Skip to main content
Top
Published in: Fluids and Barriers of the CNS 1/2020

Open Access 01-12-2020 | Multiple Sclerosis | Research

Increased age and male sex are independently associated with higher frequency of blood–cerebrospinal fluid barrier dysfunction using the albumin quotient

Authors: Massimiliano Castellazzi, Andrea Morotti, Carmine Tamborino, Francesca Alessi, Silvy Pilotto, Eleonora Baldi, Luisa M. Caniatti, Alessandro Trentini, Ilaria Casetta, Enrico Granieri, Maura Pugliatti, Enrico Fainardi, Tiziana Bellini

Published in: Fluids and Barriers of the CNS | Issue 1/2020

Login to get access

Abstract

Background

The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood–cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction.

Methods

The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40–60 and 9.0 over 60 years.

Results

1209 subjects were included in the study. 718 females and 491 males (age: 15–88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease subgroups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivariable linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group.

Conclusions

Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach.
Literature
1.
go back to reference Bechmann I, Galea I, Perry VH. What is the blood–brain barrier (not)? Trends Immunol. 2007;28:5–11.CrossRef Bechmann I, Galea I, Perry VH. What is the blood–brain barrier (not)? Trends Immunol. 2007;28:5–11.CrossRef
2.
go back to reference Liddelow SA. Fluids and barriers of the CNS: a historical viewpoint. Fluids Barriers CNS. 2011;8:2.CrossRef Liddelow SA. Fluids and barriers of the CNS: a historical viewpoint. Fluids Barriers CNS. 2011;8:2.CrossRef
3.
go back to reference Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol. 2012;33:579–89.CrossRef Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol. 2012;33:579–89.CrossRef
4.
go back to reference Freedman MS, Thompson EJ, Deisenhammer F, et al. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol. 2005;62:865–70.CrossRef Freedman MS, Thompson EJ, Deisenhammer F, et al. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol. 2005;62:865–70.CrossRef
5.
go back to reference Deisenhammer F, Bartos A, Egg R, et al. Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force. Eur J Neurol. 2006;13:913–22.CrossRef Deisenhammer F, Bartos A, Egg R, et al. Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force. Eur J Neurol. 2006;13:913–22.CrossRef
6.
go back to reference Tourtellotte WW, Potvin AR, Fleming JO, et al. Multiple sclerosis: measurement and validation of central nervous system IgG synthesis rate. Neurology. 1980;30:240–4.CrossRef Tourtellotte WW, Potvin AR, Fleming JO, et al. Multiple sclerosis: measurement and validation of central nervous system IgG synthesis rate. Neurology. 1980;30:240–4.CrossRef
7.
go back to reference Ahn SM, Byun K, Cho K, et al. Human microglial cells synthesize albumin in brain. PLoS ONE. 2008;3:e2829.CrossRef Ahn SM, Byun K, Cho K, et al. Human microglial cells synthesize albumin in brain. PLoS ONE. 2008;3:e2829.CrossRef
8.
go back to reference 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. 1977;37:385–90.CrossRef 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. 1977;37:385–90.CrossRef
9.
go back to reference Andersson M, Alvarez-Cermeno J, Bernardi G, et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry. 1994;57:897–902.CrossRef Andersson M, Alvarez-Cermeno J, Bernardi G, et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry. 1994;57:897–902.CrossRef
10.
go back to reference Brettschneider J, Claus A, Kassubek J, Tumani H. Isolated blood–cerebrospinal fluid barrier dysfunction: prevalence and associated diseases. J Neurol. 2005;252:1067–73.CrossRef Brettschneider J, Claus A, Kassubek J, Tumani H. Isolated blood–cerebrospinal fluid barrier dysfunction: prevalence and associated diseases. J Neurol. 2005;252:1067–73.CrossRef
