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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2020

01-12-2020 | Frontotemporal Dementia | Research article

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

Authors: Inger van Steenoven, Marleen J. A. Koel-Simmelink, Leonie J. M. Vergouw, Betty M. Tijms, Sander R. Piersma, Thang V. Pham, Claire Bridel, Gian-Luca Ferri, Cristina Cocco, Barbara Noli, Paul F. Worley, Mei-Fang Xiao, Desheng Xu, Patrick Oeckl, Markus Otto, Wiesje M. van der Flier, Frank Jan de Jong, Connie R. Jimenez, Afina W. Lemstra, Charlotte E. Teunissen

Published in: Molecular Neurodegeneration | Issue 1/2020

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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.
Appendix
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Literature
1.
2.
McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium. Neurology. 2017;89(1):88–100.PubMedPubMedCentralCrossRef
3.
Vekrellis K, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L. Pathological roles of alpha-synuclein in neurological disorders. Lancet Neurol. 2011;10(11):1015–25.PubMedCrossRef
4.
Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010;6(3):131–44.PubMedCrossRef
5.
Teunissen CE, Otto M, Engelborghs S, Herukka SK, Lehmann S, Lewczuk P, et al. White paper by the society for CSF analysis and clinical neurochemistry: overcoming barriers in biomarker development and clinical translation. Alzheimers Res Ther. 2018;10(1):30.PubMedPubMedCentralCrossRef
6.
Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535–62.PubMedPubMedCentralCrossRef
7.
van Steenoven I, Majbour NK, Vaikath NN, Berendse HW, van der Flier WM, van de Berg WDJ, Teunissen CE, Lemstra AW, El-Agnaf OMA. α-Synuclein species as potential cerebrospinal fluid biomarkers for dementia with lewy bodies. Mov Disord. 2018;33(11):1724–3.
8.
Hansson O, Hall S, Ohrfelt A, Zetterberg H, Blennow K, Minthon L, et al. Levels of cerebrospinal fluid alpha-synuclein oligomers are increased in Parkinson's disease with dementia and dementia with Lewy bodies compared to Alzheimer's disease. Alzheimers Res Ther. 2014;6(3):25.PubMedPubMedCentralCrossRef
9.
Mollenhauer B, Cullen V, Kahn I, Krastins B, Outeiro TF, Pepivani I, et al. Direct quantification of CSF alpha-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol. 2008;213(2):315–25.PubMedCrossRef
10.
11.
12.
Abdi F, Quinn JF, Jankovic J, McIntosh M, Leverenz JB, Peskind E, et al. Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders. J Alzheimers Dis. 2006;9(3):293–348.PubMedCrossRef
13.
Dieks JK, Gawinecka J, Asif AR, Varges D, Gmitterova K, Streich JH, et al. Low-abundant cerebrospinal fluid proteome alterations in dementia with Lewy bodies. J Alzheimers Dis. 2013;34(2):387–97.PubMedCrossRef
14.
Heywood WE, Galimberti D, Bliss E, Sirka E, Paterson RW, Magdalinou NK, et al. Identification of novel CSF biomarkers for neurodegeneration and their validation by a high-throughput multiplexed targeted proteomic assay. Mol Neurodegener. 2015;10:64.PubMedPubMedCentralCrossRef
15.
van der Flier WM, Pijnenburg YA, Prins N, Lemstra AW, Bouwman FH, Teunissen CE, et al. Optimizing patient care and research: the Amsterdam dementia cohort. J Alzheimers Dis. 2014;41(1):313–27.PubMedCrossRef
16.
McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology. 2005;65(12):1863–72.PubMedCrossRef
17.
Mulder C, Verwey NA, van der Flier WM, Bouwman FH, Kok A, van Elk EJ, et al. Amyloid-beta(1-42), total tau, and phosphorylated tau as cerebrospinal fluid biomarkers for the diagnosis of Alzheimer disease. Clin Chem. 2010;56(2):248–53.PubMedCrossRef
18.
Kang UJ, Goldman JG, Alcalay RN, Xie T, Tuite P, Henchcliffe C, et al. The BioFIND study: characteristics of a clinically typical Parkinson's disease biomarker cohort. Mov Disord. 2016;31(6):924–32.PubMedPubMedCentralCrossRef
