Health UK (Commonwealth Union) – Research conducted at Oxford’s Nuffield Department of Clinical Neurosciences has resulted in the creation of a novel blood-based test designed to detect the underlying pathology that initiates Parkinson’s disease before its primary symptoms manifest. This breakthrough offers the potential for clinicians to screen individuals at a heightened risk of developing the disease, enabling the timely implementation of precision therapies currently undergoing clinical trials.
Parkinson’s disease, the second most prevalent neurodegenerative disorder affecting seven million individuals globally, is projected to double its cases by 2040. A significant challenge in conducting clinical trials for disease modification lies in identifying patients at the earliest stages of disease development (pathogenesis) and excluding other conditions with similar symptoms (mimics).
The onset of Parkinson’s disease occurs over ten years before patients exhibit symptoms, as their brain cells struggle to manage a small protein called alpha-synuclein. This leads to the formation of abnormal clumps of alpha-synuclein, damaging vulnerable nerve cells and causing the recognizable movement disorder and often dementia. By the time Parkinson’s disease is diagnosed, a majority of these vulnerable nerve cells have already perished, and alpha-synuclein clumps have formed in various brain regions.
Predicting impairment in the pathways that handle alpha-synuclein before the onset of Parkinson’s symptoms would be invaluable. This prediction could aid clinicians in identifying individuals most likely to benefit from forthcoming disease-modifying therapies.
Published in JAMA Neurology, a study led by Shijun Yan and colleagues in the Tofaris lab demonstrates the potential of measuring a subtype of extracellular vesicles to identify alpha-synuclein changes in individuals likely to develop Parkinson’s disease. Extracellular vesicles, nanoparticles released by all cell types circulating in biofluids, including blood, transport molecular signals between cells.
Utilizing an improved antibody-based assay developed by the research group, the test involves isolating extracellular vesicles originating from nerve cells in blood and measuring their alpha-synuclein content. Professor George Tofaris emphasizes the importance of a robust assay, given that neuronally-derived extracellular vesicles constitute less than 10% of all circulating vesicles, and approximately 99% of alpha-synuclein in blood is released from peripheral cells, primarily red blood cells.
In the first study of its kind, the team examined 365 at-risk individuals from four clinical cohorts, 282 healthy controls, and 71 individuals with genetic or sporadic Parkinson’s disease. Those at the highest risk of developing Parkinson’s (over 80% probability based on research criteria) showed a two-fold increase in alpha-synuclein levels in neuronal extracellular vesicles. The test accurately differentiated 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 90% probability.
These findings suggest that the blood test, coupled with a limited clinical assessment, could be employed to screen and identify individuals at high risk of developing the disease. In further analysis, the test could also identify individuals showing evidence of neurodegeneration through imaging or pathology through a spinal fluid assay, even if they had not yet developed a movement disorder or dementia.
The Tofaris laboratory, situated within the Nuffield Department of Clinical Neurosciences and affiliated with the Kavli Institute for Nanoscience Discovery, has previously elucidated the pathway responsible for targeting alpha-synuclein for degradation within nerve cells. This same pathway may also guide alpha-synuclein to be released outside cells within extracellular vesicles, particularly in conditions characterized by inefficient intracellular protein turnover, such as aging and Parkinson’s disease.
“Collectively our studies demonstrate how fundamental investigations in alpha-synuclein biology can be translated into a biomarker for clinical application, in this case for the identification and stratification of Parkinson’s risk. A screening test that could be implemented at scale to identify the disease process early is imperative for the eventual instigation of targeted therapies as is currently done with screening programmes for common types of cancer,” explained Professor Tofaris.