11.
go back to reference Blennow K, Fredman P, Wallin A, et al. Protein analysis in cerebrospinal fluid. II. Reference values derived from healthy individuals 18–88 years of age. Eur Neurol. 1993;33:129–33.CrossRef Blennow K, Fredman P, Wallin A, et al. Protein analysis in cerebrospinal fluid. II. Reference values derived from healthy individuals 18–88 years of age. Eur Neurol. 1993;33:129–33.CrossRef
12.
go back to reference Farrall AJ, Wardlaw JM. Blood–brain barrier: ageing and microvascular disease–systematic review and meta-analysis. Neurobiol Aging. 2009;30:337–52.CrossRef Farrall AJ, Wardlaw JM. Blood–brain barrier: ageing and microvascular disease–systematic review and meta-analysis. Neurobiol Aging. 2009;30:337–52.CrossRef
13.
go back to reference Reiber H. Flow rate of cerebrospinal fluid (CSF)—a concept common to normal blood–CSF barrier function and to dysfunction in neurological diseases. J Neurol Sci. 1994;122:189–203.CrossRef Reiber H. Flow rate of cerebrospinal fluid (CSF)—a concept common to normal blood–CSF barrier function and to dysfunction in neurological diseases. J Neurol Sci. 1994;122:189–203.CrossRef
14.
go back to reference Chen RL. Is it appropriate to use albumin CSF/plasma ratio to assess blood brain barrier permeability? Neurobiol Aging. 2011;32:1338–9.CrossRef Chen RL. Is it appropriate to use albumin CSF/plasma ratio to assess blood brain barrier permeability? Neurobiol Aging. 2011;32:1338–9.CrossRef
15.
go back to reference Reiber H. Proteins in cerebrospinal fluid and blood: barriers, CSF flow rate and source-related dynamics. Restor Neurol Neurosci. 2003;21:79–96.PubMed Reiber H. Proteins in cerebrospinal fluid and blood: barriers, CSF flow rate and source-related dynamics. Restor Neurol Neurosci. 2003;21:79–96.PubMed
16.
go back to reference Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders. III. Evaluation of IgG synthesis within the central nervous system in multiple sclerosis. Scand J Clin Lab Invest. 1977;37:397–401.CrossRef Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders. III. Evaluation of IgG synthesis within the central nervous system in multiple sclerosis. Scand J Clin Lab Invest. 1977;37:397–401.CrossRef
17.
go back to reference Parrado-Fernandez C, Blennow K, Hansson M, Leoni V, Cedazo-Minguez A, Bjorkhem I. Evidence for sex difference in the CSF/plasma albumin ratio in ~ 20,000 patients and 335 healthy volunteers. J Cell Mol Med. 2018;22:5151–4.CrossRef Parrado-Fernandez C, Blennow K, Hansson M, Leoni V, Cedazo-Minguez A, Bjorkhem I. Evidence for sex difference in the CSF/plasma albumin ratio in ~ 20,000 patients and 335 healthy volunteers. J Cell Mol Med. 2018;22:5151–4.CrossRef
18.
go back to reference Cosgrove KP, Mazure CM, Staley JK. Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry. 2007;62:847–55.CrossRef Cosgrove KP, Mazure CM, Staley JK. Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry. 2007;62:847–55.CrossRef
19.
go back to reference McCarthy MM, Arnold AP, Ball GF, Blaustein JD, De Vries GJ. Sex differences in the brain: the not so inconvenient truth. J Neurosci. 2012;32:2241–7.CrossRef McCarthy MM, Arnold AP, Ball GF, Blaustein JD, De Vries GJ. Sex differences in the brain: the not so inconvenient truth. J Neurosci. 2012;32:2241–7.CrossRef
20.
go back to reference Salden HJ, Bas BM, Hermans IT, Janson PC. Analytical performance of three commercially available nephelometers compared for quantifying proteins in serum and cerebrospinal fluid. Clin Chem. 1988;34:1594–6.CrossRef Salden HJ, Bas BM, Hermans IT, Janson PC. Analytical performance of three commercially available nephelometers compared for quantifying proteins in serum and cerebrospinal fluid. Clin Chem. 1988;34:1594–6.CrossRef
