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Discovery could accelerate progress toward therapies for primary tauopathies
Zooming in on a single disease and studying it intensely is often the most productive way to find cures. But there’s no easy way to tell people living with one of the primary tauopathies apart – a group of rare brain diseases 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 these diseases, even though researchers know that the diseases differ in important ways and likely require different treatments.
Now, however, researchers at Washington University School of Medicine in St. Louis have found a biomarker that identifies, with up to 89% accuracy, people with a primary tauopathy called corticobasal degeneration (CBD). Traditional CBD diagnostic methods 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 potentially identify people who might benefit from CBD-specific treatments, the scientists said.
The study is published Nov. 24 in Nature Medicine.
“Before, the only way to know what primary tauopathy a person had was to wait until they died and then examine the person’s brain under a microscope,” said co-senior author Chihiro Sato, PhD, assistant professor of neurology. . “A patient presents 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 disease or other illnesses. This biomarker can reliably identify people with CBD, which means we can use it to enroll people in clinical trials. And, down the road, it can be the key to initiating therapies.
CBD is one of two dozen brain diseases considered tauopathies because they share one key feature: toxic tau aggregates in the brain. Individual tauopathies involve different tau subtypes and exhibit different patterns of damage to brain cells and tissues. The symptom collections of 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 the tau tangles appear during the course of the disease. In primary tauopathies, tau tangles form early, apparently on their own. In secondary tauopathies, the tangles only form after other changes have taken place in the brain. For example, in Alzheimer’s disease, the most common secondary tauopathy, brain protein beta-amyloid accumulates for years before tau tangles appear.
In 2020, Kanta Horie, PhD, research associate professor of neurology and first author of 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 patients with Alzheimer’s disease and showed that the level of new tau in cerebrospinal fluid indicates the stage of the disease and tracks the amount of tau tangles in the brain.
In this study, Horie, Sato and colleagues – including co-senior author Randall J. Bateman, MD, distinguished professor of neurology Charles F. and Joanne Knight – used the technique to search for distinctive forms of tau related to primary tauopathies. To ensure study subjects were categorized accurately, Horie, Sato, and Bateman collaborated with co-authors Adam Boxer, MD, PhD, Salvatore Spina, MD, PhD, and Lawren VandeVrede, MD, PhD. , all from the Department of Neurology at the University of California, San Francisco. The team examined brain tissue and cerebrospinal fluid from people who had died of dementia and movement disorders, and whose specific illnesses had been confirmed at autopsy. The study population included people with one of the five primary tauopathies – CBD; PSP; frontotemporal lobar degeneration with microtubule association protein tau (FTLD-MAPT) mutations; agyrophilic grain disease; and Pick’s disease – as well as Alzheimer’s disease and non-tau dementia. For comparison, they also looked at samples of people without dementia.
Two particular forms of tau – microtubule-binding region (MTBR)-tau 275 and MTBR-tau 282 – were abnormally high in the brain and low in the cerebrospinal fluid of patients with CBD and a subset of FTLD-MAPT. Further investigation 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 that specifically targets the tau type in CBD, it’s very difficult to test it without a biomarker,” Horie said. “The trial could fail even when the drug works if the population is heterogeneous. Trials of drugs that specifically target the type of tau in CBD can be improved by recruiting correctly diagnosed patients. Having a biomarker paves the way for pharmaceutical companies to improve clinical trials and accelerate research into therapies for CBD.
Several experimental tau-targeting drugs are in the works. Most were designed for patients with Alzheimer’s disease, 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 their families are desperate for effective therapies, but organizing clinical trials for this deadly disease has been difficult,” Boxer said. “Until now, we didn’t have a specific biomarker to accurately diagnose patients. This new biomarker also opens the door to testing many new tau-directed therapies for CBD, as it may allow us to directly measure the ability of these treatments to lower toxic tau protein levels in patients’ brains.
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