19.
Teunissen CE, Tumani H, Engelborghs S, Mollenhauer B. Biobanking of CSF: international standardization to optimize biomarker development. Clin Biochem. 2014;47(4–5):288–92.PubMedCrossRef
20.
Fratantoni SA, Piersma SR, Jimenez CR. Comparison of the performance of two affinity depletion spin filters for quantitative proteomics of CSF: evaluation of sensitivity and reproducibility of CSF analysis using GeLC-MS/MS and spectral counting. Proteomics Clin Appl. 2010;4(6–7):613–7.PubMedCrossRef
21.
Piersma SR, Warmoes MO, de Wit M, de Reus I, Knol JC, Jimenez CR. Whole gel processing procedure for GeLC-MS/MS based proteomics. Proteome Sci. 2013;11(1):17.PubMedPubMedCentralCrossRef
22.
Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26(12):1367–72.CrossRefPubMed
23.
Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteomics. 2014;13(9):2513–26.PubMedPubMedCentralCrossRef
24.
Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article3.PubMedCrossRef
25.
Teunissen CE, Elias N, Koel-Simmelink MJ, Durieux-Lu S, Malekzadeh A, Pham TV, et al. Novel diagnostic cerebrospinal fluid biomarkers for pathologic subtypes of frontotemporal dementia identified by proteomics. Alzheimers Dement (Amst). 2016;2:86–94.
26.
Zhou F, Lu Y, Ficarro SB, Adelmant G, Jiang W, Luckey CJ, et al. Genome-scale proteome quantification by DEEP SEQ mass spectrometry. Nat Commun. 2013;4:2171.PubMedCrossRef
27.
D'Amato F, Cocco C, Noli B, Cabras T, Messana I, Ferri GL. VGF peptides upon osmotic stimuli: changes in neuroendocrine regulatory peptides 1 and 2 in the hypothalamic-pituitary-axis and plasma. J Chem Neuroanat. 2012;44(2):57–65.PubMedCrossRef
28.
Noli B, Brancia C, D'Amato F, Ferri GL, Cocco C. VGF changes during the estrous cycle: a novel endocrine role for TLQP peptides? PLoS One. 2014;9(10):e108456.PubMedPubMedCentralCrossRef
29.
Noli B, Sanna F, Brancia C, D'Amato F, Manconi B, Vincenzoni F, et al. Profiles of VGF peptides in the rat brain and their modulations after phencyclidine treatment. Front Cell Neurosci. 2017;11:158.PubMedPubMedCentralCrossRef
30.
Xiao MF, Xu D, Craig MT, Pelkey KA, Chien CC, Shi Y, et al. NPTX2 and cognitive dysfunction in Alzheimer's disease. Elife. 2017;6.
31.
Carrette O, Demalte I, Scherl A, Yalkinoglu O, Corthals G, Burkhard P, et al. A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease. Proteomics. 2003;3(8):1486–94.PubMedCrossRef
32.
Oeckl P, Metzger F, Nagl M, von Arnim CA, Halbgebauer S, Steinacker P, et al. Alpha-, Beta-, and gamma-synuclein quantification in cerebrospinal fluid by multiple reaction monitoring reveals increased concentrations in Alzheimer's and Creutzfeldt-Jakob disease but no alteration in Synucleinopathies. Mol Cell Proteomics. 2016;15(10):3126–38.PubMedPubMedCentralCrossRef
33.
34.
Bartolomucci A, Possenti R, Mahata SK, Fischer-Colbrie R, Loh YP, Salton SR. The extended granin family: structure, function, and biomedical implications. Endocr Rev. 2011;32(6):755–97.PubMedPubMedCentralCrossRef
35.
Ferri GL, Noli B, Brancia C, D'Amato F, Cocco C. VGF: an inducible gene product, precursor of a diverse array of neuro-endocrine peptides and tissue-specific disease biomarkers. J Chem Neuroanat. 2011;42(4):249–61.PubMedCrossRef
36.
Cocco C, D'Amato F, Noli B, Ledda A, Brancia C, Bongioanni P, et al. Distribution of VGF peptides in the human cortex and their selective changes in Parkinson's and Alzheimer's diseases. J Anat. 2010;217(6):683–93.PubMedPubMedCentralCrossRef
37.
Hoshino A, Helwig M, Rezaei S, Berridge C, Eriksen JL, Lindberg I. A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer's disease. J Neurochem. 2014;128(3):419–30.PubMedCrossRef
38.
Jarvela TS, Lam HA, Helwig M, Lorenzen N, Otzen DE, McLean PJ, et al. The neural chaperone proSAAS blocks alpha-synuclein fibrillation and neurotoxicity. Proc Natl Acad Sci U S A. 2016;113(32):E4708–15.PubMedPubMedCentralCrossRef
