Evaluation of α-synuclein in CNS-originating Extracellular Vesicles for Parkinsonian Disorders: A Systematic Review and Meta-analysis

Overview

Journal CNS Neurosci Ther

Specialties Neurology
Pharmacology

Date 2023 Jul 7

PMID 37416941

Authors

Hash Brown Taha

Shomik S Ati

Affiliations

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Abstract

Background & Aims: Parkinsonian disorders, such as Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), share early motor symptoms but have distinct pathophysiology. As a result, accurate premortem diagnosis is challenging for neurologists, hindering efforts for disease-modifying therapeutic discovery. Extracellular vesicles (EVs) contain cell-state-specific biomolecules and can cross the blood-brain barrier to the peripheral circulation, providing a unique central nervous system (CNS) insight. This meta-analysis evaluated blood-isolated neuronal and oligodendroglial EVs (nEVs and oEVs) α-synuclein levels in Parkinsonian disorders.

Methods: Following PRISMA guidelines, the meta-analysis included 13 studies. An inverse-variance random-effects model quantified effect size (SMD), QUADAS-2 assessed risk of bias and publication bias was evaluated. Demographic and clinical variables were collected for meta-regression.

Results: The meta-analysis included 1,565 patients with PD, 206 with MSA, 21 with DLB, 172 with PSP, 152 with CBS and 967 healthy controls (HCs). Findings suggest that combined concentrations of nEVs and oEVs α-syn is higher in patients with PD compared to HCs (SMD = 0.21, p = 0.021), while nEVs α-syn is lower in patients with PSP and CBS compared to patients with PD (SMD = -1.04, p = 0.0017) or HCs (SMD = -0.41, p < 0.001). Additionally, α-syn in nEVs and/or oEVs did not significantly differ in patients with PD vs. MSA, contradicting the literature. Meta-regressions show that demographic and clinical factors were not significant predictors of nEVs or oEVs α-syn concentrations.

Conclusion: The results highlight the need for standardized procedures and independent validations in biomarker studies and the development of improved biomarkers for distinguishing Parkinsonian disorders.

Citing Articles

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References

Shi M, Kovac A, Korff A, Cook T, Ginghina C, Bullock K . CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease. Alzheimers Dement. 2016; 12(11):1125-1131. PMC: 5107127. DOI: 10.1016/j.jalz.2016.04.003. View

Poewe W, Seppi K, Tanner C, Halliday G, Brundin P, Volkmann J . Parkinson disease. Nat Rev Dis Primers. 2017; 3:17013. DOI: 10.1038/nrdp.2017.13. View

Dar G, Badierah R, Nathan E, Bhat M, Dar A, Redwan E . Extracellular vesicles: A new paradigm in understanding, diagnosing and treating neurodegenerative disease. Front Aging Neurosci. 2022; 14:967231. PMC: 9669424. DOI: 10.3389/fnagi.2022.967231. View

Zhao Z, Chen Z, Zhou R, Zhang X, Ye Q, Wang Y . Increased DJ-1 and α-Synuclein in Plasma Neural-Derived Exosomes as Potential Markers for Parkinson's Disease. Front Aging Neurosci. 2019; 10:438. PMC: 6339871. DOI: 10.3389/fnagi.2018.00438. View

Waninger S, Berka C, Karic M, Korszen S, Mozley P, Henchcliffe C . Neurophysiological Biomarkers of Parkinson's Disease. J Parkinsons Dis. 2020; 10(2):471-480. PMC: 7242849. DOI: 10.3233/JPD-191844. View

Xia X, Wang Y, Zheng J . Extracellular vesicles, from the pathogenesis to the therapy of neurodegenerative diseases. Transl Neurodegener. 2022; 11(1):53. PMC: 9743667. DOI: 10.1186/s40035-022-00330-0. View

