Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics
Autor: | Yolande A.L. Pijnenburg, Corey T. McMillan, Lieke H.H. Meeter, Harro Seelaar, Theo M. Luider, Murray Grossman, Caroline Graff, Linn Öijerstedt, Diana A. T. Nijholt, Roberta Ghidoni, Raquel Sánchez-Valle, Giuliano Binetti, Robert Laforce, Christoph Stingl, Marcel P. Stoop, John C. van Swieten, Luisa Benussi, Jeroen van Rooij, Emma L. van der Ende |
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Přispěvatelé: | Neurology, Divisions, Amsterdam Neuroscience - Neurodegeneration, Internal Medicine |
Rok vydání: | 2019 |
Předmět: |
Adult
Male Proteomics 0301 basic medicine Oncology Heterozygote medicine.medical_specialty Tau protein Granulin Gene mutation Cohort Studies 03 medical and health sciences 0302 clinical medicine Pick Disease of the Brain C9orf72 Internal medicine medicine Humans Research Articles Aged C9orf72 Protein biology business.industry General Neuroscience Neuronal pentraxin receptor Chromogranin A Middle Aged medicine.disease 030104 developmental biology Frontotemporal Dementia Mutation biology.protein Intercellular Signaling Peptides and Proteins Female Neurology (clinical) business Biomarkers 030217 neurology & neurosurgery Research Article Frontotemporal dementia |
Zdroj: | Annals of Clinical and Translational Neurology, 6(4), 698-707. John Wiley and Sons Ltd Annals of Clinical and Translational Neurology van der Ende, E L, Meeter, L H, Stingl, C, van Rooij, J G J, Stoop, M P, Nijholt, D A T, Sanchez-Valle, R, Graff, C, Öijerstedt, L, Grossman, M, McMillan, C, Pijnenburg, Y A L, Laforce, R, Binetti, G, Benussi, L, Ghidoni, R, Luider, T M, Seelaar, H & van Swieten, J C 2019, ' Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics ', Annals of Clinical and Translational Neurology, vol. 6, no. 4, pp. 698-707 . https://doi.org/10.1002/acn3.745 Annals of Clinical and Translational Neurology, 6(4), 698-707. John Wiley & Sons Inc. |
ISSN: | 2328-9503 |
Popis: | Objective: To identify novel CSF biomarkers in GRN-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). Methods: Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN 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 (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT 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 GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptortype 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 C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers. Interpretation: We identified and validated five novel CSF biomarkers in GRN-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. |
Databáze: | OpenAIRE |
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