Identification of exosomal biomarkers and its optimal isolation and detection method for the diagnosis of Parkinson's disease: A systematic review and meta-analysis

Nila, Irin Sultana; Sumsuzzman, Dewan Md.; Khan, Zeeshan Ahmad; Jung, Jin Ho; Kazema, Ashura Suleiman; Kim, Sang Jin; Hong, Yonggeun

doi:10.1016/j.arr.2022.101764

Cited by 29 publications

(52 citation statements)

References 97 publications

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“…Two recent meta-analyses evaluated the levels of "exosomal" α-syn in patients with PD (35,50). Nila et al (35) suggest that α-syn is increased in patients with PD compared to HCs; however, as seen in their Fig. 2., the effect is driven by a single study (6), which is the only study that evaluated α-syn in EVs isolated from saliva.…”

Section: Discussionmentioning

confidence: 98%

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

Taha

Ati²

2023

Preprint

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Parkinsonian disorders, including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS), present shared early motor symptoms but have distinct cellular and regional pathophysiology, making accurate premortem diagnosis challenging. Extracellular vesicles (EVs) provide a unique central nervous system (CNS) insight, as they contain cell-state-specific biomolecules and can cross the blood-brain barrier to the peripheral circulation. Measuring biomarkers in blood CNS-originating EVs, specifically neuronal and oligodendroglial EVs (nEVs and oEVs), has become a promising avenue for minimally invasive diagnostics. This meta-analysis aimed to evaluate the potential of blood-isolated nEVs and oEVs α-synuclein (α-syn) proteoforms in parkinsonian disorders. Thirteen studies were included, with a total of 1,565 PD, 206 MSA, 21 DLB, 172 PSP, 152 CBS patients, and 967 healthy controls (HCs). An inverse-variance random-effects model was used to quantify effect size (SMD), while QUADAS-2 assessed the risk of bias. Begg’s rank correlation and Egger’s regression tests evaluated publication bias. The findings suggest that a combination of nEVs and oEVs α-syn concentrations are higher in patients with PD compared to HCs (SMD = 0.21; p = 0.021). Interestingly, nEVs α-syn was lower in patients with PSP and CBS when compared to PD patients (SMD = -1.04; p = 0.0017) or HCs (SMD = -0.41, p < 0.001). Contrary to existing literature, α-syn levels in oEVs did not effectively differ among PD, MSA, or HCs. Meta-regressions revealed that demographic and clinical factors were not significant predictors of nEVs or oEVs α-syn concentrations. These findings emphasize the need for adopting more rigorous, standardized procedures and independent validations across all laboratories studying biomarkers in CNS-originating EVs. Furthermore, there is a pressing need for improved biomarkers to better distinguish between parkinsonian disorders.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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

Taha

Ati²

2023

Preprint

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“…To date, there is only one additional study presenting a similar meta‐analysis, 105 but we used different exclusion criteria. Most studies on biomarker discovery focus on aSyn, which clearly plays a major role in PD pathogenesis 106 .…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles for the Diagnosis of Parkinson's Disease: Systematic Review and Meta‐Analysis

Xylaki¹,

Chopra²,

Weber³

et al. 2023

Movement Disorders

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Parkinson's disease (PD) biomarkers are needed by both clinicians and researchers (for diagnosis, identifying study populations, and monitoring therapeutic response). Imaging, genetic, and biochemical biomarkers have been widely studied. In recent years, extracellular vesicles (EVs) have become a promising material for biomarker development. Proteins and molecular material from any organ, including the central nervous system, can be packed into EVs and transported to the periphery into easily obtainable biological specimens like blood, urine, and saliva. We performed a systematic review and meta‐analysis of articles (published before November 15, 2022) reporting biomarker assessment in EVs in PD patients and healthy controls (HCs). Biomarkers were analyzed using random effects meta‐analysis and the calculated standardized mean difference (Std.MD). Several proteins and ribonucleic acids have been identified in EVs in PD patients, but only α‐synuclein (aSyn) and leucine‐rich repeat kinase 2 (LRRK2) were reported in sufficient studies (n = 24 and 6, respectively) to perform a meta‐analysis. EV aSyn was significantly increased in neuronal L1 cell adhesion molecule (L1CAM)–positive blood EVs in PD patients compared to HCs (Std.MD = 1.84, 95% confidence interval = 0.76–2.93, P = 0.0009). Further analysis of the biological sample and EV isolation method indicated that L1CAM‐IP (immunoprecipitation) directly from plasma was the best isolation method for assessing aSyn in PD patients. Upcoming neuroprotective clinical trials immediately need peripheral biomarkers for identifying individuals at risk of developing PD. Overall, the improved sensitivity of assays means they can identify biomarkers in blood that reflect changes in the brain. CNS‐derived EVs in blood will likely play a major role in biomarker development in the coming years. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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“…The lack of standardized protocols for exosomal analysis and biomarker validation poses a significant obstacle to the translation of exosome-based diagnostics and therapeutics into clinical applications. [33][34][35] The variability in isolation and characterization methods, as well as the absence of well-defined reference materials, hinders the reproducibility and reliability of the results. Establishing guidelines for experimental procedures, data analysis, and reporting will improve the rigor and robustness of exosome-related studies.…”

Section: Standardization Of Exosomal Analysis and Biomarker Validationmentioning

confidence: 99%

Exosomes: emerging biomarkers unveiling cellular mysteries—a narrative review

Umeche,

Olaniyan

2023

J Bio-X Res

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Exosomes have gained recognition as potential diagnostic and prognostic markers due to their stability and disease-specific cargos. Exosomes, once dismissed as cellular debris, are now acknowledged as crucial mediators of intercellular communications and disease. These nanosized vesicles transport dynamic cargos consisting of bioactive molecules, including proteins, lipids, and nucleic acids, enabling cells to exchange information and influence each other’s behavior. This review delves into the multifaceted roles of exosomes, particularly their emergence as biomarkers for various diseases. To conduct research for this review, a comprehensive literature search strategy was employed across various databases using keywords related to exosomes, biomarkers, cellular communication, disease diagnosis, and more. Selected articles were evaluated based on their relevance, and data were extracted, synthesized, and categorized according to thematic content. Quality assessment was performed on different types of articles, ensuring robust findings. In cancer, exosomes act as liquid biopsy samples, revealing genetic mutations, and protein markers. The misfolded proteins characteristic of neurodegenerative diseases such as Alzheimer disease and Parkinson disease are carried by exosomes. Moreover, exosomes have been studied as biomarkers for cardiovascular, infectious, and autoimmune diseases. In addition to their functions as biomarkers, exosomes influence the tumor microenvironment, immune response, synaptic plasticity, and tissue regeneration. Challenges remain to fill research gaps and standardize exosome analyses. Exosomes are pivotal in intercellular communication and for disease diagnosis, offering insights into cellular processes, immunity, and regeneration. Future research may reshape our understanding of cellular communication and drive therapeutic interventions. Although challenges must be addressed, exosomes hold undeniable potential for use in personalized medicine and biomedical research.

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Identification of exosomal biomarkers and its optimal isolation and detection method for the diagnosis of Parkinson's disease: A systematic review and meta-analysis

Cited by 29 publications

References 97 publications

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

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

Extracellular Vesicles for the Diagnosis of Parkinson's Disease: Systematic Review and Meta‐Analysis

Exosomes: emerging biomarkers unveiling cellular mysteries—a narrative review

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