Leakage of brain-originated proteins in peripheral blood: temporal profile and diagnostic value in early ischemic stroke

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Abstract

The clinical value of determination of CNS-specific proteins in peripheral blood at the acute phase of ischemic stroke is unclear. S-100 protein and neurone specific enolase were serially quantified in peripheral blood at the acute and subacute phase of ischemic stroke (hours 4, 8, 10, 24 and 72 after onset of symptoms). Whereas S-100 protein was detected in none of the matched control subjects, this protein was observed in 17/24 of the stroke patients. Patients with detectable S-100 protein had significantly larger infarctions. Cortical infarctions had already significantly increased S-100 concentrations at days 1 and 3 compared to subcortical or brainstem infarctions. Patients with volumes of brain lesion of >5 ccm exhibited significantly increased serum levels of S-100 at hours 10, 24 and 72 compared to those with lesion volumes of <5 ccm. At hours 10, 24 and 72, concentrations of S-100 correlated with scores of neurological outcome. Although kinetics of release of neurone specific enolase showed a similar pattern of release in blood, no significant association to outcome or extent of brain damage was observed. These results suggest that S-100 protein and not NSE may represent a useful serum marker of brain damage in acute stroke.

Introduction

There is increasing evidence that a considerable part of the ischemic brain tissue does not immediately become necrotic, but succumbs to delayed degeneration (Pulsinelli et al., 1982). This constitutes the rationale for hyperacute treatments aimed to restore perfusion and to protect neuronal tissue from necrosis. However, early diagnosis of structural brain damage, and exclusion of reversible functional cerebral disorders associated with focal neurological deficits is often difficult. Although some reports have noted slight hypodensities and mass effects on computerized tomography within hours (Fieschi et al., 1989, Tomsick et al., 1990), general consensus is that ischemic changes are usually not evident on a scan until 24–48 hours after infarction and that it should be used to exclude conditions mimicking ischemia (e.g., hematoma or tumor).

Molecular markers of brain injury have, therefore, attracted considerable attention (Schmechel et al., 1978, Usui et al., 1994). S-100 is a calcium-binding acid protein soluble in 100% ammonium-sulfate, and constitutes a major component of the cytosol of glial cells (Endo et al., 1981). Neurone-specific enolase (NSE) is a dimeric glycolytic enzyme, which originates from the cytoplasm of neurons and neuroendocrine cells (Marangos and Schmechel, 1987). Earlier studies investigated the leakage of these proteins in CSF and showed that CSF-concentrations of S-100 (Persson et al., 1987, Aurell et al., 1991) and NSE (Hardemark et al., 1988) are elevated in cerebral ischemia. Invasive CSF-sampling in stroke patients is, however, difficult in many cases. The possibility of a simple blood test, that can be added to the initial routine laboratory work-up and that allows serial investigations, is attractive.

Recently, it has been shown that S-100 and NSE can be detected in the peripheral blood of stroke patients (Fagnart et al., 1988, Cunningham et al., 1991, Schaarschmidt et al., 1994, Niebroj-Dobosz et al., 1994) and in experimental cerebral ischemia (Horn et al., 1995). However, the association of these potential markers, i.e., S-100 to clinical outcome and extent of brain damage has not been characterized in a large number of patients. More importantly, appearance of CNS-specific proteins have, to our knowledge, not been serially investigated in a large cohort earlier than 24 h after onset of disease, when information concerning the presence of structural brain damage is of actual therapeutic relevance. Since their extravasation is likely to be transient, understanding of their kinetics is the prerequisite for a possible clinical use.

In this study, the kinetics of passage of S-100 protein and NSE from CNS in peripheral blood were comparatively characterized in ischemic stroke, beginning within the first hours of disease, and their appearance in blood has been related to extent of brain damage and clinical outcome.

Section snippets

Patients.

Twenty-four consecutive patients (14 females, 10 males), aged between 65–89 (median 72) years, admitted within 4 h after onset of symptoms of ischemic stroke were studied. Diagnosis was based on history, neurological exam and computerized tomography. Patients with TIA, hemorrhage or conditions interfering with the aim of the study (e.g., malignancies, other types of brain injury, severe renal or hepatic diseases) were excluded. The neurological deficits were determined between the second and

Kinetics of release of S-100 in blood

Whereas S-100 protein was detectable in none of the control subjects, this protein was found in 17/24 (71%) of the stroke patients (i.e., 3/24 at hour 4, 5/24 at hour 8, 9/24 at hour 10, 14/23 at hour 24, and 12/21 at hour 72). Whereas at hour 4, concentrations of S-100 did not significantly differ between stroke patients and controls, levels of S-100 protein were significantly increased at hour 8 and remained significantly increased for the entire study period (Fig. 1).

Kinetics of release of NSE in blood

Mean concentrations of

Discussion

Modern approaches to patients with cerebral infarction depend on early diagnosis. This study demonstrated that the brain specific S-100 protein was released in systemic circulation of stroke patients in relation to extent of brain damage within less than 24 h. This protein could not be detected in any of the healthy subjects. Since leakage of this protein from its intracellular glial localization via the extracellular space into the circulation depends on astroglial cell disintegration, its

Acknowledgements

The authors acknowledge the excellent technical assistance of I. Poltersdorf and A. Kornmüller. We thank H.O. Müller for the interesting discussions. We gratefully acknowledge the support from KLIMA 69 (1995).

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