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New Study Identifies Promising Blood Biomarker for Early Detection of Parkinson’s Disease

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Researchers have identified a promising new blood biomarker that could help in the early detection of Parkinson’s disease (PD) and related dementias – a breakthrough that could significantly improve early diagnosis and intervention. An international team led by Shijun Yan and colleagues did the study, which was published in JAMA Neurology. It looks at how α-synuclein levels in neuronally derived extracellular vesicles (L1EVs) in the serum might help find people who are very likely to get Parkinson’s disease.

Parkinson’s disease is a progressive neurodegenerative disorder that exhibits motor symptoms like tremors, rigidity, and bradykinesia. Non-motor symptoms like rapid eye movement (REM), sleep behaviour disorder (iRBD), hyposmia (a reduced sense of smell), and other prodromal markers that can appear decades before the clinical onset of the disease frequently precede these symptoms. Currently, there is no reliable blood test to identify individuals in this prodromal phase, making early intervention challenging.

Dr George Tofaris, professor of neurology and translational neuroscience at the University of Oxford, said: “The pathology of Parkinson’s disease starts decades before patients present to the clinic with the typical motor symptoms. At present, we do not have a way to identify those at risk before the irreversible stage of the disease starts. Our motivation was to develop a biomarker that could fill this gap. This is urgently needed for the design of preventative clinical trials and eventually the instigation of disease-modifying therapies when they become available.”

The retrospective cross-sectional study looked at serum samples from 576 people in the Oxford Discovery, Marburg, Cologne, and Parkinson’s Progression Markers Initiative (PPMI) cohorts, among others. Participants were recruited between July 2013 and August 2023, and the serum samples were analysed between April 2022 and September 2023. The study had three groups: a derivation group and two validation groups. The derivation group had people with iRBD, the validation groups had people with hyposmia, and the third group had healthy controls.

The main thing that was used to measure the outcome was the amount of α-synuclein in L1EVs, which was taken from serum and measured using electrochemiluminescence. The biomarker’s ability to tell the difference between people who were at risk and people who were not was tested using the area under the receiver operating characteristic (ROC) curve (AUC).

The study discovered that people with iRBD and other early signs of the disease had significantly higher levels of serum L1EV α-synuclein compared to healthy controls. A derived threshold of 17.75 pg/mL was established, which distinguished participants with a high probability of having prodromal PD from those with minimal risk. The AUC for differentiating participants with iRBD from controls was 0.91 (95% CI, 0.86-0.96), indicating high sensitivity and specificity. Furthermore, in the second validation group, the biomarker correctly identified 80% of individuals who later phenoconverted to PD or related dementia.

Professor Tofaris highlighted the key findings and implications of the study: “In the first study of its kind, we studied 365 at-risk individuals from four clinical cohorts (Oxford Discovery, Marburg, Cologne, and the US-based Parkinson’s Progression Markers Initiative), 282 healthy controls, and 71 people with genetic or sporadic Parkinson’s disease. We found that those with the highest risk of developing Parkinson’s (more than 80% probability based on research criteria) had a two-fold increase in alpha-synuclein levels in neuronal extracellular vesicles and the test could accurately differentiate them from those with low risk (less than 5% probability) or healthy controls. Overall, the test could distinguish an individual with a high risk of developing Parkinson’s from a healthy control with a 90% probability.”

The research also showed that the amount of L1EV α-synuclein was related to the level of α-synuclein in cerebrospinal fluid (CSF), which is a sign of PD pathology. People with positive CSF α-synuclein SAA had higher levels of L1EV α-synuclein. This suggests that the biomarker could be used as an early warning sign of neuronal α-synucleinopathy.

In further analysis, Professor Tofaris noted: “The test could also identify those who had evidence of neurodegeneration detected by imaging, or pathology detected by a spinal fluid assay, but had not yet developed a movement disorder or dementia.”

These findings suggest that serum L1EV α-synuclein could be used as a screening test for Parkinson’s disease in at-risk individuals, potentially allowing for earlier diagnosis and intervention. The study’s authors emphasise the need for further validation in longitudinal cohorts to confirm the biomarker’s utility in predicting PD progression.

Professor Tofaris also shared the future plans for the research: “We are further validating the biomarker in longitudinal cohorts and also developing the platforms to facilitate the application of the biomarker assay at scale.”

The results provide strong evidence that L1EV α-synuclein is a robust biomarker for identifying individuals at high risk of developing Parkinson’s disease. This could pave the way for early therapeutic strategies aimed at slowing or preventing disease progression.

The study’s limitations include its cross-sectional design and the need for neuropathological confirmation of the cases. However, the consistent findings across diverse cohorts underscore the biomarker’s potential clinical utility.

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