia.
Two special forms of rope -; microtubule binding region (MTBR)-tau 275 and MTBR-tau 282-; were unusually high in brain and low in cerebrospinal fluid in patients with CBD and a subset of FTLD-MAPT. Further studies showed that these forms of tau distinguish people with CBD from those with other primary tauopathies with 84% to 89% accuracy, depending on the disease.
“Even if there is an experimental drug available that specifically targets that type of tau in CBD, it’s very challenging to test it without a biomarker,” Horie said. “The trial can fail, even when the drug works, if the population is heterogeneous. Drug trials that specifically target the type of tau in CBD can be improved by enrolling correctly diagnosed patients. Having a biomarker opens a path for pharmaceutical companies to improve clinical trials and accelerate research into therapies for CBD.”
Several experimental drugs targeting tau are in the pipeline. Most are designed with Alzheimer’s patients in mind, but they can be effective as therapies for primary tauopathies. Horie’s technique could be used to find biomarkers for other primary tauopathies, opening the door to more clinical trials, the researchers said.
“CBD patients and families are desperate for effective therapies, but organizing clinical trials for this deadly disease has been challenging,” Boxer said. “Until now, we have not had a specific biomarker to accurately diagnose patients. This new biomarker also opens the door to testing many new tau-targeted treatments for CBD because it may allow us to directly measure the ability of these treatments to lower the toxicity. tau protein levels in patients’ brains.”
Washington University School of Medicine
Horie, K., et al. (2022) CSF tau microtubule binding region identifies pathological changes in primary tauopathies. Natural medicine. doi.org/10.1038/s41591-022-02075-9.