A new tracer for brain imaging could offer a clear window into the development of Alzheimer’s disease and other neurodegenerative conditions. The tracing agent, which highlights the accumulation of toxic tau protein deposits in the brain, could distinguish between a range of conditions called tauopathies that can be difficult to tell apart at the early stages, such as frontotemporal dementia and progressive supranuclear palsy.
Tau is a protein involved in maintaining the structure of neurons. In tauopathies, including Alzheimer’s disease, it aggregates to form knots inside the cells, eventually killing them.
PET scans are a common diagnostic technique used in hospitals, relying on a radioactive tracing agent to reveal the location of a molecule of interest. Earlier this year, the US Food and Drug Administration approved the first tau PET tracer for Alzheimer’s disease, Tauvid. It has proved challenging to find reliable PET tracers that can bind to the various forms of tau seen in different tauopathies.
In pursuit of a tau tracer that would offer a sharper signal than previous iterations in development, researchers adapted an existing tracer to make it last longer in the body. The new tracer, known as 18F-PM-PBB3, carries a radioactive fluorine isotope to the tau tangles and releases a positron particle detected by a PET scanner when it binds its target.
While the developers succeeded in enhancing tau visualization, their tracer also had the unexpected effect of binding to a greater variety of tau deposits seen across different tauopathies. This means that the same tracer could be used as a diagnostic test for multiple neurodegenerative conditions.
The researchers tested the tracer in 39 patients with a range of tau-related conditions, including Alzheimer’s disease. Based on the location of the tracer’s signal on the brain scans, the team was able to predict accurately the type of disease, which was confirmed in some cases by later autopsies. Their results appear today (October 29) in Neuron.
In the development of Alzheimer’s disease, the tau deposits are thought to follow on from the accumulation of amyloid-β plaques. Although most efforts to create treatments for Alzheimer’s have focused on amyloid, the presence of tau is thought to be more closely linked to the development of symptoms. The researchers were able to accurately predict the severity of the symptoms of Alzheimer’s disease in 17 people based on the abundance of tau seen in the scans.
“Even during the clinical trials for anti-amyloid drugs, we also need to pursue the tau accumulation in those patients to see whether or not the tau accumulation, which is closely associated with the neuronal death, could be suppressed as a result of the amyloid-β suppression,” says coauthor Makoto Higuchi of the National Institute of Radiological Sciences in Japan.
The tracer may have the biggest effect on diseases other than Alzheimer’s. Experimental tracers that had previously been developed were unable to detect all forms of tau seen in tauopathies. “One of the problems with the old tracers was that the tau pathology in Alzheimer’s disease could be detected, but there were problems with detecting it in the other tauopathies. So this opens new perspectives. Now we really can image the pathology in the patients, and we can make the link with the symptoms,” says Ilse Dewachter, a neuroscientist at Hasselt University in Belgium who was not involved in the study.
In conditions such as frontotemporal dementia, which can be caused by tau, the early symptoms can be significant behavioral changes and a loss of inhibition, leading to social problems. “Even without the radical cure for the tauopathy, we can socially assist those people by predicting the emerging, symptomatic problems in each of the subjects. That’s the major advantage of imaging tau deposits in the brain,” says Higuchi.
PET scans would be too expensive for use in mass screening for dementia, but Higuchi notes that they could still be helpful in developing tests that instead look for biomarkers in the blood or cerebrospinal fluid. As part of such an effort, scans would first categorize individuals as being tau-positive or tau-negative, and then researchers could identify biomarkers that distinguish between the two groups.
The imaging might also help identify the right people to take part in clinical trials, as proteins other than tau can cause frontotemporal dementia.
“If you want to be able to develop trials for patients who present with the same syndromes, we need to know what subtype of pathology they have. So far, we have no biomarker. It’s really, really hard right now to guess if it’s tau or another [protein aggregating],” says Renaud La Joie, a neuroscientist at the University of California, San Francisco, who was not involved in the study. “For non-Alzheimer’s trials, we really need help screening the right patients.”
Higuchi and his colleagues have patented the tracer and licensed it to APRINOIA Therapeutics, which is testing its use as a diagnostic tool for Alzheimer’s disease in clinical trials in the US, China, and Japan. Higuchi says he hopes that they will soon be able to do clinical trials for diagnosing other forms of dementia.
K. Tagai et al., “High-contrast in vivo imaging of tau pathologies in Alzheimer’s and non-Alzheimer’s disease tauopathies,” Neuron, doi:10.1016/j.neuron.2020.09.042, 2020.