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Letter
Immunochemical detection of #-synuclein autoantibodies in Parkinson’s disease: correlation between plasma and CSF levels. Istvan Horvath, Igor A. Iashchishyn, Lars Forsgren, and Ludmilla A Morozova-Roche ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00063 • Publication Date (Web): 06 Mar 2017 Downloaded from http://pubs.acs.org on March 7, 2017
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Immunochemical Detection of α-Synuclein Autoantibodies in Parkinson’s Disease: Correlation Between Plasma and CSF Levels Istvan Horvath1,#, Igor A. Iashchishyn1,2,#, Lars Forsgren3, and Ludmilla A. MorozovaRoche1,*
1
Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
2
Department of General Chemistry, Sumy State University, Sumy, Ukraine.
3
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
#
Authors with equal contribution
*Corresponding author: Ludmilla A. Morozova-Roche (
[email protected])
Running title: Correlation between α-synuclein autoantibody levels in Parkinson’s plasma and CSF Key words: biomarkers, blood plasma, cerebrospinal fluid, ELISA, Parkinson’s disease, αsynuclein autoantibodies.
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ABSTRACT Autoantibodies to Parkinson’s disease (PD) amyloidogenic protein – α-synuclein were recognized as a prospective biomarker for early disease diagnostics, yet there is inconsistency in previous reports, potentially related to PD status. Therefore, plasma and cerebrospinal fluid (CSF) of the cross-sectional cohort of 60 individuals including recently diagnosed PD patients with mild and moderate PD and age-matched controls were examined by ELISA. Nonparametric statistics was used for data analysis. We found significantly elevated levels of αsynuclein autoantibodies in both plasma and CSF in mild PD compared to controls, followed by some decrease in moderate PD. Receiver operating characteristic and effect size analyses confirmed the diagnostic power of α-synuclein antibodies in both plasma and CSF. For the first time we showed the correlation between plasma and CSF α-synuclein antibody levels for mild, moderate and combined PD groups. This indicates the potentiality of α-synuclein antibodies as PD biomarker and the increased diagnostic power of their simultaneous analysis in plasma and CSF.
INTRODUCTION Parkinson’s disease (PD) is the second most common chronic neurodegenerative disease characterized by motor and cognitive dysfunctions. PD affects more than 1% of individuals over 60 y.o. and ca. 4% – over 80 y.o.1 The increasing number of PD patients, due to growing elderly population, leads to rapidly escalating cost for the healthcare system. The major pathology of PD arises from abnormal amyloid accumulations of α-synuclein, mostly in the form of Lewy bodies and Lewy neurites, and loss of dopaminergic neurons in the substantia nigra, though a detailed map of disease progression remains unclear.2 A definitive diagnosis of PD is difficult to achieve, especially in its early stage, when the accuracy does not exceed 26% for untreated or not clearly responsive subjects and 53% for subjects responsive to medication.3 Modern neuroimaging techniques, such as dopamine transporter scans, incur a high cost, they are not readily accessible and therefore not optimal for a first-line PD screening. There is also a long latency between the onset of pathological processes and appearance of clinical symptoms. The latter are often not evident until some 60-80% of dopaminergic neurons have been lost, leaving very limited options for therapeutic intervention.4 Therefore, the development of biomarker-based diagnostics capable of detecting PD in the earliest stage, when neurons at risk can be protected and general treatments can be more effective, is of ma-
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jor importance. The criteria proposed for these biomarkers are that they should be linked to fundamental features of PD.5 Serological assays have demonstrated that amyloid self-assembly of α-synuclein is allied with humoral immunity.6-8 Autoantibodies involved in clearance pathways and tissue homeostasis are suggested to play an active role throughout PD progression and may have a protective power reducing α-synuclein level.6 Autoimmune responses to α-synuclein in blood plasma/sera as a marker of PD were studied previously,6-18 however the results are mixed. Contributory problems have been the lab-to-lab variability associated with assays and sample collecting procedures as well as the diverse nature of patient cohorts.16 As PD is an inherently heterogeneous disease, the reported variation may be related to clinical disease duration, severity, age of onset, familial or sporadic origin and disease subtype (typical or atypical). Therefore more studies on different PD groups are needed. The increased content of α-synuclein autoantibodies was reported in early versus late PD stages in different cohorts by using ELISA, immunoblotting, surface plasmon resonance and electrochemistry.6-8, 14, 15, 18 Combined PD groups without differentiated disease stages12, 16 and late PD cohorts with mean clinical disease durations of ca. 10 years,10,13 have shown no difference or even a decline13 in α-synuclein antibody levels compared to controls. Interestingly, it has been reported that the serum α-synuclein antibody concentrations in both typical PD and atypical Parkinsonism were highest in the patients with
