Serum S100beta: a noninvasive marker of blood-brain barrier function and brain lesions

Abstract

Background: S100beta protein is expressed constitutively by brain astrocytes. Elevated S100beta levels in cerebrospinal fluid and serum reported after head trauma, subarachnoid hemorrhage, and stroke were correlated with the extent of brain damage. Because elevated serum S100beta also was shown to indicate blood-brain barrier (BBB) dysfunction in the absence of apparent brain injury, it remains unclear whether elevation of serum levels of S100beta reflect BBB dysfunction, parenchymal damage, or both.

Methods: The authors conducted a prospective study of serum S100beta levels in six patients who underwent hyperosmotic BBB disruption (BBBD) with intraarterial chemotherapy for primary central nervous system lymphoma. In addition, 53 serum S100beta samples were measured in 51 patients who had a variety of primary or metastatic brain lesions at the time of neuroimaging.

Results: S100beta was correlated directly with the degree of clinical and radiologic signs of BBBD in patients who were enrolled in the hyperosmotic study. In patients with neoplastic brain lesions, gadolinium enhancement on a magnetic resonance image was correlated with elevated S100beta levels (n = 45 patients; 0.16 +/- 0.1 microg/L; mean +/- standard error of the mean) versus nonenhancing scans (n = 8 patients; 0.069 +/- 0.04 microg/L). Primary brain tumors (n = 8 patients; 0.12 +/- 0.08) or central nervous system metastases also presented with elevated serum S100beta levels (n = 27 patients; 0.14 +/- 0.34). Tumor volume was correlated with serum S100beta levels only in patients with vestibular schwannoma (n = 6 patients; 0.13 +/- 0.10 microg/L) but not in patients with other brain lesions.

Conclusions: S100beta was correlated directly with the extent and temporal sequence of hyperosmotic BBBD, further suggesting that S100beta is a marker of BBB function. Elevated S100beta levels may indicate the presence of radiologically detectable BBB leakage. Larger prospective studies may better determine the true specificity of S100beta as a marker for BBB function and as an early detection or follow-up marker of brain tumors.

FIGURE 1

The correlation between serum S100β levels and the effectiveness of brain-blood barrier (BBB) disruption (BBBD) by intraarterial mannitol. (A) Experiments from a total of 54 procedures show elevation of S100β levels after BBBD. However, S100β levels increased significantly only after intraarterial chemotherapy (approximately 10 minutes after mannitol injection). (B) The correlation between initial S100β increase after mannitol injection (S100β_post) and pre-BBBD S100β levels (S100_pre) in serum. Note that a significant elevation after osmotic BBBD occurred only when pre-BBBD levels were < 10 μg/L. (C) The same as A but with data points that were obtained with S100β < 10 μg/L purged. Note the significant increase in S100β immediately after BBBD. Asterisks indicate P < 0.01. Data are shown as the mean ± standard error of the mean. NICU: NeuroIntensive Care Unit.

FIGURE 2

Immunocytochemical detection of S100β in brain lesions. Note that metastases from breast carcinoma display abundant S100β immunoreactivity, as visualized by immunoperoxidase reaction (brown). In contrast, samples from brain tissue invaded by primary central nervous system lymphoma (PCNSL) were characterized by a virtual absence of S100β immunoreactivity, consistent with the fact that PCNSL typically is devoid of normal central nervous system tissue. The insets show enlarged vessel structures to emphasize the lack of perivascular immunoreactivity for S100β protein.

FIGURE 3

The correlation between radiologic findings, brain lesions, and serum S100β levels. (A1–A3) Actual MRI scans from selected patients (for details, see text) showing a meningioma with extensive peritumoral edema (A1); a meningioma from a postresection, negative MRI scan (A2); and breast carcinoma metastases (A3). (A) Box plot of S100β levels in patients undergoing contrast-enhanced magnetic resonance imaging (MRI) scans. Note that negative findings correlated well with normal S100β levels (dotted line). The error bars represent maximal and minimal levels in each group. (B) S100β levels in patients affected by a variety of tumor pathologies. (C) There was a lack of correlation between tumor size and S100β levels in serum. Data were obtained from meta-static and primary brain tumor samples. (D) There was a positive correlation between S100β levels and the size of vestibular schwannoma (P < 0.01). Gd: gadolinium; Allmets: all metastatic brain tumors; Breast Met: breast metastases.

FIGURE 4

Time dependent changes in magnetic resonance imaging (MRI)-gadolinium signals and serum S100β levels in a patient with glioblastoma. The first image was obtained 6 weeks after surgery to remove a malignancy from a male patient age 80 years. The numbers indicate S100β levels determined from a blood sample that was taken the same day of MRI investigations. The second image was taken 2 months later, while distal recurrence was evident 6 months after surgical resection. Note the concomitant increase in the S100β level.