Way of Visualizing Alpha-Synuclein Clumps in Living Brain Reported

PET scan and probe used to capture brain areas of toxic protein in 3 patients

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by Steve Bryson, PhD |

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Using a newly created probe and non-invasive PET scans, researchers were able to visualize sites of alpha-synuclein protein clumps — associated with nerve damage in Parkinson’s disease — in the brains of living patients, scientists reported.

This method may help in diagnosing conditions related to alpha-synuclein clumping, referred to as [alpha]-synucleinopathies, the team noted.

“We are encouraged by our findings, and investigations into the visualization of [alpha]-synuclein aggregates in [alpha]-synucleinopathies are currently underway,” Makoto Higuchi, MD, PhD, and Kiwamu Matsuoka, MD, PhD, the study’s co-lead authors with the National Institutes for Quantum Science and Technology, in Japan, said in a press release.

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The work, “High-Contrast Imaging of α-Synuclein Pathologies in Living Patients with Multiple System Atrophy,” was published as a new observation letter in the journal Movement Disorders.

In Parkinson’s disease, the alpha-synuclein protein forms toxic clumps, often called Lewy bodies, inside nerve cells that produce dopamine, a molecule that sends messages between nerve cells. Abnormally low dopamine levels result, causing problems with motor and certain non-motor abilities.

Probe signals strongly capture areas of protein clumping

Alpha-synuclein clumping has also been closely linked to several neurodegenerative disorders, including multiple system atrophy (MSA) and Lewy body dementia. MSA is a condition whereby nerve cell damage affects the autonomic nervous system that controls automatic, or subconscious, functions like breathing, bladder function, blood pressure, and muscle control.

However, the direct visualization of alpha-synuclein clumping in the brain to support a diagnosis of these conditions has been challenging due to the lack of sensitive imaging agents.

A team of researchers led by Higuchi and Matsuoka, collaborating with Eisai, Ono Pharmaceuticals, and Takeda Pharmaceuticals, have successfully visualized alpha-synuclein clumps in patients’ brains.

To achieve this, the team developed a non-toxic, radioactive small molecule probe called 18F-SPAL-T-06 that selectively binds to alpha-synuclein clumps and can be visualized by PET imaging scans.

“The pre-competitive collaboration between a research institute and three pharmaceutical companies enabled us to develop the radioligand, 18F-SPAL-T-06, for the in vivo [living organism] imaging of alpha-synuclein aggregates,” Higuchi said.

Building on successful studies using postmortem brain tissue of MSA patients, the probe was visualized in the brains of three individuals with MSA as well as one 72-year-old healthy control.

Two patients, a 56-year-old and 61-year-old woman, had MSA with predominant parkinsonism (MSA-P), characterized by limb rigidity, slowness of movement (bradykinesia), and orthostatic hypotension, or low blood pressure when standing after sitting or lying down.

The third patient, a 70-year-old woman, had MSA with predominant cerebellar ataxia (MSA-C), with a history of walking and balance disturbances, slurred speech, orthostatic hypotension, and mild limb rigidity.

PET scans were performed about two hours after the injection of 18F-SPAL-T-06.

Enhanced 18F-SPAL-T-06 signals were retained in various areas of the brain, including the putamen and cerebellar white matter, of the MSA-P and MSA-C patients. In contrast, there were minimal signals in the same brain areas for the healthy individual.

The increased radioactive molecule binding agreed with the predominant distributions of alpha-synuclein clumps in patients with these MSA subtypes, the researchers noted.

“Remarkably, we observed enhanced 18F-SPAL-T-06 retention in the putamen, pons, and cerebellar white matter and peduncles of the patients with MSA-P and MSA-C, in sharp contrast to minimal radio signals in the corresponding areas in the brain of the [healthy control],” Higuchi said.

“The present study provides the first in vivo demonstration of PET imaging of [alpha]-synuclein pathologies in MSA-P and MSA-C … allowing visual read of images in each individual for a diagnostic purpose,” the scientists wrote.

“Encouraged by the current findings, PET assays of the 18F-SPAL-T-06 binding in allied [alpha]-synucleinopathies exemplified by idiopathic Parkinson’s disease and dementia with Lewy bodies are underway,” the team noted.

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