Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach
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-through...
Main Authors: | , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2020-06-01
|
Series: | Molecular Neurodegeneration |
Subjects: | |
Online Access: | http://link.springer.com/article/10.1186/s13024-020-00388-2 |
id |
doaj-b358195c633d43b1b1052579bc71230b |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach Molecular Neurodegeneration Biomarkers Cerebrospinal fluid Dementia with Lewy bodies Lewy body dementia Proteomics |
author_facet |
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 |
author_sort |
Inger van Steenoven |
title |
Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach |
title_short |
Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach |
title_full |
Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach |
title_fullStr |
Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach |
title_full_unstemmed |
Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach |
title_sort |
identification of novel cerebrospinal fluid biomarker candidates for dementia with lewy bodies: a proteomic approach |
publisher |
BMC |
series |
Molecular Neurodegeneration |
issn |
1750-1326 |
publishDate |
2020-06-01 |
description |
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. |
topic |
Biomarkers Cerebrospinal fluid Dementia with Lewy bodies Lewy body dementia Proteomics |
url |
http://link.springer.com/article/10.1186/s13024-020-00388-2 |
work_keys_str_mv |
AT ingervansteenoven identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT marleenjakoelsimmelink identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT leoniejmvergouw identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT bettymtijms identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT sanderrpiersma identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT thangvpham identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT clairebridel identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT gianlucaferri identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT cristinacocco identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT barbaranoli identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT paulfworley identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT meifangxiao identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT deshengxu identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT patrickoeckl identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT markusotto identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT wiesjemvanderflier identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT frankjandejong identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT connierjimenez identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT afinawlemstra identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach AT charlotteeteunissen identificationofnovelcerebrospinalfluidbiomarkercandidatesfordementiawithlewybodiesaproteomicapproach |
_version_ |
1724853992147648512 |
spelling |
doaj-b358195c633d43b1b1052579bc71230b2020-11-25T02:24:41ZengBMCMolecular Neurodegeneration1750-13262020-06-0115111510.1186/s13024-020-00388-2Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approachInger van Steenoven0Marleen J. A. Koel-Simmelink1Leonie J. M. Vergouw2Betty M. Tijms3Sander R. Piersma4Thang V. Pham5Claire Bridel6Gian-Luca Ferri7Cristina Cocco8Barbara Noli9Paul F. Worley10Mei-Fang Xiao11Desheng Xu12Patrick Oeckl13Markus Otto14Wiesje M. van der Flier15Frank Jan de Jong16Connie R. Jimenez17Afina W. Lemstra18Charlotte E. Teunissen19Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCNeurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCAlzheimer Center Erasmus MC, Department of Neurology, Erasmus Medical CenterAlzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCOncoProteomics Laboratory, Department of Medical Oncology, Vrije Universiteit Amsterdam, Amsterdam UMCOncoProteomics Laboratory, Department of Medical Oncology, Vrije Universiteit Amsterdam, Amsterdam UMCNeurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCNEF-laboratory, Department of Biomedical Sciences, University of CagliariNEF-laboratory, Department of Biomedical Sciences, University of CagliariNEF-laboratory, Department of Biomedical Sciences, University of CagliariSolomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineSolomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineSolomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineDepartment of Neurology, Ulm University HospitalDepartment of Neurology, Ulm University HospitalAlzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCAlzheimer Center Erasmus MC, Department of Neurology, Erasmus Medical CenterOncoProteomics Laboratory, Department of Medical Oncology, Vrije Universiteit Amsterdam, Amsterdam UMCAlzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCNeurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCAbstract 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.http://link.springer.com/article/10.1186/s13024-020-00388-2BiomarkersCerebrospinal fluidDementia with Lewy bodiesLewy body dementiaProteomics |