Objective Parkinson’s disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson’s from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson’s disease, multiple system atrophy and other proteinopathies.
Methods We performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson’s and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins.
Results Mean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson’s disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson’s disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson’s disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson’s disease progression.
Conclusions Increased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson’s disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson’s disease from atypical parkinsonism.
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Contributors CJ, FH, AK, RH, CC, HW and JWR collected, analysed and interpreted data. GKT, YH and JJD analysed and interpreted data. FH, SE, AP, GK, GD, DB, BB, MTH and GKT characterised patients and collected specimens. CJ and GKT wrote the manuscript and prepared figures with input from all authors. GKT designed and supervised the study.
Funding The work was funded by EPSRC (EP/M006204/1), the Weston Foundation, a Wellcome Trust Intermediate Clinical Fellowship (097479/Z/11/Z), the Wellcome Beit Prize (097479/Z/11/A) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre to GKT. FH was supported by the Thiemann foundation. The Oxford Discovery cohort is funded by the Monument Trust Discovery Award from Parkinson’s UK and supported by the NIHR Oxford Biomedical Research Centre, the NIHR Clinical Research Network and the Dementias and Neurodegenerative Diseases Research Network (DeNDRoN).
Disclaimer The opinion expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies.
Competing interests HW and JR are employees of Eli Lilly and Company.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplementary information. Anonymised individual participant data and the study protocol will be shared with qualified parties on request to the corresponding author.