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Neurodegeneration
Original research
Beta-synuclein in cerebrospinal fluid as an early diagnostic marker of Alzheimer’s disease
  1. Steffen Halbgebauer1,
  2. Patrick Oeckl1,
  3. Petra Steinacker1,
  4. Deniz Yilmazer-Hanke2,
  5. Sarah Anderl-Straub1,
  6. Christine von Arnim1,
  7. Lutz Froelich3,
  8. Luis Aragão Gomes4,
  9. Lucrezia Hausner3,
  10. Andre Huss1,
  11. Holger Jahn5,
  12. Jochen Weishaupt1,
  13. Albert C Ludolph1,
  14. Dietmar R Thal4,6,7,
  15. Markus Otto1
  1. 1 Department of Neurology, University Hospital Ulm, Ulm, Baden-Württemberg, Germany
  2. 2 Clinical Neuroanatomy, Department of Neurology, University of Ulm, Ulm, Baden-Württemberg, Germany
  3. 3 Department of Geriatric Psychiatry, Central Institute of Mental Health Medical Faculty, University of Heidelberg, Mannheim, Baden-Württemberg, Germany
  4. 4 Department of Pathology, UZ-Leuven, Leuven, Belgium
  5. 5 Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  6. 6 Laboratory for Neuropathology, Department of Imaging and Pathology and Leuven Brain Institute, KU Leuven, Leuven, Belgium
  7. 7 Laboratory for Neuropathology, Institute of Pathology, Ulm University, Ulm, Baden-Württemberg, Germany
  1. Correspondence to Professor Markus Otto, Department of Neurology, University Hospital Ulm, 89069 Ulm, Baden-Württemberg, Germany; markus.otto{at}uni-ulm.de

Abstract

Objective Synaptic loss plays a major role in Alzheimer’s disease (AD). However so far no neurochemical marker for synaptic loss has been introduced into clinical routine. By mass spectrometry beta-synuclein was established as a candidate marker. We now aimed to set up a novel ELISA for beta-synuclein for evaluation of its potential as a diagnostic and predictive marker for AD.

Methods We analysed in total 393 patients from four specialised centres. The diagnostic groups comprised: AD (n=151), behavioural variant frontotemporal dementia (bvFTD, n=18), Parkinson syndrome (n=46), Creutzfeldt-Jakob disease (CJD, n=23), amyotrophic lateral sclerosis (ALS, n=29), disease control (n=66) and 60 non-neurodegenerative control patients. Results were compared with core AD biomarkers (total tau, phospho-tau and amyloid-β peptide 1–42). Additionally, coexistence of beta-synuclein with vesicular glutamate transporter 1 (VGLUT1) was determined and beta-synuclein levels were quantified in brain homogenates.

Results Beta-synuclein levels quantified with the newly established ELISA correlated strongly with antibody-free quantitative mass spectrometry data (r=0.92 (95% CI: 0.89 to 0.94), p<0.0001). Cerebrospinal fluid (CSF) beta-synuclein levels were increased in AD-mild cognitive impairment (p<0.0001), AD dementia (p<0.0001) and CJD (p<0.0001), but not in bvFTD, Parkinson syndrome or ALS. Furthermore, beta-synuclein was localised in VGLUT1-positive glutamatergic synapses, and its expression was significantly reduced in brain tissue from patients with AD (p<0.01).

Conclusion We successfully established a sensitive and robust ELISA for the measurement of brain-enriched beta-synuclein, which we could show is localised in glutamatergic synapses. We confirmed previous, mass spectrometry-based observations of increased beta-synuclein levels in CSF of patients with AD and CJD supporting its potential use as a marker of synaptic degeneration.

https://doi.org/10.1136/jnnp-2020-324306

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    Footnotes

    • Contributors All authors made substantial contributions to conception and design, and/or acquisition of data, and/or analysis and interpretation of data. All authors gave final approval of the version to be submitted and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SH and MO—conception and design of the study. SH, PO, PS, DY-H, SA-S, CvA, LF, LAG, LH, AH, HJ, JW, ACL, DRT and MO—sample collection and data management. SH and MO—study management and coordination. SH and PS—statistical methods and analysis. SH, PO, PS, DY-H, SA-S, CvA, LF, LAG, LH, AH, HJ, JW, ACL, DRT and MO—interpretation of results. SH and MO—manuscript writing (first draft). SH, PO, PS, DY-H, SA-S, CvA, LF, LAG, LH, AH, HJ, JW, ACL, DRT and MO—critical revision of the manuscript.

    • Funding This study was supported by grants from the Foundation of the State of Baden-Württemberg (D.3830), the Corona Stiftung Germany (D.5341) and DRT receives funding from FWO (Odysseus grant no. G0F8516N).

    • Competing interests DRT received speaker honorary or travel reimbursement from Novartis Pharma AG (Switzerland), UCB (Belgium), GE-Healthcare (UK), Biogen (USA); and collaborated with Novartis Pharma AG (Switzerland), Probiodrug (Germany), GE-Healthcare (UK) and Janssen Pharmaceutical Companies (Belgium). MO gave scientific advice for Fujirebio, Roche, Biogen and Axon. The foundation of the state Baden-Wuerttemberg handed in a patent for the measurement of beta-synuclein.

    • Patient consent for publication Not required.

    • Ethics approval The study was approved by local Ethics Committees (approval numbers: Ulm 20/10, 54/08, 342/14, Hamburg OB-071/04, Mannheim 2012-245N-MA, Göttingen 100305, Leuven S-59295) and conducted following the Declaration of Helsinki. All participants gave their written informed consent to participate in the study.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplemental information.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.