Refined Test Improves Parkinson’s Disease Diagnosis

Synucleinopathies are a group of neurodegenerative diseases, including Parkinson’s disease and dementia with Lewy bodies, characterized by the accumulation of misfolded alpha-synuclein proteins in the brain and spinal cord. These proteins, when misfolded, interact with properly folded alpha-synuclein, causing them to misfold as well. The misfolded proteins then aggregate and form fibrils, which spread to neighboring neurons, similar to how a virus infects other cells. The spread of these fibrils continues to cause further damage, and the process becomes self-perpetuating. Due to the similarity of symptoms to other neurodegenerative disorders and the lack of reliable biomarkers, synucleinopathies are often diagnosed late or misdiagnosed. While it's simple to use a swab to measure a virus in a patient’s nose, no similar method exists for testing the brain for protein aggregates.

A research team, including a scientist from RIKEN (Saitama, Japan), has developed a refined lab test that measures protein aggregate levels in samples from patients with neurodegenerative diseases. This advancement could enhance diagnostic accuracy and aid drug development for these conditions. Seed amplification assays, which are emerging as promising tools for diagnosing these diseases, can detect protein aggregates not only from post-mortem brain tissue but also from less invasive sources, such as skin scrapings or deep nasal swabs from living patients with synucleopathies. These assays can help determine the presence of aggregating fibrils, and more advanced versions can quantify the level of aggregation.

These more sophisticated assays involve preparing serial dilutions of a patient’s sample and running multiple replicate reactions at each dilution to determine the point at which half of the wells show signs of aggregation. A higher concentration of aggregating seeds is indicated by a greater dilution required to stop the aggregation process. This method is similar to assays used to count infectious viruses. The research team has improved the seed amplification assay by refining the dilution factor, increasing the number of replicates per dilution, and selecting an optimal algorithm to estimate the seed concentration. Their work has led to significant improvements in the reproducibility and quantitative accuracy of the assay.

“Our study highlights how assay design can markedly improve the measurement of disease-related alpha-synuclein aggregates across a variety of clinically relevant samples,” said Catherine Beauchemin of the RIKEN Center for Interdisciplinary Theoretical and Mathematical Sciences. “This should enable more precise evaluation of seeding activity to support important clinical and research applications.”

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