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Originally published as JCO Early Release 10.1200/JCO.2008.19.8598 on March 30 2009 © 2009 American Society of Clinical Oncology.
CSF Antithrombin III and Disruption of the Blood-Brain BarrierInstitute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Gothenburg; and Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden To the Editor: There is considerable excitement about the possibility of discovering novel biomarkers for CNS disorders using proteomics techniques.1 A recent explorative proteomics study on CSF protein changes associated with CNS lymphomas reported either higher or lower CSF levels of a number of proteins.2 One of these potential biomarkers, antithrombin III (ATIII), was selected for additional studies, and increased CSF levels were also found by enzyme-linked immunosorbent assay in a series of 24 patients with high-grade non-Hodgkin's lymphoma.2 The authors concluded that ATIII represents a novel CSF biomarker for CNS lymphoma that may facilitate the clinical assessment of these patients. Before a changed CSF level of a protein can be translated into a clinically useful biomarker, there are several confounding factors that have to be evaluated.3 One of the most central of these is to evaluate if the protein comes from the brain, or from the periphery by passage from the blood across the blood-brain barrier to the CSF. Indeed, ATIII is normally produced by hepatocytes and secreted to the blood in high amounts.4 ATIII in blood is well known to clinicians as a test used for evaluation of patients with coagulation disturbances. It is also well known that impaired blood-brain barrier function is a common feature of CNS lymphomas.5,6 Thus, there is a great risk that the high CSF ATIII levels in the lymphoma patients examined by Roy et al2 are merely caused by an unspecific leakage of ATIII across the blood-brain barrier. In clinical neurochemistry, the standard way to assess whether a protein is derived from the brain or the periphery is to correlate the CSF/serum ratio of the protein with the CSF/serum ratio of albumin.7 This is because albumin is produced by the liver only, and thus, all albumin in CSF comes from the serum by passage across the blood-brain barrier. Here, we report the results of an examination of the relationship between ATIII levels in CSF and the blood-brain barrier function. The study included matched serum and CSF samples from 38 patients who underwent lumbar puncture after receiving clinical results suggestive of neurological disease. The samples were analyzed for ATIII using the same assay as the one used by Roy et al (ATIII Bioassay, US Biologic, Swampscott, MA).2 A serial dilution of a reference plasma sample with an ATIII concentration of 200 µg/mL was used as standard. The patients were grouped according to the degree of blood-brain barrier impairment, as reflected by the CSF/serum albumin ratio.7 Albumin levels in CSF and serum were measured by immunonephelometry on a Beckman Immage Immunochemistry system (Beckman Coulter Inc, Fullerton, CA). The albumin ratio was calculated as CSF albumin (mg/L)/serum albumin (g/L), and the CSF/serum ATIII ratio was calculated as CSF ATIII (µg/mL)/serum ATIII (mg/mL). We found that the concentration of ATIII was approximately 100 times higher in serum than in CSF (Table 1). Indeed, CSF ATIII levels were significantly higher in patients with elevated albumin ratio, and there was a strong linear correlation between CSF/serum albumin and ATIII ratios (Fig 1). The blood-brain barrier function, approximated by the albumin ratio, explained as much as 80% of the variation in ATIII.
We conclude that ATIII in CSF is largely derived from the periphery by passage from serum to CSF across the blood-brain barrier. Although Roy et al did detect tumor-tissue RNA expression of ATIII,2 our results show that the contribution of CNS-derived ATIII to the total ATIII protein concentration in CSF is negligible. Altogether, these results show that ATIII is not a biomarker for CNS lymphomas, but rather still another measure of the blood-brain barrier integrity. This story also calls for caution against the use of explorative proteomics techniques without applying existing knowledge on standard clinical neurochemical methods for CSF biomarker development. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENT We thank Åsa Källén, Monica Christiansson, and Sara Hullberg for skilful technical assistance. REFERENCES 1. Zetterberg H, Ruetschi U, Portelius E, et al: Clinical proteomics in neurodegenerative disorders. Acta Neurol Scand 118:1–11, 2008.[CrossRef][Medline] 2. Roy S, Josephson SA, Fridlyand J, et al: Protein biomarker identification in the CSF of patients with CNS lymphoma. J Clin Oncol 26:96–105, 2008. 3. Blennow K: CSF biomarkers for Alzheimer's disease: Use in early diagnosis and evaluation of drug treatment. Expert Rev Mol Diagn 5:661–672, 2005.[CrossRef][Medline] 4. Kaiserman D, Whisstock JC, Bird PI: Mechanisms of serpin dysfunction in disease. Expert Rev Mol Med 8:1–19, 2006.[Medline] 5. Ernerudh J, Olsson T, Berlin G, et al: Cerebrospinal fluid immunoglobulins and beta 2-microglobulin in lymphoproliferative and other neoplastic diseases of the central nervous system. Arch Neurol 44:915–920, 1987. 6. Plotkin SR, Batchelor TT: Primary nervous-system lymphoma. Lancet Oncol 2:354–365, 2001.[CrossRef][Medline] 7. Tibbling G, Link H, Ohman S: Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest 37:385–390, 1977.[Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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