Different patterns of exosomal α‐synuclein between Parkinson's disease and probable rapid eye movement sleep behavior disorder

Abstract

Background and purpose The insidious onset of Parkinson's disease (PD) makes early diagnosis difficult. Notably, idiopathic rapid eye movement sleep behavior disorder (iRBD) was reported as a prodrome of PD, which may represent a breakthrough for the early diagnosis of PD. However, currently there is no reliable biomarker for PD diagnosis. Considering that α‐synuclein (α‐Syn) and neuroinflammation are known to develop prior to the onset of clinical symptoms in PD, it was hypothesized that plasma total exosomal α‐Syn (t‐exo α‐Syn), neural‐derived exosomal α‐Syn (n‐exo α‐Syn) and exosomal apoptosis‐associated speck‐like protein containing a caspase activation and recruitment domain (ASC) may be potential biomarkers of PD. Methods In this study, 78 PD patients, 153 probable iRBD patients (pRBD) and 63 healthy controls (HCs) were recruited. α‐Syn concentrations were measured using a one‐step paramagnetic particle‐based chemiluminescence immunoassay, and ASC levels were measured using the Ella system. Results It was found that t‐exo α‐Syn was significantly increased in the PD group compared to the pRBD and HC groups (p < 0.0001), whilst n‐exo α‐Syn levels were significantly increased in both the PD and pRBD groups compared to HCs (p < 0.0001). Furthermore, although no difference was found in ASC levels between the PD and pRBD groups, there was a positive correlation between ASC and α‐Syn in exosomes. Conclusions Our results suggest that both t‐exo α‐Syn and n‐exo α‐Syn were elevated in the PD group, whilst only n‐exo α‐Syn was elevated in the pRBD group. Additionally, the adaptor protein of inflammasome ASC is correlated with α‐Syn and may facilitate synucleinopathy.

ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities

“…Our results also demonstrated that ASC levels positively correlate with α‑synuclein pathology as the disease progresses, accompanied by an increase in the number of ASC specks. This finding was consistent with what we observed when quantifying the levels of these two proteins in plasma exosomes from PD patients [ 61 ], suggesting that ASC protein may be involved in the propagation of inflammasome-involved pathology triggered by PFFs.…”

Diagnostic Accuracy of Biomarkers in CNS-originating Extracellular Vesicles for Parkinsonian Disorders: A meta-analysis

“…Comparison of the hierarchical bivariate SROC (Fig. 4A) obtained from studies using plasma (11,34,35,36,42,43) or serum (26, 27, 28, 38, 39, 40, 41) also suggested that the studies using serum had, on average, slightly better accuracy, though there was a decent overlap in the con dence intervals of both models. It should also be noted that out of the seven studies using serum, three (27,28,39) and two (40,41), respectively, originated from the same research group while all studies from plasma originated from unique research groups, suggesting a potential overlap in methodologies which may in uence the results.…”

“…Thirteen studies have attempted to differentiate patients with PD from HCs using biomarkers in nEVs (11,26,27,28,34,35,36,38,39,40,41,42,43) and/or oEVs (40,41). The AUC ranged between 0.61-0.89 with the highest AUC obtained in 2021 by Jiang et al (27), while the sensitivity (Fig.…”

“…However, there was a lack of clear reporting on the sampling method, which made the assessment of the risk of bias in patient selection unclear. One study excluded participants from their analysis and was deemed to have a high risk of bias (42). The measurement of biomarkers in nEVs and oEVs was considered to have a low risk of bias in the index test domain, as it is an objective measure unaffected by prior knowledge of the clinical status.…”

“…Three studies evaluated biomarkers in nEVs in attempt to differentiate patients with RBD vs. HCs (28, 39,42) and are analyzed using a univariate approach. The forest plots for sensitivity, speci city, DOR, posLR and negLR are shown in Figs.…”