21.
go back to reference Reiber H. External quality assessment in clinical neurochemistry: survey of analysis for cerebrospinal fluid (CSF) proteins based on CSF/serum quotients. Clin Chem. 1995;41:256–63.CrossRef Reiber H. External quality assessment in clinical neurochemistry: survey of analysis for cerebrospinal fluid (CSF) proteins based on CSF/serum quotients. Clin Chem. 1995;41:256–63.CrossRef
22.
go back to reference Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444–52.CrossRef Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444–52.CrossRef
23.
go back to reference Gastaldi M, Zardini E, Leante R, et al. Cerebrospinal fluid analysis and the determination of oligoclonal bands. Neurol Sci. 2017;38:217–24.CrossRef Gastaldi M, Zardini E, Leante R, et al. Cerebrospinal fluid analysis and the determination of oligoclonal bands. Neurol Sci. 2017;38:217–24.CrossRef
24.
go back to reference Franciotta D, Avolio C, Capello E, Lolli F. Consensus recommendations of the Italian Association for Neuroimmunology for immunochemical cerebrospinal fluid examination. J Neurol Sci. 2005;237:5–11.CrossRef Franciotta D, Avolio C, Capello E, Lolli F. Consensus recommendations of the Italian Association for Neuroimmunology for immunochemical cerebrospinal fluid examination. J Neurol Sci. 2005;237:5–11.CrossRef
25.
go back to reference Seyfert S, Kunzmann V, Schwertfeger N, Koch HC, Faulstich A. Determinants of lumbar CSF protein concentration. J Neurol. 2002;249:1021–6.CrossRef Seyfert S, Kunzmann V, Schwertfeger N, Koch HC, Faulstich A. Determinants of lumbar CSF protein concentration. J Neurol. 2002;249:1021–6.CrossRef
27.
go back to reference Teunissen C, Menge T, Altintas A, et al. Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis. Multiple Scler. 2013;19:1802–9.CrossRef Teunissen C, Menge T, Altintas A, et al. Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis. Multiple Scler. 2013;19:1802–9.CrossRef
28.
go back to reference Weaving G, Batstone GF, Jones RG. Age and sex variation in serum albumin concentration: an observational study. Ann Clin Biochem. 2016;53:106–11.CrossRef Weaving G, Batstone GF, Jones RG. Age and sex variation in serum albumin concentration: an observational study. Ann Clin Biochem. 2016;53:106–11.CrossRef
29.
go back to reference Yin H, Wan Q, Tian Y, Zhao B, Deng Y. Female hormone 17beta-estradiol downregulated MMP-2 expression and upregulated A1PI expression in human corneal stromal cells. Cell Biochem Biophys. 2018;76:265–71.CrossRef Yin H, Wan Q, Tian Y, Zhao B, Deng Y. Female hormone 17beta-estradiol downregulated MMP-2 expression and upregulated A1PI expression in human corneal stromal cells. Cell Biochem Biophys. 2018;76:265–71.CrossRef
30.
go back to reference Gu C, Wang F, Hou Z, et al. Sex-related differences in serum matrix metalloproteinase-9 screening non-calcified and mixed coronary atherosclerotic plaques in outpatients with chest pain. Heart Vessels. 2017;32:1424–31.CrossRef Gu C, Wang F, Hou Z, et al. Sex-related differences in serum matrix metalloproteinase-9 screening non-calcified and mixed coronary atherosclerotic plaques in outpatients with chest pain. Heart Vessels. 2017;32:1424–31.CrossRef
31.
go back to reference Castellazzi M, Ligi D, Contaldi E, et al. Multiplex matrix metalloproteinases analysis in the cerebrospinal fluid reveals potential specific patterns in multiple sclerosis patients. Front Neurol. 2018;9:1080.CrossRef Castellazzi M, Ligi D, Contaldi E, et al. Multiplex matrix metalloproteinases analysis in the cerebrospinal fluid reveals potential specific patterns in multiple sclerosis patients. Front Neurol. 2018;9:1080.CrossRef
32.
