Alpha-synuclein Test May Aid Earlier Diagnosis

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Researchers have developed a highly-sensitive alpha-synuclein-based test that accurately distinguishes people with Parkinson’s from those without the disease and those with other alpha-synucleinopathies, which sometimes are difficult to distinguish based on symptoms alone.

The test also was able to predict the future conversion to Parkinson’s among people with rapid eye movement sleep behavior disorder (RBD), a condition linked to an increased risk of Parkinson’s and related disorders.

“We know that people may well have been misdiagnosed with, and treated for, another condition before receiving their correct diagnosis of Parkinson’s,” Beckie Port, PhD, said in a press release. Port is research communications manager at Parkinson’s UK, which funded the research.

“This could be a significant development towards a future early diagnostic test for Parkinson’s,” which “would enable the newly diagnosed to access vital treatment and support to manage their Parkinson’s symptoms sooner,” Port added.

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“An early diagnostic test could also speed up research into new drugs that slow the condition, which could prevent people from ever developing symptoms associated with Parkinson’s,” Port said.

The findings were reported in the study, “Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies,” published in the journal Brain.

Several neurodegenerative diseases are associated with the abnormal, toxic accumulation of aggregates of a protein called alpha-synuclein in the brain and spinal cord. Called alpha-synucleinopathies, these conditions include Parkinson’s, Lewy body dementia (LBD), and multiple system atrophy (MSA).

Given that their symptoms “can resemble one another,” the researchers wrote, early clinical diagnosis “is difficult, leading to misdiagnosis in up to 40% of cases.”

In addition, RBD of unknown cause — a sleep disorder in which a person physically acts out vivid, often unpleasant dreams — is the strongest clinical predictor of alpha-synucleinopathies, mostly Parkinson’s and LBD. Previous studies showed that 73.5% of RBD patients convert to such conditions after 12 years.

As such, there is a need for improved tests that can accurately discriminate Parkinson’s from other alpha-synucleinopathies and identify RBD patients at higher risk of conversion to Parkinson’s.

This would allow timely treatment initiation in Parkinson’s patients and facilitate recruitment of high-risk RBD patients “into clinical trials aimed at delaying or preventing the onset of synucleinopathies,” the researchers wrote.

Now, an international team of researchers in the U.K., France, Germany, Italy, and Canada developed a robust and reproducible version of the Real-Time Quaking-Induced Conversion (RT-QuIC) test that can help in just that.

The test uses a fluorescent probe to measure the abnormal clumping of alpha-synuclein in the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord.

This type of test was shown previously to distinguish Parkinson’s from non-alpha-synuclein-related neurodegenerative diseases with 100% sensitivity (percentage of Parkinson’s cases being correctly identified) and 95% specificity (percentage of unaffected cases being correctly ruled out).

In the current study, the team analyzed CSF samples from 74 Parkinson’s patients, 24 MSA patients, 45 people with RBD of unknown cause, and 55 healthy individuals. They also looked at potential links between the test’s parameters and patients’ clinical data.

Patients’ mean age ranged from 65.3 to 76.4 years at sample collection and disease duration since diagnosis ranged from 2.1 to 5.7 years. Healthy people had a mean age of 63.8.

Results showed that the test correctly identified Parkinson’s in 89% of cases, and correctly ruled it out in 96% of those without the condition.

While there was no significant association between RT-QuIC quantitative parameters and Parkinson’s clinical scores, maximum rate of reaction (Vmax) significantly differed among patients with slow versus fast motor symptom progression.

A total of 75% of MSA patients also tested positive for abnormal alpha-synuclein clumps, reflecting a 75% sensitivity for the test. Notably, CSF samples from MSA patients showed significantly longer time needed to reach half of the maximum fluorescence value (T50) and lower Vmax, relative to Parkinson’s patients, suggesting the presence of fewer abnormal alpha-synuclein clumps.

These parameters showed a moderate ability to distinguish people with Parkinson’s from those with MSA.

The test also correctly identified 64% of RBD patients, reaching sensitivity values of about 90% in three of the four independent groups of patients. Similar to MSA, RBD was associated with significantly longer T50 and lower Vmax, compared with Parkinson’s.

During follow-up, 14 RBD patients (31%) converted to an alpha-synucleinopathy — most commonly Parkinson’s (64.3%) — after a mean of 2.5 years (range, 0.2–7.9 years). Notably, nine of these converters (64.3%) had tested positive in the test, suggesting it could be useful for predicting Parkinson’s before symptoms appear.

These findings highlight the added value of the alpha-synuclein RT-QuIC test in diagnosing Parkinson’s disease and likely differentiating between patients with different progression rates.

The data also showed the test can be used to discriminate Parkinson’s patients from those with MSA and that it has the potential to be an early biomarker of alpha-synucleinopathies, particularly Parkinson’s, in people with RBD years before conversion.

Among the study’s limitations, the researchers noted the low number of MSA patients and the absence of additional CSF samples across follow-up.

“We believe that future efforts should focus on further optimization of the assay” to allow the “widespread clinical implementation of the [alpha-synuclein] RT-QuIC in future,” the team wrote.

They also emphasized that further studies following RBD patients are needed to better understand the relationship between the test’s results and the progression from prodromal, or early, stage of alpha-synucleinopathies to full-blown disease.

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