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Scientific article
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Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach

Published inMolecular neurodegeneration, vol. 15, no. 1, 36
Publication date2020-06-18
First online date2020-06-18
Abstract

Background: Diagnosis of dementia with Lewy bodies (DLB) is challenging, largely due to a lack of diagnostic tools. Cerebrospinal fluid (CSF) biomarkers have been proven useful in Alzheimer's disease (AD) diagnosis. Here, we aimed to identify novel CSF biomarkers for DLB using a high-throughput proteomic approach.

Methods: We applied liquid chromatography/tandem mass spectrometry with label-free quantification to identify biomarker candidates to individual CSF samples from a well-characterized cohort comprising patients with DLB (n = 20) and controls (n = 20). Validation was performed using (1) the identical proteomic workflow in an independent cohort (n = 30), (2) proteomic data from patients with related neurodegenerative diseases (n = 149) and (3) orthogonal techniques in an extended cohort consisting of DLB patients and controls (n = 76). Additionally, we utilized random forest analysis to identify the subset of candidate markers that best distinguished DLB from all other groups.

Results: In total, we identified 1995 proteins. In the discovery cohort, 69 proteins were differentially expressed in DLB compared to controls (p < 0.05). Independent cohort replication confirmed VGF, SCG2, NPTX2, NPTXR, PDYN and PCSK1N as candidate biomarkers for DLB. The downregulation of the candidate biomarkers was somewhat more pronounced in DLB in comparison with related neurodegenerative diseases. Using random forest analysis, we identified a panel of VGF, SCG2 and PDYN to best differentiate between DLB and other clinical groups (accuracy: 0.82 (95%CI: 0.75-0.89)). Moreover, we confirmed the decrease of VGF and NPTX2 in DLB by ELISA and SRM methods. Low CSF levels of all biomarker candidates, except PCSK1N, were associated with more pronounced cognitive decline (0.37 < r < 0.56, all p < 0.01).

Conclusion: We identified and validated six novel CSF biomarkers for DLB. These biomarkers, particularly when used as a panel, show promise to improve diagnostic accuracy and strengthen the importance of synaptic dysfunction in the pathophysiology of DLB.

eng
Keywords
  • Biomarkers
  • Cerebrospinal fluid
  • Dementia with Lewy bodies
  • Lewy body dementia
  • Proteomics
  • Aged
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / diagnosis
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Biomarkers / cerebrospinal fluid
  • Cognitive Dysfunction / cerebrospinal fluid
  • Cognitive Dysfunction / diagnosis
  • Cohort Studies
  • Dementia / diagnosis
  • Female
  • Humans
  • Lewy Body Disease / cerebrospinal fluid
  • Male
  • Middle Aged
  • Peptide Fragments / cerebrospinal fluid
  • Proteomics
  • Tau Proteins / cerebrospinal fluid
Affiliation Not a UNIGE publication
Funding
  • NIA NIH HHS - [P30 AG066507]
  • NINDS NIH HHS - [R35 NS097966]
  • EU Joint Programme – Neurodegenerative Disease Research - [01ED1512]
  • Regione Autonoma della Sardegna - [2012-CRP-60834]
  • ZonMw - [733050102]
  • Stichting Dioraphte - [Not applicable]
  • Bundesministerium für Bildung und Forschung - [01GI1007A]
  • Deutsche Forschungsgemeinschaft - [SFB 1237]
Citation (ISO format)
VAN STEENOVEN, Inger et al. Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach. In: Molecular neurodegeneration, 2020, vol. 15, n° 1, p. 36. doi: 10.1186/s13024-020-00388-2
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Identifiers
ISSN of the journal1750-1326
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