go back to reference Na W, Lee JY, Kim WS, Yune TY, Ju BG. 17beta-estradiol ameliorates tight junction disruption via repression of MMP transcription. Mol Endocrinol. 2015;29:1347–61.CrossRef Na W, Lee JY, Kim WS, Yune TY, Ju BG. 17beta-estradiol ameliorates tight junction disruption via repression of MMP transcription. Mol Endocrinol. 2015;29:1347–61.CrossRef
33.
go back to reference Loke H, Harley V, Lee J. Biological factors underlying sex differences in neurological disorders. Int J Biochem Cell Biol. 2015;65:139–50.CrossRef Loke H, Harley V, Lee J. Biological factors underlying sex differences in neurological disorders. Int J Biochem Cell Biol. 2015;65:139–50.CrossRef
34.
go back to reference Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders. II. Relation of the concentration of the proteins in serum and cerebrospinal fluid. Scand J Clin Lab Invest. 1977;37:391–6.CrossRef Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders. II. Relation of the concentration of the proteins in serum and cerebrospinal fluid. Scand J Clin Lab Invest. 1977;37:391–6.CrossRef
35.
go back to reference Felgenhauer K. Protein size and cerebrospinal fluid composition. Klin Wochenschr. 1974;52:1158–64.CrossRef Felgenhauer K. Protein size and cerebrospinal fluid composition. Klin Wochenschr. 1974;52:1158–64.CrossRef
36.
go back to reference Chen RL, Chen CP, Preston JE. Elevation of CSF albumin in old sheep: relations to CSF turnover and albumin extraction at blood–CSF barrier. J Neurochem. 2010;113:1230–9.PubMed Chen RL, Chen CP, Preston JE. Elevation of CSF albumin in old sheep: relations to CSF turnover and albumin extraction at blood–CSF barrier. J Neurochem. 2010;113:1230–9.PubMed
37.
go back to reference McPherson K, Healy MJ, Flynn FV, Piper KA, Garcia-Webb P. The effect of age, sex and other factors on blood chemistry in health. Clin Chim Acta. 1978;84:373–97.CrossRef McPherson K, Healy MJ, Flynn FV, Piper KA, Garcia-Webb P. The effect of age, sex and other factors on blood chemistry in health. Clin Chim Acta. 1978;84:373–97.CrossRef
38.
go back to reference Byun K, Bayarsaikhan E, Kim D, et al. Activated microglial cells synthesize and secrete AGE-albumin. Anat Cell Biol. 2012;45:47–52.CrossRef Byun K, Bayarsaikhan E, Kim D, et al. Activated microglial cells synthesize and secrete AGE-albumin. Anat Cell Biol. 2012;45:47–52.CrossRef
39.
go back to reference Maeda M, Akai F, Nishida S, Yanagihara T. Intracerebral distribution of albumin after transient cerebral ischemia: light and electron microscopic immunocytochemical investigation. Acta Neuropathol. 1992;84:59–66.CrossRef Maeda M, Akai F, Nishida S, Yanagihara T. Intracerebral distribution of albumin after transient cerebral ischemia: light and electron microscopic immunocytochemical investigation. Acta Neuropathol. 1992;84:59–66.CrossRef
40.
go back to reference Park JH, Park JA, Ahn JH, et al. Transient cerebral ischemia induces albumin expression in microglia only in the CA1 region of the gerbil hippocampus. Mol Med Rep. 2017;16:661–5.CrossRef Park JH, Park JA, Ahn JH, et al. Transient cerebral ischemia induces albumin expression in microglia only in the CA1 region of the gerbil hippocampus. Mol Med Rep. 2017;16:661–5.CrossRef
Metadata
Title
Increased age and male sex are independently associated with higher frequency of blood–cerebrospinal fluid barrier dysfunction using the albumin quotient
Authors
Massimiliano Castellazzi
Andrea Morotti
Carmine Tamborino
Francesca Alessi
Silvy Pilotto
Eleonora Baldi
Luisa M. Caniatti
Alessandro Trentini
Ilaria Casetta
Enrico Granieri
Maura Pugliatti
Enrico Fainardi
Tiziana Bellini
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Fluids and Barriers of the CNS / Issue 1/2020
Electronic ISSN: 2045-8118
DOI
https://doi.org/10.1186/s12987-020-0173-2

Other articles of this Issue 1/2020

Fluids and Barriers of the CNS 1/2020 Go to the issue