α‐Synuclein in Plasma‐Derived Extracellular Vesicles Is a Potential Biomarker of Parkinson's Disease

Abstract

A BS TRACT: Background: Extracellular vesicles are small vesicles that are released from many cells, including neurons. α-Synuclein has recently been described in extracellular vesicles derived from the central nervous system and may contribute to the spreading of disease pathology in α-synuclein-related neurodegeneration. Objectives: We aimed to examine the potential diagnostic value of α-synuclein in plasma extracellular vesicles from patients with Parkinson's disease (PD). Methods: Preanalytical variables were studied to establish an optimized assay for preparation of plasma extracellular vesicles and detection of extracellular vesicle-derived α-synuclein. Plasma samples were obtained from 2 independent cohorts. The Tübingen cohort contained 96 patients with PD, 50 patients with dementia with Lewy bodies, 50 patients with progressive supranuclear palsy (PSP), and 42 healthy controls; the Kassel cohort included 47 patients with PD, 43 patients with dementia with Lewy bodies, and 36 controls with secondary parkinsonian syndromes. Extracellular vesicles were prepared from total plasma by size exclusion chromatography and quantified by nanoparticle tracking analysis, α-synuclein content was measured by an electrochemiluminescence assay. Results: α-Synuclein concentration in plasma extracellular vesicles provided the best discrimination between PD, dementia with Lewy bodies, PSP, and healthy controls, with an area under the curve of 0.804 (PD vs dementia with Lewy bodies), 0.815 (PD vs. PSP), and 0.769 (PD vs healthy controls) in the Tübingen cohort. Results were validated in the Kassel cohort. Conclusions: The concentration of α-synuclein in plasma extracellular vesicles may serve as a potential diagnostic biomarker for PD.

Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson’s disease and other synucleinopathies

“…They also reported a significant but weak correlation between exosomal aSyn levels and disease severity 59 . Several other studies also showed increased levels of EV-associated aSyn in plasma and serum of PD patients 175 – 180 . In contrast, Si et al reported decreased levels of serum EV-derived aSyn in PD patients 181 .…”

“…The availability of different protocols to isolate EVs from biological fluids (CSF, plasma, urine, and saliva) prompted studies to evaluate their potential as diagnostic biomarkers for PD and other NDDs. Several studies have reported changes in aSyn levels in CSF 174 , plasma/serum 59 , 175 – 181 , and salivary exosomes in PD and synucleinopathy patients 182 . Other studies reported that exosomal aSyn species can seed aSyn aggregation in vitro and pathology formation and spreading in vivo.…”

Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies

“…An important side-benefit of CNS-derived exosomes, if they are indeed bona fide mediators of disease, is their potential for use as biomarkers. Analyses of plasma CNS-derived exosomes from PD patients and healthy controls reveal correlations between the amount of exosomal asyn with PD diagnoses and severity ( 50 – 52 ). In another study, the ratio of multimeric and phosphorylated asyn species to total asyn was higher in PD patients' plasma exosomes when compared to healthy controls ( 53 ).…”

Extracellular Vesicles Derived From Plasma of Patients With Neurodegenerative Disease Have Common Transcriptomic Profiling

“…However, due to the invasiveness and risk on CSF collection, plasma-derived EVs are being studied. For instance, it has been proved that EVs are potential carriers of misfolded toxic proteins, such as amyloid-beta (Aβ) peptide and tau in AD (Saman et al, 2012 ; Rajendran et al, 2014 ; Ghidoni et al, 2018 ), α-synuclein in PD (Stuendl et al, 2021 ), and TDP-43 in ALS and FTD (Iguchi et al, 2016 ; Sproviero et al, 2018 , 2019 ). Increased levels of t-tau, p-tau, and Aβ42 in plasma/serum neurally derived blood exosomes were demonstrated to be an early biomarker for AD and cognitive decline progression (Fiandaca et al, 2015 ).…”