Cystatin C in cerebrospinal fluid and multiple sclerosis

Hansson, Sara; Simonsen, Anja Hviid; Zetterberg, Henrik; Andersen, Oluf; Haghighi, Sara; Fagerberg, Inger; Andréasson, Ulf; Westman‐Brinkmalm, Ann; Wallin, Anders; Rüetschi, Ulla; Blennow, Kaj

doi:10.1002/ana.20945

Cited by 33 publications

(26 citation statements)

References 8 publications

(15 reference statements)

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“…From long-term stability studies, it is already known that A␤ 1-42 concentrations in samples frozen at Ϫ80°C are stable for at least 2 years (6,18 ), as are concentrations of T-tau and P-tau 181P when stored at Ϫ20°C for at least for 2 and 4 years, respectively (12,18 ). A storage artifact is seen for cystatin C analysis after freezing at Ϫ20°C, but not at Ϫ80°C (24 ). Long-term stability of CSF samples in liquid N 2 , or direct freezing of a sample in liquid N 2 compared with other freezing conditions, has never been investigated extensively.…”

Section: Freezing Temperaturementioning

confidence: 99%

Importance and Impact of Preanalytical Variables on Alzheimer Disease Biomarker Concentrations in Cerebrospinal Fluid

2015

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BACKGROUND Analyses of cerebrospinal fluid (CSF) biomarkers (β-amyloid protein, total tau protein, and hyperphosphorylated tau protein) are part of the diagnostic criteria of Alzheimer disease. Different preanalytical sample procedures contribute to variability of CSF biomarker concentrations, hampering between-laboratory comparisons. The aim of this study was to explore the influence of fractionated sampling, centrifugation, freezing temperature, freezing delay, and freeze–thaw cycles on CSF biomarker analyses. METHODS We studied fractionated sampling in sequential aliquots of lumbar CSF. Centrifuged and noncentrifuged samples from the same fraction were compared. CSF samples were subjected to different protocols (liquid nitrogen, −80 °C, and −20 °C; 24 h at 2–8 °C; and 24 and 48 h at room temperature). To study the influence of freeze–thaw cycles, samples were thawed up to 4 times and refrozen at −80 °C. CSF was collected in polypropylene tubes. We measured CSF biomarker concentrations with commercially available single-analyte Innotest assays. RESULTS CSF biomarker concentrations from non–blood-contaminated samples are not influenced by centrifugation or fractionated sampling. Freezing temperature and delayed storage can affect biomarker concentrations; freezing of CSF samples at −80 °C as soon as possible after collection is recommended. Consecutive freezing and thawing of CSF samples up to 3 times had little effect. CONCLUSIONS Temperature of freezing, delay until freezing, and freeze–thaw cycles significantly influence CSF biomarker concentrations, stressing the need for standard operating procedures for preanalytical sample handling. The differences observed in this study are, however, relatively small, and the impact on the clinical value of these CSF biomarkers needs to be determined.

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Section: Freezing Temperaturementioning

confidence: 99%

Importance and Impact of Preanalytical Variables on Alzheimer Disease Biomarker Concentrations in Cerebrospinal Fluid

2015

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“…To detect reliable molecular biomarkers, it is imperative to handle biological fluids according to standardized procedures and to evaluate the effects of preanalytical parameters on the final result to avoid artifacts (1,2 ). Earlier studies on urine, plasma, and cerebrospinal fluid (CSF) 9 have shown that sample handling can affect the stability of proteins as well as metabolites (3)(4)(5)(6)(7)(8)(9)(10)(11).…”

confidence: 99%

The Impact of Delayed Storage on the Measured Proteome and Metabolome of Human Cerebrospinal Fluid

