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Age- and sex-related changes of S-100 protein concentrations in cerebrospinal fluid and serum in patients with no previous history of neurological disorder.

S-100 is a calcium-binding protein synthesized in astroglial cells in all parts of the central nervous system (CNS). It is present in the body in different subchains, of which the beta form (96%) predominates in the brain [1]. S-100 protein is normally not detectable in serum [1], but previous studies have demonstrated that increased S-100 concentrations in cerebrospinal fluid (CSF) are an index of the active phase of cell injury in patients with acute multiple sclerosis exacerbations, intracranial tumors, acute encephalomyelitis, and spinal cord compression [2]. High CSF concentrations of the S-100 protein have also been demonstrated in patients with glioblastoma, cervical compression, polyneuropathy, hydrocephalus, subarachnoid hemorrhage, encephalitis, meningitis, and cerebral infarction [3-8]. A previous study demonstrated age-related reference values for S-100 protein in CSF in children and adults with distinct neurological disorders [9].

We sampled serum and CSF from 75 men and 35 women undergoing various surgical procedures in spinal anesthesia. The patients had no actual or previous history of neurological disease. The study was performed to establish reference intervals of S-100 protein in CSF and serum.

From August 1995 to June 1996, serum and CSF samples were obtained from 110 patients undergoing surgery in spinal anesthesia. Before inclusion in the study, the patients answered a questionnaire concerning known neurological symptoms or diseases, and their hospital records were investigated. The inclusion criteria were as follows: no history of previous neurological symptoms or disease, no previous investigation in a neurological department, no present symptoms indicating any neurological disease, no evidence of malignant disease, age between 20 and 89 years, and signed informed consent form. The patients were divided into three age groups: 20-39 years, 40-59 years, and 60-89 years.

To determine S-100 protein concentration, 1 mL of CSF was taken from the spinal needle (gauge 25) immediately before the spinal anesthesia was performed. Simultaneously, 5 mL of serum was taken from a venous cannula. The samples were stored at -70[degrees]C within 10 min for later analysis.

The concentrations of S-100 protein in CSF and serum were analyzed by using a commercially available two-site IRMA kit (Sangtec Medical, Bromma, Sweden). Calibrators (1, 5, 10, and 20 [micro]g/L), controls (high and low), and diluent (also used as zero calibrator) were delivered from Sangtec Medical. CSF and serum samples were diluted with phosphate buffer and subsequently incubated with a plastic bead coated with monoclonal anti-S-100 antibody. After a 1-h incubation, the beads were washed to remove any unbound material. [sup.125]I-labeled anti-S-100 antibody was added, and after a 2-h incubation and subsequent washing, the amount of radioactive label bound to immobilized S-100 was measured in a gamma counter.

The sensitivity was 0.13 [micro]g/L S-100 protein, and the precision (CV) was: low concentration, 10%; high concentration, 5%.

The same calibration curves were used for CSF and serum, and each sample was analyzed in duplicate.

The procedure of collecting CSF from the 110 patients undergoing surgery in spinal anesthesia was approved by the ethical committee at the University Hospital of Tromso.

The scatter diagrams of S-100 protein contained one clear outlier (10.2 [micro]g/L), which was excluded, resulting in a normal distibution of values. P-values for sex dependency were calculated by using a two-tailed Student's t-test. The relation between age and S-100 protein in CSF in men and women was evaluated by using simple regression analysis. The median values and distribution percentiles in three age groups of men and women were estimated.

The mean age for men (n = 75) was 48 [+ or -] 15 years and for women (n = 35), 47 [+ or -] 15 years. The frequency distribution of age in men and women was equal.

S-100 protein was not dectable in any serum samples. There was a significant difference between men and women in S-100 protein concentrations in CSF (mean 1.9 [+ or -] 0.7 vs 1.5 [+ or -] 0.5 [micro]g/L, P = 0.0026). Fig. 1 illustrates the S-100 protein concentrations as a function of age (years) in both sexes. Concentrations of S-100 protein in CSF increased with age in both sexes, but this relation was less pronounced in women.

Table 1 lists age-related percentiles for the distribution of S-100 protein concentrations in men and women.

This is the first report of reference values of S-100 protein in CSF in patients with no previous history of neurological disorder. In 1992, van Engelen et al. [9] reported age-related changes of S-100 protein concentrations in CSF from children and adults undergoing neurological examination but without evidence of an organic neurological disease. The present report confirms their results, demonstrating an increase of S-100 protein concentrations in CSF with age from 21 to 84 years. Futhermore, we found sex-related dependency of S-100 protein in CSF, with significantly higher concentrations in men than in women.


There are several explanations for an age-related increase in S-100 protein in CSF: (a) The age dependency reflects increasing myelin loss with age; (b) the S-100 protein concentrations in the cells increase with age, whereas the turnover of the cells remains constant; or (c) the increase could be a result of increased half-life attributable to a reduced CSF bulk flow at older age [9-121.

S-100 protein was not detectable in serum in the present material including only neurologically healthy patients. Detectable serum S-100 protein indicates damage to glial cells and a reduced integrity of the blood-brain barrier (BBB). Ingebrigtsen et al. [13] reported increased serum concentrations of S-100 protein in patients with minor head injury. The protein was detectable in serum within 12 h after the injury, indicating a BBB dysfunction.

Persson et al. [61 demonstrated increased CSF concentrations of S-100 protein in ischemic stroke patients between 18 h and 4 days after the stoke. Thus, normal values of S-100 protein in CSF or serum do not exclude neurological disease, and serial measurements can elucidate the dynamics of the pathological process in relation to therapy.

