title: Quantitative proteomics and metabolomics analysis of normal human cerebrospinal fluid samples.
abstract: The analysis of cerebrospinal fluid (CSF) is used in biomarker discovery studies for various neurodegenerative central nervous system (CNS) disorders. However, little is known about variation of CSF proteins and metabolites between patients without neurological disorders. A baseline for a large number of CSF compounds appears to be lacking. To analyze the variation in CSF protein and metabolite abundances in a number of well-defined individual samples of patients undergoing routine, non-neurological surgical procedures, we determined the variation of various proteins and metabolites by multiple analytical platforms. A total of 126 common proteins were assessed for biological variations between individuals by ESI-Orbitrap. A large spread in inter-individual variation was observed (relative standard deviations [RSDs] ranged from 18 to 148%) for proteins with both high abundance and low abundance. Technical variation was between 15 and 30% for all 126 proteins. Metabolomics analysis was performed by means of GC-MS and nuclear magnetic resonance (NMR) imaging and amino acids were specifically analyzed by LC-MS/MS, resulting in the detection of more than 100 metabolites. The variation in the metabolome appears to be much more limited compared with the proteome: the observed RSDs ranged from 12 to 70%. Technical variation was less than 20% for almost all metabolites. Consequently, an understanding of the biological variation of proteins and metabolites in CSF of neurologically normal individuals appears to be essential for reliable interpretation of biomarker discovery studies for CNS disorders because such results may be influenced by natural inter-individual variations. Therefore, proteins and metabolites with high variation between individuals ought to be assessed with caution as candidate biomarkers because at least part of the difference observed between the diseased individuals and the controls will not be caused by the disease, but rather by the natural biological variation between individuals.
authors.affiliation: Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Marcel P
authors.initials: MP
authors.lastname: Stoop
authors.forename: Leon
authors.initials: L
authors.lastname: Coulier
authors.forename: Therese
authors.initials: T
authors.lastname: Rosenling
authors.forename: Shanna
authors.initials: S
authors.lastname: Shi
authors.forename: Agnieszka M
authors.initials: AM
authors.lastname: Smolinska
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Buydens
authors.forename: Kirsten
authors.initials: K
authors.lastname: Ampt
authors.forename: Christoph
authors.initials: C
authors.lastname: Stingl
authors.forename: Adrie
authors.initials: A
authors.lastname: Dane
authors.forename: Bas
authors.initials: B
authors.lastname: Muilwijk
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Luitwieler
authors.forename: Peter A E
authors.initials: PA
authors.lastname: Sillevis Smitt
authors.forename: Rogier Q
authors.initials: RQ
authors.lastname: Hintzen
authors.forename: Rainer
authors.initials: R
authors.lastname: Bischoff
authors.forename: Sybren S
authors.initials: SS
authors.lastname: Wijmenga
authors.forename: Thomas
authors.initials: T
authors.lastname: Hankemeier
authors.forename: Alain J
authors.initials: AJ
authors.lastname: van Gool
authors.forename: Theo M
authors.initials: TM
authors.lastname: Luider
mesh_terms: D016022:Case-Control Studies; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D002853:Chromatography, Liquid; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics; D040901:Proteomics; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
references.citation: J Proteome Res. 2009 Mar;8(3):1404-14
references.pmid: 19159215
references.citation: Curr Opin Microbiol. 2009 Oct;12(5):547-52
references.pmid: 19695948
references.citation: Exp Brain Res. 1999 Oct;128(3):278-90
references.pmid: 10501800
references.citation: J Pharm Biomed Anal. 1993 Aug;11(8):651-64
references.pmid: 8257730
references.citation: Anal Chem. 2000 Dec 15;72(24):5886-91
references.pmid: 11140753
references.citation: Neurosci Lett. 1996 Jul 12;212(2):91-4
references.pmid: 8832646
references.citation: Neurology. 2007 Feb 27;68(9):666-9
references.pmid: 17325273
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D521-6
references.pmid: 17202168
references.citation: PLoS One. 2007 Jul 04;2(7):e595
references.pmid: 17611627
references.citation: Mol Cell Proteomics. 2005 Dec;4(12):2010-21
references.pmid: 16249172
references.citation: J Proteome Res. 2008 Feb;7(2):720-30
references.pmid: 18186601
references.citation: Curr Clin Pharmacol. 2008 May;3(2):123-31
references.pmid: 18700307
references.citation: Clin Neurosci. 1994;2(3-4):229-45
references.pmid: 7749893
references.citation: Anal Chem. 2003 Dec 1;75(23):6449-54
references.pmid: 14640713
references.citation: Anal Chem. 2000 Oct 15;72(20):5125-30
references.pmid: 11055737
references.citation: Anal Chem. 2009 Feb 1;81(3):1121-9
references.pmid: 19125563
references.citation: Childs Nerv Syst. 2000 Nov;16(10-11):776-99
references.pmid: 11151732
references.citation: Neurol Sci. 2003 Dec;24 Suppl 5:S271-4
references.pmid: 14652787
references.citation: J Neurol. 2009 Feb;256(2):168-75
references.pmid: 19224317
references.citation: Int J Neurosci. 2006 Aug;116(8):927-36
references.pmid: 16861158
references.citation: Proteomics. 2007 Feb;7(3):469-73
references.pmid: 17211832
references.citation: Anal Chem. 2006 Feb 15;78(4):1272-81
references.pmid: 16478122
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Aug 15;871(2):164-73
references.pmid: 18502700
references.citation: Neuroimaging Clin N Am. 2008 Nov;18(4):577-88, ix
references.pmid: 19068403
references.citation: J Neurol. 2008 Oct;255(10):1508-14
references.pmid: 18685917
references.citation: Eur Arch Psychiatry Clin Neurosci. 2008 Nov;258 Suppl 5:44-9
references.pmid: 18985294
references.citation: Expert Rev Proteomics. 2005 Jan;2(1):57-70
references.pmid: 15966853
references.citation: Lancet. 2002 Apr 6;359(9313):1221-31
references.pmid: 11955556
references.citation: J Chromatogr B Biomed Sci Appl. 1999 Aug 6;731(1):73-81
references.pmid: 10491991
references.citation: Anal Chem. 2008 May 15;80(10):3751-6
references.pmid: 18393531
references.citation: Anal Biochem. 2000 Jan 15;277(2):187-95
references.pmid: 10625505
references.citation: Anal Chem. 2009 Oct 15;81(20):8538-44
references.pmid: 19764780
references.citation: Acta Neurol Scand. 1992 Sep;86(3):291-7
references.pmid: 1384263
references.citation: Dement Geriatr Cogn Disord. 2008;26(2):117-22
references.pmid: 18654083
references.citation: Mol Cell Proteomics. 2005 Dec;4(12):2000-9
references.pmid: 16199891