et al. 2011

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BACKGROUND Because cerebrospinal fluid (CSF) is in close contact with diseased areas in neurological disorders, it is an important source of material in the search for molecular biomarkers. However, sample handling for CSF collected from patients in a clinical setting might not always be adequate for use in proteomics and metabolomics studies. METHODS We left CSF for 0, 30, and 120 min at room temperature immediately after sample collection and centrifugation/removal of cells. At 2 laboratories CSF proteomes were subjected to tryptic digestion and analyzed by use of nano-liquid chromatography (LC) Orbitrap mass spectrometry (MS) and chipLC quadrupole TOF-MS. Metabolome analysis was performed at 3 laboratories by NMR, GC-MS, and LC-MS. Targeted analyses of cystatin C and albumin were performed by LC–tandem MS in the selected reaction monitoring mode. RESULTS We did not find significant changes in the measured proteome and metabolome of CSF stored at room temperature after centrifugation, except for 2 peptides and 1 metabolite, 2,3,4-trihydroxybutanoic (threonic) acid, of 5780 identified peptides and 93 identified metabolites. A sensitive protein stability marker, cystatin C, was not affected. CONCLUSIONS The measured proteome and metabolome of centrifuged human CSF is stable at room temperature for up to 2 hours. We cannot exclude, however, that changes undetectable with our current methodology, such as denaturation or proteolysis, might occur because of sample handling conditions. The stability we observed gives laboratory personnel at the collection site sufficient time to aliquot samples before freezing and storage at −80 °C.

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“…The importance of sample conservation has been exemplified by a recent controversy with respect to cystatin C, a secreted cystein protease inhibitor [46][47][48][49]. Irani et al [47] analyzed the CSF proteome profile of patients with multiple sclerosis and those affected by other neurological diseases or transverse myelitis.…”

Section: Sample Collection and Conservationmentioning

confidence: 99%

“…The authors concluded that this ratio could be used as a biomarker to identify a subgroup of multiple sclerosis patients. However, other investigations disputed this finding and indicated that the cleavage product is an artifact of sample conservation [46,48,50]. Hansson et al [48] used a proteomic approach similar to that employed by Irani and coworkers to analyze CSF obtained from 43 multiple sclerosis and 46 healthy controls.…”

Section: Sample Collection and Conservationmentioning

confidence: 99%

“…However, other investigations disputed this finding and indicated that the cleavage product is an artifact of sample conservation [46,48,50]. Hansson et al [48] used a proteomic approach similar to that employed by Irani and coworkers to analyze CSF obtained from 43 multiple sclerosis and 46 healthy controls. They found that both the full-length and the 12.5 kDa cleavage products were not different in multiple sclerosis patients as compared to controls concluding that the cleavage product is an artifact of sample conservation.…”

Section: Sample Collection and Conservationmentioning

confidence: 99%

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Proteomic strategies in multiple sclerosis and its animal models

Elkabes

2007

Proteomics Clinical Apps

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The early and precise diagnosis, the prognosis, and the clinical management of multiple sclerosis, remain a considerable challenge. In recent years, the development of novel and powerful proteomic techniques prompted the use of these approaches for the search of unique biomarkers in the cerebrospinal fluid of multiple sclerosis patients. A few studies have also utilized proteomics to delineate the profile of differentially expressed proteins in animal models of the human disease in order to gain global insights into affected pathways. The identification of differentially expressed proteins may be an initial step in the discovery of novel targets and mechanisms that play critical roles in the pathology of multiple sclerosis. Based on these findings, future investigations may elucidate the events leading to demyelination, axonal damage, and neurodegeneration, providing better insights into mechanisms governing the onset and progression of the disease. Although these proteomic studies provide valuable information, they are also faced with a number of challenges. The present review discusses some of the strengths and limitations of proteomic investigations as applied to multiple sclerosis.

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Cystatin C in cerebrospinal fluid and multiple sclerosis

Cited by 33 publications

References 8 publications

Importance and Impact of Preanalytical Variables on Alzheimer Disease Biomarker Concentrations in Cerebrospinal Fluid

Importance and Impact of Preanalytical Variables on Alzheimer Disease Biomarker Concentrations in Cerebrospinal Fluid

The Impact of Delayed Storage on the Measured Proteome and Metabolome of Human Cerebrospinal Fluid

Proteomic strategies in multiple sclerosis and its animal models

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