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      Differential Diagnosis of Multiple System Atrophy-Parkinsonism and Parkinson's Disease Using α-Synuclein and External Anal Sphincter Electromyography

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          Abstract

          Background and aim: Discriminating multiple system atrophy-parkinsonism (MSA-P) from Parkinson's disease (PD) is challenging. We aimed to provide a new method to make an identification between MSA-P and PD by combining biofluid marker with electrophysiology marker.

          Methods: The XYCQ EV Enrichment KIT was applied to extract extracellular vesicles (EVs) from saliva. The levels of α-syn which included total α-syn (α- syn Total), phosphorylated-ser129 α-syn (α-syn PS129) and oligomeric α-syn (α-syn Olig) in EVs of saliva were tested by new developed Electrochemiluminescence (ECL) assays. We collected multi-motor unit potential (MUP) of all participants who conducted external anal sphincter electromyography (EAS-EMG). The duration, phase, amplitude and satellite potential of EAS-EMG were analyzed. The Receiver operator characteristic (ROC) curve was adopted to analyze the diagnostic utility of α-syn in EVs of saliva, EAS-EMG for MSA-P.

          Results: In EVs of saliva, the α-syn Total concentrations were lower in MSA-P than PD ( P = 0.003). No significant difference was shown in α-syn Olig and α-syn PS129. α-syn Total 4.46 pg/ng distinguished MSA-P from PD with area under the curve (AUC) 0.804. Compared with PD, the duration, phase and satellite potential of EAS-EMG in MSA-P were increased ( P = 0.002, 0.008, 0.001). There was no significant difference in amplitude. ROC curve showed that the duration (AUC: 0.780), phase (AUC: 0.751), and satellite potential (AUC: 0.809) had both diagnostic value for MSA-P. The combination of α-syn Total in salivary EVs and EAS-EMG (including duration, phase and satellite potential) could efficiently make a differentiation between MSA-P and PD with sensitivity of 100% and specificity of 86%. The AUC value was 0.901.

          Conclusion: The study suggested the combination of α-syn Total in salivary EVs and EAS-EMG could help efficiently distinguish MSA-P from PD.

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          Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson's disease.

          Omar M. A. El-Agnaf, Sultan A. Salem, Katerina E. Paleologou … (2006)
          To date there is no accepted clinical diagnostic test for Parkinson's disease (PD) based on biochemical analysis of blood or cerebrospinal fluid (CSF). alpha-Synuclein (alpha-syn) protein has been linked to the pathogenesis of PD with the discovery of mutations in the gene encoding alpha-syn in familial cases with early-onset PD. Lewy bodies and Lewy neurites, which constitute the main pathological features in the brains of patients with sporadic PD and dementia with Lewy bodies, are formed by the conversion of soluble monomers of alpha-syn into insoluble aggregates. We recently reported the presence of alpha-syn in normal human blood plasma and in postmortem CSF. Here, we investigated whether alpha-syn can be used as a biomarker for PD. We have developed a novel ELISA method that detects only oligomeric "soluble aggregates" of alpha-syn. Using this ELISA, we report the presence of significantly elevated (P=0.002) levels of oligomeric forms of alpha-syn in plasma samples obtained from 34 PD patients compared with 27 controls; 52% (95% confidence intervals 0.353-0.687) of the PD patients displayed signals >0.5 OD with our ELISA assay in comparison to only 14.8% (95% confidence intervals 0.014-0.281) for the control cases. An analysis of the test's diagnostic value revealed a specificity of 0.852 (95% confidence intervals 0.662-0.958), sensitivity of 0.529 (95% confidence intervals 0.351-0.702) and a positive predictive value of 0.818 (95% confidence intervals 0.597-0.948). These observations offer new opportunities for developing diagnostic tests for PD and related diseases and for testing therapeutic agents aimed at preventing or reversing the aggregation of alpha-syn.
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            Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression.

