Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics.

TitleNovel CSF biomarkers in genetic frontotemporal dementia identified by proteomics.
Publication TypeJournal Article
Year of Publication2019
Authorsvan der Ende, EL, Meeter, LH, Stingl, C, van Rooij, JGJ, Stoop, MP, Nijholt, DAT, Sanchez-Valle, R, Graff, C, Öijerstedt, L, Grossman, M, McMillan, C, Pijnenburg, YAL, Laforce, Jr, R, Binetti, G, Benussi, L, Ghidoni, R, Luider, TM, Seelaar, H, van Swieten, JC
JournalAnn Clin Transl Neurol
Volume6
Issue4
Pagination698-707
Date Published2019 Apr
ISSN2328-9503
Abstract

Objective: To identify novel CSF biomarkers in -associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS).Methods: Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high-resolution targeted MS method, was performed on an international cohort ( = 210) of presymptomatic and symptomatic and mutation carriers.Results: Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptor-type tyrosine-protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin-A (CHGA), and V-set and transmembrane domain-containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic mutation carriers had lower levels of NPTXR and CHGA than noncarriers.Interpretation: We identified and validated five novel CSF biomarkers in associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers.

DOI10.1002/acn3.745
Alternate JournalAnn Clin Transl Neurol
PubMed ID31019994
PubMed Central IDPMC6469343