Abstract
Cerebrospinal fluid is investigated in biomarker studies for various neurological disorders of the central nervous system due to its proximity to the brain. Currently, only a limited number of biomarkers have been validated in independent studies. The high variability in the protein composition and protein abundance of cerebrospinal fluid between as well as within individuals might be an important reason for this phenomenon. To evaluate this possibility, we investigated the inter- and intraindividual variability in the cerebrospinal fluid proteome globally, with a specific focus on disease biomarkers described in the literature. Cerebrospinal fluid from a longitudinal study group including 12 healthy control subjects was analyzed by label-free quantification (LFQ) via LC-MS/MS. Data were quantified via MaxQuant. Then, the intra- and interindividual variability and the reference change value were calculated for every protein. We identified and quantified 791 proteins, and 216 of these proteins were abundant in all samples and were selected for further analysis. For these proteins, we found an interindividual coefficient of variation of up to 101.5% and an intraindividual coefficient of variation of up to 29.3%. Remarkably, these values were comparably high for both proteins that were published as disease biomarkers and other proteins. Our results support the hypothesis that natural variability greatly impacts cerebrospinal fluid protein biomarkers because high variability can lead to unreliable results. Thus, we suggest controlling the variability of each protein to distinguish between good and bad biomarker candidates, e.g., by utilizing reference change values to improve the process of evaluating potential biomarkers in future studies.
Highlights
Human cerebrospinal fluid (CSF) is a clear body fluid that is produced by filtration of blood in the choroid plexus of the first three brain ventricles
Via unbiased label-free quantification (LFQ) via LC-multiple sclerosis (MS)/MS, we investigated CSF samples obtained from a longitudinal study group of 12 healthy control subjects (12 samples for every time point: 0 months, T0; 24 months, T24; 48 months, T48) and determined the intra- and interindividual variability, as well as the reference change value, for each protein
We investigated the analytical variation in our method (CVa)
Summary
Human cerebrospinal fluid (CSF) is a clear body fluid that is produced by filtration of blood in the choroid plexus of the first three brain ventricles. CSF contains less than five cells per μL. The total protein concentration of CSF varies between 0.2% and 0.5% of the total protein concentration of blood [1]. The concentration of blood-derived proteins increases from the ventricles to the cistern to the lumbar CSF. It is assumed that the remaining 20% of CSF proteins are released from the central nervous system (CNS) [2]. The primary role of CSF is to protect the CNS from mechanical shocks [3, 4]. Another important function of CSF is to maintain metabolite clearance from the adult brain by circulation. CSF supports the homeostatic balance in the brain and, therewith, normal brain activity [4]
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