Developing a diagnostic test for Parkinson’s: Detecting alpha-synuclein
Researchers are closing in on a test for Parkinson’s by focusing on the presence of clumps of a protein called alpha-synuclein.
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Diagnosis of Parkinson’s can currently be a long and unsettling process. This is because there is currently no simple diagnostic test for the condition. In a recent survey of more than 2,000 people with Parkinson’s, carried out by Parkinson’s UK, more than a quarter reported they were misdiagnosed with a different condition before receiving a Parkinson’s diagnosis.
With no definitive test for the condition, diagnosis is made by a neurologist based on a combination of symptoms such as tremor, slowness, stiffness and balance issues. A DaTSCAN is sometimes used to help specialists confirm the loss of dopamine-producing cells that cause the symptoms of Parkinson’s. However, a similar loss may also occur in some other rarer neurological conditions, and furthermore, some of the symptoms of Parkinson’s can overlap with other conditions, such as multiple system atrophy (MSA), especially in the early stages when progression is gradual and symptoms are more subtle.
Parkinson’s also tends to develop gradually and it may be many months, even years, before the symptoms become obvious enough for an individual to visit their GP. While there are several known risk factors for Parkinson’s — including RBD (REM sleep behaviour disorder), certain lifestyle and environmental factors, and age — there is currently no way of knowing who might go on to develop Parkinson’s.
Therefore, there is a vital need to improve the tools used to diagnose Parkinson’s earlier and with improved accuracy.
68-year-old Angela Wilson shared her experience of misdiagnosis and what a diagnostic test would mean for people with Parkinson’s and their loved ones:
“In 2008, I had two frozen shoulders. It began with the right shoulder where my Parkinson’s affects my mobility the most. But at that time I didn’t know I had the condition. It was misdiagnosed and was put down as a muscle strain. Eventually, it was diagnosed as a frozen shoulder. In late 2011, I began to notice a very obvious tremor in my right arm, my right leg dragging along and problems with sleeping and constipation. My tremor became more exaggerated when I was under stress. It was only in 2016, that I was finally diagnosed with Parkinson’s by a neurologist who had previously said I didn’t have the condition.
“If I had been diagnosed from the very start, I would have been given medication and had a better quality of life.
“My experience with being misdiagnosed for several years was a really worrying time. I am lucky to have had my husband by my side along with supportive friends. It would be absolutely wonderful if there was a test that could detect Parkinson’s easily and quickly.”
Measuring alpha-synuclein
Alpha-synuclein is a protein known to form sticky clumps in the brain cells of people with Parkinson’s. These clumps are believed to contribute to the death of dopamine-producing nerve cells, resulting in the symptoms associated with Parkinson’s.
There is research underway to understand where problems with alpha-synuclein start, and recent research has highlighted the role of the gut in Parkinson’s. Scientists are also interested in what causes the protein to clump together and how they might target it with new treatments that remove the troublesome forms of the protein. Alongside this, there is research looking at using the protein as a way to diagnose and measure the progression of Parkinson’s.
A recent research project — funded by Parkinson’s UK and carried out at the Oxford Parkinson’s Disease Centre (OPDC) — set out to investigate and build upon evidence for a specific test that aims to measure the clumping of alpha-synuclein in samples from people with Parkinson’s…and the results are in.
What did the researchers do?
The test under investigation is called α-synuclein real-time quaking-induced conversion (αSyn-RT-QuIC). This method involves collecting cerebrospinal fluid (CSF) from participants, where clinicians use a needle to take fluid from the lower back (lumbar puncture). These samples were then analysed in the lab by shaking them with special liquids that allow the researchers to see if more clumps of alpha-synuclein formed (a technique called “quaking”). The idea is that where clumps were already present in the test sample, more clumps would form in the quaking.
This research aimed to build on previous studies which were done at a small scale, to show that the test was reproducible and accurate at a larger scale. This is needed to demonstrate that alpha-synuclein quaking could be used as a reliable way to diagnose and possibly monitor the progression of Parkinson’s.
But the researchers weren’t finished there, they also wanted to see if the test could distinguish between different subtypes of Parkinson’s and separate those with Parkinson’s from people with similar conditions such as MSA. Finally, they used the test in people with RBD, who have a higher than normal risk of Parkinson’s, to try and predict who would develop the condition.
In this study, CSF samples were taken from 74 people with Parkinson’s, 24 people with MSA, 45 people with RBD and 23 controls.
What did the research show?
The test showed 89% accuracy for correctly identifying people with Parkinson’s and 96% accuracy for correctly identifying people without the condition. It was also able to distinguish people with MSA from people with Parkinson’s and importantly helped to identify people with RBD who had abnormal alpha-synuclein and later developed Parkinson’s.
Subtyping Parkinson’s is a hot topic in research at the moment as it might help predict progression and improve future treatments. To find out if alpha-synuclein might be key to identifying the different subtypes of Parkinson’s, the researchers grouped participants based on the similarity of their symptoms. They reported that the test could successfully distinguish between different clinical subtypes of Parkinson’s.
However, the test results did not seem to relate to the severity of symptoms in Parkinson’s. Therefore, further research would be needed to investigate whether the test could be used to measure progression and response to future therapies.
What’s next?
Dr Laura Parkkinen, Head of Neuropathology research in OPDC and Associate Professor in Nuffield Department of Clinical Neurosciences in University of Oxford, said:
“The most exciting finding of the study is that the detected clumps of alpha-synuclein differed between different clinical Parkinson’s subtypes and between people with Parkinson’s and MSA. These differences could represent distinct “strain profiles” which could not only provide a way to distinguish between different neurodegenerative disorders (MSA versus Parkinson’s) but also provide a way to distinguish variations within a single condition. How the “strain profiles” vary within Parkinson’s and how they relate to clinical subtypes will need to be investigated further.
“We now need to understand what the differences are in the clumping of alpha-synuclein between Parkinson’s, dementia with Lewy bodies and MSA. By getting these answers, we will hopefully be able to create a blueprint for effective diagnosis and therapeutics for these conditions.”
With researchers closing in on a diagnostic test for Parkinson’s, they are providing a window into the brain to overcome some of the biggest challenges in Parkinson’s today.
Help drive research forwards
This vital research was funded by Parkinson’s UK.
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