Serum neuronal exosomes predict and differentiate Parkinson’s disease from atypical parkinsonism

Abstract

ObjectiveParkinson’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.MethodsWe 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.ResultsMean 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.ConclusionsIncreased 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.

Downregulation of exosomal miR‑1273a increases cisplatin resistance of non‑small cell lung cancer by upregulating the expression of syndecan binding protein

“…Numerous studies have confirmed that exosomal miRNAs may be used as biomarkers for early cancer detection and monitoring compared with traditional blood-based cancer markers (37)(38)(39). The present study also demonstrated a significant reduction in exosomal miR-1273a in the plasma of patients who were not sensitive to platinum-based chemotherapy.…”

Immune profiling of plasma-derived extracellular vesicles identifies Parkinson disease

“…26 The combination of multiple markers improved the diagnostic accuracy of neuronal-derived exosomes as shown by a recent work on quantification of both αSyn and clusterin differentiating PD from other proteinopathies and from MSA with high accuracy (AUC 0.98 and 0.94, respectively). 27 This analysis of multiple immune surface markers of circulating EVs in PD and AP shows a high diagnostic performance, likely due to the advantage of simultaneously profiling several EV subpopulations. First of all, we demonstrated that plasma EV concentration was higher in patients with PD.…”

Extracellular Vesicles as Nanotherapeutics for Parkinson’s Disease

“…EV-associated α-Syn has been detected in saliva, plasma, CSF, and serum from PD patients. Although sometimes its levels were found controversial in different reports, it is possible to envisage the use of EV-α-Syn as a valid PD biomarker in the near future [161][162][163][164][165][166][167][168][169][170][171].…”

“…Also, the presence of DJ-1 inside EVs has been analyzed in urine and plasma samples from PD patients. EV-DJ-1 levels are higher in PD subjects compared to controls, even if further studies need to confirm its validity as a novel PD biomarker [164,175,176]. Another interesting finding about EV-based biomarkers can be ascribed to the presence of cellular prion protein (PrPC) in EVs derived from PD patient plasma samples [177].…”