Abstract
Cerebrospinal fluid (CSF) is a potential source of biomarkers for many disorders of the central nervous system, including Alzheimer disease (AD). Prior to comparing CSF samples between individuals to identify patterns of disease-associated proteins, it is important to examine variation within individuals over a short period of time so that one can better interpret potential changes in CSF between individuals as well as changes within a given individual over a longer time span. In this study, we analyzed 12 CSF samples, composed of pairs of samples from six individuals, obtained 2 weeks apart. Multiaffinity depletion, two-dimensional DIGE, and tandem mass spectrometry were used. A number of proteins whose abundance varied between the two time points was identified for each individual. Some of these proteins were commonly identified in multiple individuals. More importantly, despite the intraindividual variations, hierarchical clustering and multidimensional scaling analysis of the proteomic profiles revealed that two CSF samples from the same individual cluster the closest together and that the between-subject variability is much larger than the within-subject variability. Among the six subjects, comparison between the four cognitively normal and the two very mildly demented subjects also yielded some proteins that have been identified in previous AD biomarker studies. These results validate our method of identifying differences in proteomic profiles of CSF samples and have important implications for the design of CSF biomarker studies for AD and other central nervous system disorders.
Highlights
Cerebrospinal fluid (CSF) is a potential source of biomarkers for many disorders of the central nervous system, including Alzheimer disease (AD)
We discovered CSF proteins whose abundances fluctuate even within the same individual over a short time span as well as observed a greater similarity in the proteomic profiles between samples from the same individual compared with samples from different individuals
There have been some studies on the diurnal variation in CSF neurotransmitter concentrations [40]; to our knowledge, there are no reports that systematically study the normal variability in CSF protein abundance within individuals over a short period of time
Summary
Cerebrospinal fluid (CSF) is a potential source of biomarkers for many disorders of the central nervous system, including Alzheimer disease (AD). Comparison between the four cognitively normal and the two very mildly demented subjects yielded some proteins that have been identified in previous AD biomarker studies These results validate our method of identifying differences in proteomic profiles of CSF samples and have important implications for the design of CSF biomarker studies for AD and other central nervous system disorders. Because it is in direct contact with the brain interstitial fluid, biochemical changes taking place in the brain are often reflected in CSF These features make CSF potentially a very useful source of biomarkers for diagnosis and response to treatment as well as for providing information on pathological processes underlying a number of central nervous system disorders, including Alzheimer disease (AD) Knowledge of fluctuations in protein abundance within an individual over a short ester; Cy3, 1-(5-carboxypentyl)-1Ј-propylindocarbocyanine halide Nhydroxysuccinimidyl ester; Cy5, 1-(5-carboxypentyl)-1Ј-methylindodicarbocyanine halide N-hydroxysuccinimidyl ester; LP, lumbar puncture; CDR, Clinical Dementia Rating; DIA, Differential In-gel Analysis; BVA, Biological Variation Analysis; apoE, apolipoprotein E; T1, time point 1; T2, time point 2
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