PT  - JOURNAL ARTICLE
AU  - Steffen Halbgebauer
AU  - Patrick Oeckl
AU  - Petra Steinacker
AU  - Deniz Yilmazer-Hanke
AU  - Sarah Anderl-Straub
AU  - Christine von Arnim
AU  - Lutz Froelich
AU  - Luis Aragão Gomes
AU  - Lucrezia Hausner
AU  - Andre Huss
AU  - Holger Jahn
AU  - Jochen Weishaupt
AU  - Albert C Ludolph
AU  - Dietmar R Thal
AU  - Markus Otto
TI  - Beta-synuclein in cerebrospinal fluid as an early diagnostic marker of Alzheimer’s disease
AID  - 10.1136/jnnp-2020-324306
DP  - 2021 Apr 01
TA  - Journal of Neurology, Neurosurgery & Psychiatry
PG  - 349--356
VI  - 92
IP  - 4
4099  - http://jnnp.bmj.com/content/92/4/349.short
4100  - http://jnnp.bmj.com/content/92/4/349.full
SO  - J Neurol Neurosurg Psychiatry2021 Apr 01; 92
AB  - 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.