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Scientific result | Neurodegenerative diseases | Mass spectrometry

Alzheimer's or Lewy bodies dementia? The answer with high-resolution mass spectrometry


​A team from SPI, in collaboration with the metabolic biochemistry service and the Institute of Memory and Alzheimer's Disease (IM²A) of the university hospitals Pitié-Salpêtrière, has developed a method for the simultaneous quantification of tau and α-synuclein proteins in human cerebrospinal fluid by high-resolution mass spectrometry. A promising new approach for the differential diagnosis of Lewy bodies dementia and Alzheimer's disease. 

Published on 7 November 2019

Abstract

Tau and α-synuclein are central in several neurodegenerative diseases, including Alzheimer Disease (AD), Dementia with Lewy Bodies (DLB) and Parkinson Disease (PD). New analytical methods for precise quantification of cerebrospinal fluid (CSF) levels of both tau and α-synuclein are required to differentiate between dementias or monitor therapeutic responses. Notably, levels of total α-synuclein reported by ELISA are inconsistent among studies, impacted by antibody specificity or lack of standardization. Here, we report on the development and validation of a sensitive and robust mass spectrometry-based assay for the simultaneous quantification of tau and α-synuclein in CSF. The optimized workflow avoided any affinity reagents, and involved the combination of two enzymes, Glu-C and trypsin for optimal sequence coverage of α-synuclein acidic C-terminus. Up to 7 α-synuclein peptides were quantified, including the C-terminal peptide (132–140), resulting in a sequence coverage of 54% in CSF. The lower limits of quantification (LLOQ) ranged from 0.1 ng mL−1 to 1 ng mL−1 depending on the peptide. Regarding CSF tau, 4 peptides common to all isoforms were monitored, and LLOQ ranged from 0.5 ng mL−1 to 0.75 ng mL−1. The multiplex method was successfully applied to CSF samples from AD and DLB patients, two clinically overlapping neurodegenerative diseases. CSF α-synuclein levels were significantly lower in DLB patients compared to AD and controls. Moreover, tau and α-synuclein concentrations showed opposite trends in AD and DLB patients, suggesting the benefit of combining the two biomarkers for differentiation of DLB from AD and controls.

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