39.
Xu D, Hopf C, Reddy R, Cho RW, Guo L, Lanahan A, et al. Narp and NP1 form heterocomplexes that function in developmental and activity-dependent synaptic plasticity. Neuron. 2003;39(3):513–28.PubMedCrossRef
40.
O'Brien RJ, Xu D, Petralia RS, Steward O, Huganir RL, Worley P. Synaptic clustering of AMPA receptors by the extracellular immediate-early gene product Narp. Neuron. 1999;23(2):309–23.PubMedCrossRef
41.
Moran LB, Hickey L, Michael GJ, Derkacs M, Christian LM, Kalaitzakis ME, et al. Neuronal pentraxin II is highly upregulated in Parkinson's disease and a novel component of Lewy bodies. Acta Neuropathol. 2008;115(4):471–8.PubMedCrossRef
42.
Chang MC, Park JM, Pelkey KA, Grabenstatter HL, Xu D, Linden DJ, et al. Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons. Nat Neurosci. 2010;13(9):1090–7.PubMedPubMedCentralCrossRef
43.
44.
Tejeda HA, Shippenberg TS, Henriksson R. The dynorphin/kappa-opioid receptor system and its role in psychiatric disorders. Cell Mol Life Sci. 2012;69(6):857–96.PubMedCrossRef
45.
Singh IN, Goody RJ, Goebel SM, Martin KM, Knapp PE, Marinova Z, et al. Dynorphin a (1-17) induces apoptosis in striatal neurons in vitro through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor-mediated cytochrome c release and caspase-3 activation. Neuroscience. 2003;122(4):1013–23.PubMedCrossRef
46.
Hurd YL. Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex. Mol Psychiatry. 2002;7(1):75–81.PubMedCrossRef
47.
Crocker A, Espana RA, Papadopoulou M, Saper CB, Faraco J, Sakurai T, et al. Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology. 2005;65(8):1184–8.PubMedCrossRef
48.
Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27(3):469–74.PubMedCrossRefPubMedCentral
49.
Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014;146(5):1387–94.CrossRefPubMed
50.
Colom-Cadena M, Pegueroles J, Herrmann AG, Henstridge CM, Munoz L, Querol-Vilaseca M, et al. Synaptic phosphorylated alpha-synuclein in dementia with Lewy bodies. Brain. 2017;140(12):3204–14.PubMedPubMedCentralCrossRef
51.
Schulz-Schaeffer WJ. The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia. Acta Neuropathol. 2010;120(2):131–43.PubMedPubMedCentralCrossRef
52.
Calo L, Wegrzynowicz M, Santivanez-Perez J, Grazia SM. Synaptic failure and alpha-synuclein. Mov Disord. 2016;31(2):169–77.PubMedCrossRef
53.
Rockenstein E, Nuber S, Overk CR, Ubhi K, Mante M, Patrick C, et al. Accumulation of oligomer-prone alpha-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain. 2014;137(Pt 5):1496–513.PubMedPubMedCentralCrossRef
54.
Scott DA, Tabarean I, Tang Y, Cartier A, Masliah E, Roy S. A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. J Neurosci. 2010;30(24):8083–95.PubMedPubMedCentralCrossRef
55.
Bereczki E, Branca RM, Francis PT, Pereira JB, Baek JH, Hortobagyi T, et al. Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach. Brain. 2018;141(2):582–95.PubMedPubMedCentralCrossRef
56.
van Steenoven I, Aarsland D, Weintraub D, Londos E, Blanc F, van der Flier WM, et al. Cerebrospinal fluid Alzheimer's disease biomarkers across the Spectrum of Lewy body diseases: results from a large multicenter cohort. J Alzheimers Dis. 2016;54(1):287–95.PubMedPubMedCentralCrossRef
Metadata
Title
Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach
Authors
Inger van Steenoven
Marleen J. A. Koel-Simmelink
Leonie J. M. Vergouw
Betty M. Tijms
Sander R. Piersma
Thang V. Pham
Claire Bridel
Gian-Luca Ferri
Cristina Cocco
Barbara Noli
Paul F. Worley
Mei-Fang Xiao
Desheng Xu
Patrick Oeckl
Markus Otto
Wiesje M. van der Flier
Frank Jan de Jong
Connie R. Jimenez
Afina W. Lemstra
Charlotte E. Teunissen
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2020
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-020-00388-2

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