Radiotracer Improves Detection of Tau Accumulation in Patients with Dementia

Using a single PET tracer could lead to earlier detection, as well as differentiation, of neurodegenerative disorders that are characterized by tau protein buildup in the brain.

In a study published Oct. 29 in Neuron, a team of investigators from the National Institutes for Quantum and Radiological Science and Technology in Chiba, Japan, outlined how adding fluorine-18 to an existing, chemically modified imaging probe can make it much easier to assess how much tau accumulates in the brains of patients who have frontotemporal lobar degeneration (FTLD) disorders and Alzheimer's disease.

THIS FIGURE SHOWS ASSOCIATIONS BETWEEN THE CLINICAL DISEASE SEVERITY AND THE EXTENT OF AREAS SHOWING INCREASED 18F-PM-PBB3 BINDING IN THE AD SPECTRUM. CREDIT: TAGAI, ONO, AND KUBOTA ET AL

“This study provided the first demonstration that abnormal tau protein deposits in Alzheimer’s disease and diverse FTLD disorders can be captured with high contrast, allowing an individual-based diagnosis of these illnesses with high accuracy,” said Makoto Higuchi, M.D., Ph.D., head of the department of functional brain imaging. “This finding indicates that a single PET tracer can cover the diagnosis and differentiation of a wide range of neurodegenerative dementias and is applicable to clinical workup in hospitals equipped with PET scanners.”

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Abnormal amounts of tau are found, using PET scans, in the brains of patients with Alzheimer’s and FTLD disorder. To date, though, it has been difficult to accurately determine how much tau actually builds up in patients with FTLD because 11C-PBB3 – the imaging probe used to visualize tau deposits – breaks down quickly after it is injected. Consequently, it does not have enough time to enter the brain in large concentrations.

Higuchi, along with his colleague Hitoshi Shimada, M.D., Ph.D., principal research fellow in the Brain Disorder Translational Research team, found a way to conquer this obstacle. Using chemical modifications, they turned PBBE into a more metabolically stable compound, called PM-PBB3, and they labeled it with fluorine-18.

They used the probe on 39 patients living with Alzheimer’s disease and various FTLD disorders, such as Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration. Not only did the team find that the probe could distinguish between the types of neurodegeneration based on location of the buildup, but they also determined 18F-PM-PBB3 uptake in the patients’ brains was approximately twice as high as what they experienced with 11C-PBB3. These results were confirmed with biopsy and autopsy.

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The beneficial impact also extended further, they said. By testing 18F-PM-PBB3 in three individuals with mild cognitive impairment and 14 with Alzheimer’s, Higuchi’s team discovered their technique identified tau deposits at pre-clinical levels in a way that providers could differentiate patients based on the severity of their disease.

Overall, the team said, their findings point to the potential of this high-contrast imaging has for early diagnosis, disease staging, and accurate identification of disease subtype.

“This diagnosis of diverse dementias at an early stage is difficult on the basis of symptoms, but [it] will be enabled with the aid of the present imaging method,” Higuchi said. “These clear distinctions have not been possible with the use of previous tau PET probes.”

And, the future is full of possibilities for this technique, he said, such as being used in animal studies to shed light on the underlying mechanisms of FTLD. But, in humans, longer-term clinical studies with larger sample sizes are also needed to examine a broader range of neuropsychiatric disorders. The technique can also be used to evaluate potential anti-tau therapies in pre-clinical and clinical trials, as well as play a role in selecting and stratifying patients for clinical trials. Lastly, Higuchi said, it could contribute to the development of blood-based biomarkers for the diagnosis of varying types of dementia.

To reach these goals, the team is partnering with venture company APRINOIA Therapeutics to run clinical trials, assessing the use of the imaging probe as a diagnostic agent.

“We hope to establish a next-generation diagnostic workflow for dementing diseases consisting of mass screening of the elderly population by blood tests followed by imaging workup for making a decision on the selection of appropriate treatment,” Higuchi said, noting the approach is scalable and easy to implement because PET scanners are widely available.

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