Parkinson’s disease is characterized by the spread and aggregation of misfolded α-synuclein, toxic to neurons and the cause of motor neuron loss. A misfolded molecule of α-synuclein encourages other α-synuclein molecules to also misfold in the same way, and the dysfunction spreads slowly from neuron to neuron. When present in a neuron, misfolded α-synuclein will appear inside the extracellular vesicles, such as exosomes, secreted by that cell. Some of these vesicles enter the circulatory system, where they can be detected in a blood sample.
The possibility to detect misfolded α-synuclein (α-syn) in different tissues and body fluids is currently revolutionizing the diagnosis of Parkinson’s disease (PD) and it is hoped that a more secure and much earlier diagnosis will soon be possible. In this context one of the most promising advances is the use of α-syn seed amplification assays (SAA), utilizing the seeding activity of pathological α-syn conformers to introduce aggregation of recombinant α-syn.
We recently demonstrated that a SAA for the detection of pathological α-syn in neuronal-derived extracellular vesicles (NEs) purified from blood, distinguishes PD patients from healthy controls with high sensitivity. This study set out to 1) confirm the previously reported high sensitivity of this blood-based SAA in a larger cohort of individuals with PD and 2) additionally explore changes of α-synuclein seeding in blood in the course of PD.
In the cross-sectional dataset, 79 of 80 PD patients (mean age 69 years; 56% male) and none of the healthy controls (n = 20, mean age 70 years; 55% male) showed seeding activity (sensitivity 98.8%). When comparing subgroups divided by disease duration, longer disease duration was associated with lower α-synuclein seeding activity. In the longitudinal analysis 10/11 patients showed a gradual decrease of α-synuclein seeding activity over time. This study cannot explain the pathophysiological processes behind this observed decrease. However, it can be hypothesized that spreading of α-syn is more pronounced in the early stages of the disease.
