Extracellular Vesicles Prove Potential Value as α-Synuclein Biomarker in Parkinson Disease

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The data suggest that central nervous system-derived extracellular vesicles in the blood will likely play a key role in biomarker development, especially for patients with Parkinson disease, in the coming years.

Mary Xylaki, PhD, a postdoctoral researcher in the department of neurology at the University Medical Center Goettingen, in Goettingen, Germany

Mary Xylaki, PhD

In a recently published systematic review and meta-analysis in Movement Disorders, findings showed extracellular vesicles (EVs) of α-synuclein (α-Syn) significantly increased in neuronal L1 cell adhesion molecule (L1CAM)-positive blood EVs among patients with Parkinson disease (PD) compared with healthy controls (HCs). These results suggest that L1CAM-immunoprecipitation (IP) directly from plasma could potentially be the most effective isolation method for assessing α-Syn in patients with PD, which could aid clinicians in diagnosing the movement disorder.1

All told, many proteins and ribonucleic acids were identified in EVs among patients with PD yet only α-Syn and LRRK2 were reported in sufficient studies (n = 24 and 6, respectively) to conduct this meta-analysis. The total α-Syn in all included studies (n = 62) showed a nonsignificant increase in PD (standardized mean difference [Std.MD], 1.02; 95% CI, 0.23–1.82; P = .01). Notably, total EVs isolated from blood samples did not show any change between patients with PD and HCs (Std.MD, 0.26; 0.95% CI, −1.65–2.16; P = .79), whereas neuronal L1CAM-positive EVs showed a significant increase in the PD group (Std.MD, 1.84; 95% CI, 0.76–2.93; P = .0009).

“Our meta-analysis indicated that total α-Syn in neuronal L1CAM-positive EVs isolated from blood plasma using IP is a promising biomarker. In addition, interesting results were found for oligomeric α-Syn isolated from EVs irrespective of their origin and isolation method. Finally, although some studies assess LRRK2 levels in urinal EVs, the meta-analysis failed to identify a significant change between PD and HC,” lead author Mary Xylaki, PhD, a postdoctoral researcher in the department of neurology at the University Medical Center Goettingen, in Goettingen, Germany, and colleagues wrote.1

Clinical Takeaways

  1. Neuronal blood extracellular vesicles containing α-synuclein (α-Syn) could be a promising diagnostic tool for Parkinson disease (PD).
  2. The diagnostic potential of extracellular vesicles (EVs) is particularly notable in blood plasma, especially when using L1CAM-immunoprecipitation to isolate α-synuclein.
  3. Oligomeric α-Syn, a toxic form of the protein, may serve as a more robust biomarker for PD, offering insights into the disease's progression and mechanisms.

The investigators conducted a systematic review and meta-analysis of articles that recorded biomarker assessment in EVs among patients with PD and HCs. The literature search utilized PubMed, Web of Science, and Google Scholar databases to gather studies published between published between 2014 and 2022. The keywords in the search included “Parkinson's disease,” “exosomes,” “biomarker,” and “diagnosis,” which were also used in different combinations. Researchers only used studies that presented EV isolation from biological specimens and dysregulation of EV composition and contents. The biomarkers were assessed using random effects meta-analysis and the calculated Std.MD.

READ MORE: First-In-Human Trial of Nurr1 Activator HL192 in Parkinson Disease Initiated

“The majority of studies assess EV α-Syn in plasma and serum, whereas only a few assessed urine, cerebrospinal fluid, and saliva EVs. We could compare only plasma and serum as EV sources. More studies are needed to assess the diagnostic potential of EVs from other fluids. We show that plasma EVs have a higher and significant increase in α-Syn in PD compared with HC versus a smaller nonsignificant change that was found in serum EVs. The main difference between plasma and serum is clot formation. Different coagulants are used to prevent clotting in the case of plasma,” Xylaki et al noted.1

When the authors in this study filtered based on the biological specimen, significance only showed for the neuronal EVs isolated from plasma (Std.MD, 2.48; 95% CI, 0.57–4.41; P = .01) and not from serum (Std.MD, 0.97; 95% CI, −0.08–2.02; P = .07). In additional analysis of the EV isolation method, authors noted the observed effects were mostly attributed to studies that conducted direct IP from the plasma sample (Std.MD, 3.08; 95% CI, 1.33–4.82; P = .00001) instead of combining IP after another type of isolation method (Std.MD, 0.39; 95% CI, −0.08 to 0.85; P = .0003).

The authors noted that meta-analysis of LRRK2 showed no change in total LRRK2 among PD patients and HCs in urinal EVs (Std.MD, −0.11; 95% CI, −0.45 to 0.24; P = .54) and no change in phosphorylated Ser1292 LRRK2 (Std.MD, 0.07; 95% CI, −0.88 to 1.01; P = .89). For added context, PD patients and HCs with and without the LRRK2 mutation were pooled in this meta-analysis as only 2 of 3 studies reported on these groups separately. In these 2 studies, LRRK2 levels had differed in mutant and nonmutant carriers in both groups with higher levels of LRRK2 and phosphorylated Ser1292 LRRK2 detected in urinal EVs of the mutant carriers. Additionally, the meta-analysis of oligomeric α-Syn levels had significantly higher levels in patients with PD compared with HCs (Std.MD, 3.36; 95% CI, 1.69–5.58; P = .0003). The authors noted that this finding suggests that oligomeric aSyn might be a more robust biomarker as it is the most toxic form and is also implicated in disease propagation.2,3

“Although several biomarkers are reported in the literature, there are not sufficient studies to perform a meta-analysis for most of them. In short, α-Syn remains interesting for PD diagnosis and also in EV studies that showed a higher α-Syn concentration in neuronal blood EVs isolated using IP from plasma. Very few studies performed exploratory analysis, only 6 studies assessed EV protein contents using mass spectrometry, and only 8 studies assessed RNA contents using next-generation sequencing. Identifying novel targets is important for diagnosis and mechanistic studies as the EV cargo reflects the content of the cell of origin and can shed light on overseen mechanisms,” Xylaki et al noted.1

REFERENCES
1. Xylaki M, Chopra A, Weber S, Bartl M, Outeiro TF, Mollenhauer B. Extracellular Vesicles for the Diagnosis of Parkinson's Disease: Systematic Review and Meta-Analysis. Mov Disord. 2023;38(9):1585-1597. doi:10.1002/mds.29497
2. Danzer KM, Kranich LR, Ruf WP, et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener. 2012;7:42. Published 2012 Aug 24. doi:10.1186/1750-1326-7-42
3. Danzer KM, Krebs SK, Wolff M, Birk G, Hengerer B. Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alpha-synuclein pathology. J Neurochem. 2009;111(1):192-203. doi:10.1111/j.1471-4159.2009.06324.x
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