            Douglas Galasko, Elaine R. Peskind, J Bradner … (2011)
            There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of Parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ-1 and/or α-synuclein in the cerebrospinal fluid (CSF) is a potential index for Parkinson disease diagnosis, but not for PD severity. Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1-42 (Aβ(1-42)), Flt3 ligand, and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these 5 markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ-1 and α-synuclein. The major results were further validated in an independent cohort of cross-sectional PD patients as well as in PD cases with CSF samples collected longitudinally. The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease (AD) and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/Aβ(1-42) that positively correlated with PD severity in cross-sectional samples as well as with PD progression in longitudinal samples. We have demonstrated that this panel of 7 CSF proteins could aid in Parkinson disease diagnosis, differential diagnosis, and correlation with disease severity and progression. Copyright © 2011 American Neurological Association.
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              Alpha-Synuclein as a Biomarker for Parkinson's Disease.

              Anzari Atik, Tessandra Stewart, Jing Zhang (2016)
              Parkinson's disease (PD) is a common neurodegenerative disorder, characterized pathologically by the presence of α-synuclein (α-syn)-rich Lewy bodies. As clinical diagnosis of PD is challenging, misdiagnosis is common, highlighting the need for disease-specific and early stage biomarkers. Both early diagnosis of PD and adequate tracking of disease progression could significantly improve outcomes for patients, particularly in regard to existing and future disease modifying treatments. Given its critical roles in PD pathogenesis, α-syn may be useful as a biomarker of PD. The aim of this review is, therefore, to summarize the efficacy of tissue and body fluid α-syn measurements in the detection of PD as well as monitoring disease progression. In comparison to solid tissue specimens and biopsies, biofluid α-syn levels may be the most promising candidates in PD diagnosis and progression based on specificity, sensitivity and availability. Although α-syn has been tested most extensively in cerebrospinal fluid (CSF), the relatively invasive procedure for collecting CSF is not suitable in most clinical settings, leading to investigation of plasma, blood and saliva as alternatives. The exploration of combined biomarkers, along with α-syn, to improve diagnostic accuracy is also likely required.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Neurol
                Journal ID (publisher-id): Front. Neurol.
                Title: Frontiers in Neurology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-2295
                Publication date (Electronic): 17 September 2020
                Publication date Collection: 2020
                Volume: 11
                Electronic Location Identifier: 1043
                Affiliations
                [1] 1Department of Movement Disorders, Center for Neurology, Beijing Tiantan Hospital, Capital Medical University , Beijing, China
                [2] 2China National Clinical Research Center for Neurological Diseases , Beijing, China
                [3] 3Department of Laboratory Medicine, Peking University Third Hospital , Beijing, China
                [4] 4Parkinson's Disease Center, Beijing Institute for Brain Disorders, Capital Medical University , Beijing, China
                Author notes

                Edited by: Tobias Warnecke, University Hospital Münster, Germany

                Reviewed by: Mohamed Mosaad Salama, Mansoura University, Egypt; Chien Tai Hong, Taipei Medical University, Taiwan

                *Correspondence: Tao Feng bxbkyjs@ 123456sina.com

                This article was submitted to Movement Disorders, a section of the journal Frontiers in Neurology

                †These authors share first authorship

                Article
                DOI: 10.3389/fneur.2020.01043
                PMC ID: 7527535
                PubMed ID: 33041984
                SO-VID: 7fee573c-e1c8-461a-9de2-88fcaab730d3
                Copyright © Copyright © 2020 Cao, Wu, Liu, Jiang, Wang, Wang and Feng.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 07 May 2020
                Date accepted : 10 August 2020
                Page count
                Figures: 3, Tables: 3, Equations: 0, References: 36, Pages: 8, Words: 4792
                Categories
                Subject: Neurology
                Subject: Original Research

                ScienceOpen disciplines: Neurology
                Keywords: multiple system atrophy,parkinson's disease,α-synuclein,external anal sphincter electromyography,saliva
                Data availability:
                ScienceOpen disciplines: Neurology
                Keywords: multiple system atrophy, parkinson's disease, α-synuclein, external anal sphincter electromyography, saliva

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