Blommer J, Pitcher T, Mustapic M, Eren E, Yao P, Vreones M . Extracellular vesicle biomarkers for cognitive impairment in Parkinson's disease. Brain. 2022; 146(1):195-208. PMC: 10060702. DOI: 10.1093/brain/awac258. View

McKeith I, Boeve B, Dickson D, Halliday G, Taylor J, Weintraub D . Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017; 89(1):88-100. PMC: 5496518. DOI: 10.1212/WNL.0000000000004058. View

Mavroeidi P, Vetsi M, Dionysopoulou D, Xilouri M . Exosomes in Alpha-Synucleinopathies: Propagators of Pathology or Potential Candidates for Nanotherapeutics?. Biomolecules. 2022; 12(7). PMC: 9313025. DOI: 10.3390/biom12070957. View

10.

Younas N, Fernandez Flores L, Hopfner F, Hoglinger G, Zerr I . A new paradigm for diagnosis of neurodegenerative diseases: peripheral exosomes of brain origin. Transl Neurodegener. 2022; 11(1):28. PMC: 9082915. DOI: 10.1186/s40035-022-00301-5. View

11.

Lacroix R, Judicone C, Poncelet P, Robert S, Arnaud L, Sampol J . Impact of pre-analytical parameters on the measurement of circulating microparticles: towards standardization of protocol. J Thromb Haemost. 2012; 10(3):437-46. DOI: 10.1111/j.1538-7836.2011.04610.x. View

12.

Kuzkina A, Bargar C, Schmitt D, Rossle J, Wang W, Schubert A . Diagnostic value of skin RT-QuIC in Parkinson's disease: a two-laboratory study. NPJ Parkinsons Dis. 2021; 7(1):99. PMC: 8593128. DOI: 10.1038/s41531-021-00242-2. View

13.

Acera A, Gomez-Esteban J, Murueta-Goyena A, Galdos M, Azkargorta M, Elortza F . Potential Tear Biomarkers for the Diagnosis of Parkinson's Disease-A Pilot Study. Proteomes. 2022; 10(1). PMC: 8788479. DOI: 10.3390/proteomes10010004. View

14.

Jayachandran M, Miller V, Heit J, Owen W . Methodology for isolation, identification and characterization of microvesicles in peripheral blood. J Immunol Methods. 2011; 375(1-2):207-14. PMC: 3253871. DOI: 10.1016/j.jim.2011.10.012. View

15.

Wang K, Shen J, Xu Y . An Update on Peripheral Blood Extracellular Vesicles as Biomarkers for Parkinson's Disease Diagnosis. Neuroscience. 2022; 511:131-146. DOI: 10.1016/j.neuroscience.2022.11.017. View

16.

Dutta S, Hornung S, Taha H, Biggs K, Siddique I, Chamoun L . Development of a Novel Electrochemiluminescence ELISA for Quantification of α-Synuclein Phosphorylated at Ser in Biological Samples. ACS Chem Neurosci. 2023; 14(7):1238-1248. PMC: 10080651. DOI: 10.1021/acschemneuro.2c00676. View

17.

Niu M, Li Y, Li G, Zhou L, Luo N, Yao M . A longitudinal study on α-synuclein in plasma neuronal exosomes as a biomarker for Parkinson's disease development and progression. Eur J Neurol. 2020; 27(6):967-974. DOI: 10.1111/ene.14208. View

18.

Tauro B, Greening D, Mathias R, Ji H, Mathivanan S, Scott A . Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. Methods. 2012; 56(2):293-304. DOI: 10.1016/j.ymeth.2012.01.002. View

19.

Taha H, Ati S . Evaluation of α-synuclein in CNS-originating extracellular vesicles for Parkinsonian disorders: A systematic review and meta-analysis. CNS Neurosci Ther. 2023; 29(12):3741-3755. PMC: 10651986. DOI: 10.1111/cns.14341. View

20.

. The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Mov Disord. 2003; 18(7):738-50. DOI: 10.1002/mds.10473. View