The commercially available IRMA kit for analysis of S-100 protein in CSF and serum estimates values as low as 0.2 [micro]g/L with an acceptable precision. In one sample, the calibrators and controls showed higher concentrations of the protein than described from the manufacturer. Consequently, a consistent use of local laboratory controls in addition to the ordinary delivered calibrators and controls is recommended.

Recently, Lamers et al. [7] evaluated the value of neuron-specific enolase, S-100 protein, and myelin basic protein in CSF in patients who underwent a diagnostic lumbar puncture for a clinical indication such as CNS infection or another neurological disorder. In patients with cerebrovascular accidents such as minor cerebral infarcts, a significant increase in S-100 protein in CSF was demonstrated. The authors conclude that the concentrations of proteins in CSF depend on several factors, such as the distance between the affected brain area and the CSF compartment, the severity and extent of brain damage, the regional variability of these proteins in the brain, and the possible degradation of these proteins by macrophages and (or) proteinases either locally or in the CSF. Consequently, normal or increased concentrations of CSF-specific proteins in individual patients must be evaluated with caution. Although S-100 protein and other nervous-system-specific proteins are very sensitive indices of pathology [14], normal serum or CSF values do not exclude CNS disease.

The present study underlines the importance of considering both age and sex when S-100 protein concentrations in CSF are evaluated in patients with different neurological disorders.

We thank Sangtec Medical, Bromma, Sweden, for supporting analyzing kits.


[1.] Fagnart OC, Sindic CMJ, Laterre C. Particle counting immunoassay of S100 protein in serum. Possible relevance in tumors and ischemic disorders of the central nervous system. Clin Chem 1988;34:1387-91.

[2.] Michetti F, Massaro A, Russo G, Rigon G. The S-100 antigen in cerebrospinal fluid as a possible index of cell injury in the central nervous system. J Neurol Sci 1980;44:259-63.

[3.] Aurell A, Rosengren LE, Karlsson B, Olsson JE, Zbornikova V, Haglid KG. Determination of S-100 and glial fibrillary acidic protein concentrations in cerebrospinal fluid after brain infarction. Stroke 1991;22:1254-8.

[4.] Kato K, Nakajima T, Ishiguro Y, Matsutani. Sensitive enzyme immunoassay for S-100 protein: determination in human cerebrospinal fluid. Biomed Res 1982;3:24-8.

[5.] Mokuno K, Kato K, Kawai K, Matsuoka Y, Yanagi T, Sobue I. Neuron-specific enolase and S-100 protein levels in cerebrospinal fluid of patients with various neurological diseases. J Neurol Sci 1983;60:443-51.

[6.] Persson L, Hardemark HG, Gustafsson J, Rundstrom G, Mendel-Hartvig I, Esscher T, PahIman S. S-100 protein and neuron-specific-enolase in cerebrospinal fluid and serum: markers of cell damage in human central nervous tissue. Stroke 1987;18:911-8.

[7.] Lamers KJB, van Engelen BGM, Gabreels FJM, Hommes OR, Borm GF, Wevers RA. Cerebrospinal neuron-specific enolase, S-100 and myelin basic protein in neurological disorders. Acta Neurol Scand 1995;92:247-51.

[8.] Sindic CJM, Chalon MP, Cambiaso CL, Laterre EC, Masson PL. Assessment of damage to the central nervous system by determination of S-100 protein in the cerebrospinal fluid. J Neurol Neurosurg Psychiatry 1982;45:1130-5.

[9.] van Engelen BGM, Lamers KJB, Gabreels FJM, Wevers RA, van Geel WJA, Borm GF. Age-related changes of neuron-specific enolase, S-100 protein, and myelin basic protein concentrations in cerebrospinal fluid. Clin Chem 1992;38:813-6.

[10.] Henriksson L, Voigt K. Age-dependent difference of distribution and clearance patterns in normal RIHSA cisternograms. Neuroradiology 1976;12: 103-7.

[11.] Loefberg H, Grubb A0, Sveger T, Olsson JE. The cerebrospinal fluid and plasma concentrations of gamma-trace beta2 microglobulin at various ages and in neurological disorders. J Neurol 1980;223:159-70.

[12.] Schliep G, Felgenhauer K. Serum-CSF protein gradients, the blood-CSF barrier and the local immune response. J Neurol 1978;218:77-96.

[13.] Ingebrigtsen T, Romner B, Langbakk B. Increased serum concentrations of protein S-100 after minor head injury: a biochemical serum marker with prognostic value? J Neurol Neurosurg Psychiatry 1995;59:103-4.

[14.] Royds JA, Timberly WR, Taylor CB. Levels of enolase and other enzymes in the cerebrospinal fluid as indices of pathological change. J Neurol Neurosurg Psychiatry 1981;44:1129-35.

Oystein Nygaard, Bodil Langbakk, (1) and Bertil Romner * (Depts. of Neurosurgery and Clin. Chem., Univ. Hosp. of Tromso, 9038 Tromso, Norway; * author for correspondence: fax + 47 77 62 70 52)
Table 1. Percentiles for the distribution of S-100 protein
concentrations ([micro]g/L) in CSF in three age groups of
patients with no previous history of neurological disorders.


Age, years P10 P25 P50 P75 P90

 20-39 1.0 1.1 1.4 2.0 2.2
 40-59 1.2 1.3 1.8 2.2 2.5
 60-89 1.4 1.9 2.2 2.7 3.1


Age, years P10 P25 P50 P75 P90

 20-39 0.8 0.8 1.4 1.6 2.2
 40-59 0.9 1.2 1.4 1.6 2.4
 60-89 1.1 1.3 1.7 2.1 2.3

10th to 90th percentiles (P = percentile).
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Title Annotation:Technical Briefs
Author:Nygaard, Oystein; Langbakk, Bodil; Romner, Bertil
Publication:Clinical Chemistry
Date:Mar 1, 1997
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