Researchers visualize α-synuclein pathology in living patients with neurodegenerative disease

White arrows indicate 18F-SPAL-T-06 accumulation, suggesting α-synuclein aggregates in putamen, yellow arrows in pons, yellow triangle in cerebellar white matter, and white triangle in peduncles. On the other hand, the red arrows indicate the accumulation of 18F-SPAL-T-06 in the choroid plexus outside the brain tissues, which is considered to be independent of α-synuclein aggregates. MSA-P: multiple system atrophy with predominant parkinsonism; MSA-C: multiple system atrophy with predominant cerebellar ataxia. Credit: Makoto Higuchi, National Institutes for Quantum Science and Technology

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the aggregation of α-synuclein in the brain. Now, Japanese scientists, in collaboration with three pharmaceutical companies, have developed a radioligand that facilitates the imaging of α-synuclein aggregates in patients with MSA. Their findings have the potential to completely change the diagnostic scenario for neurodegenerative diseases.

α-Synuclein is a neuronal protein involved in functions such as vesicle trafficking and neurotransmitter release. It is usually found in abundance in a healthy brain. However, α-synuclein aggregation has been closely linked to several neurodegenerative disorders, including Parkinson’s disease, multiple system atrophy (or MSA), and dementia with Lewy bodies.

MSA is a movement disorder that also affects the autonomic nervous system, which controls essential functions such as movement, breathing, and digestion. Thus, imaging of α-synuclein aggregates in vivo (or directly in a living organism), could be a potential diagnostic confirmation of SMA. However, the road to live imaging of α-synuclein has been marred by obstacles, including the lack of sensitive imaging agents.

Now, a collaborative effort of researchers from the National Institutes for Quantum Science and Technology, including Dr. Makoto Higuchi and Dr. Kiwamu Matsuoka from the Quantum Life and Medical Science Directorate, Institute for Quantum Medical Science has completely changed the scenario with three pharmaceutical companies —Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Company Limited. They succeeded in visualizing α-synuclein aggregates in the brains of patients.

To achieve this feat, the team developed a radioligand, 18F-SPAL-T-06, to be used as a probe for positron emission tomography (PET). “The pre-competitive collaboration between a research institute and three pharmaceutical laboratories enabled us to develop the radioligand, 18F-SPAL-T-06, for in vivo imaging of α-synuclein aggregates,” says Dr. Higuchi, attributing the success to teamwork. The team’s findings were published in the journal Movement disorders.

Prior to clinical evaluations, in vitro studies on the binding properties of 18F-SPAL-T-06 had been conducted on post-mortem brain tissue from MSA patients and healthy individuals, showing promising results. For first-in-man imaging studies, researchers recruited three patients who were clinically diagnosed with MSA and a 72-year-old healthy control (HC). Of the three patients with MSA, two were identified as having MSA with predominant parkinsonism (MSA-P) and one with MSA with predominant cerebellar ataxia (MSA-C). PET scan with 18F-SPAL-T-06 was performed on all patients and specific binding was estimated by radioligand retention in the tissue.

“Remarkably, we have seen an improvement 18F-SPAL-T-06 retention in the putamen, pons and white matter and cerebellar peduncles of patients with MSA-P and MSA-C, in stark contrast to minimal radio signals in corresponding brain areas of HC , “says Dr. Higuchi.

The researchers also found that 18F-SPAL-T-06 has high affinity for MSA-like α-synuclein aggregates and does not cross-react with other off-target components, indicating its high specificity and potential use as a probe for the diagnosis of MSA.

Regarding the long-term applications of their work, Dr. Higuchi and Dr. Matsuoka say, “We are encouraged by our findings, and investigations into the visualization of α-synuclein aggregates in other α-synucleinopathies are currently underway.

Light on protein aggregation in Parkinson’s disease

More information:
High contrast imaging of α-synuclein pathologies in living patients with multiple system atrophy, Movement disorders (2022). DOI: 10.1002/mds.29186

Provided by the National Institutes for Quantum Science and Technology

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