Restorative Neurology and Neuroscience - Volume 21, issue 3-4

Authors: Herrmann, Manfred | Johnsson, Per | Romner, Bertil

Article Type: Research Article

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 75-77, 2003

Authors: Reiber, Hansotto

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) routine analysis for diagnosis of neurological diseases is based on the concepts for discrimination of blood-derived and brain-derived immunoglobulin fractions in CSF. The actual molecular flux/CSF flow theory of the blood/CSF barrier function, which founded the hyperbolic discrimination lines in quotient diagrams, is derived from the laws of molecular diffusion combined with CSF flow rate. It emerged from this theory that the decrease of CSF flow rate is sufficient to explain …quantitatively the increase of CSF protein concentrations as observed in many neurological diseases. With this concept of CSF flow rate as the modulator of the normal and pathological blood-CSF barrier function, we got for the first time a theoretical frame work to explain also quantitatively the dynamics of brain-derived proteins and their source related (neurons and glial cells or leptomeningal cells) differences. The review of the anatomical, physiological and biophysical knowledge points to the new interpretations: The changing albumin quotient is an indicator of changing CSF flow rate and not for a morphological "leakage" of the blood-brain barrier. As an application of these concepts the dynamics of brain-derived molecules in blood are discussed with two examples: beta trace protein, flowing with CSF into venous blood, and neuron-specific enolase, passing from tissue into blood the opposite direction of serum proteins, again a gradient-dependent protein diffusion across the intact blood vessel wall. Show more

Keywords: blood-CSF barrier function, blood-brain barrier, Cerebrospinal fluid, CSF flow, brain-derived proteins, blood-derived proteins, protein dynamics, theory

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 79-96, 2003

Authors: Van Eldik, Linda J. | Wainwright, Mark S.

Article Type: Research Article

Abstract: Glia play active and vital roles in the CNS, including regulation of brain development, maintenance of cellular homeostasis and reparative responses to acute and chronic neurologic insults. However, in pathological conditions, glial function may be dysregulated resulting in enhanced neuroinflammation and further neurologic injury. The fundamental concept that aberrant regulation of a normally beneficial process may instead result in pathology is exemplified by the properties of the glial-derived protein, S100B. In the developing brain and …following acute glial activation in response to injury, S100B acts as a neurotrophic factor and neuronal survival protein. In contrast, overproduction of S100B by activated glia can lead to exacerbation of neuroinflammation and neuronal dysfunction. This duality of S100B actions, both reparative and degenerative, is consistent with the compelling clinical evidence of the association between increases in S100B levels and outcome following brain injury. S100B levels generally correlate with the severity of damage and may have predictive value for adverse neurological outcomes. The cumulative data support the potential of S100B as a biomarker for brain damage, implicate glial activation as a possible treatment target in acute and chronic CNS disorders, and highlight the dual role of glia in the reparative and pathologic responses to neurologic injury. Show more

Keywords: S100, neurotrophic, neuronal death, neuroinflammation, brain damage, calcium binding protein, glial activation, astrocyte

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 97-108, 2003

Authors: Marchi, Nicola | Rasmussen, Peter | Kapural, Miranda | Fazio, Vince | Kight, Kelly | Mayberg, Marc R. | Kanner, Andrew | Ayumar, Barbara | Albensi, Ben | Cavaglia, Marco | Janigro, Damir

Article Type: Research Article

Abstract: Purpose: Occurrence of brain damage is frequently associated with abnormal blood-brain barrier (BBB) function. Two brain-specific proteins, S100β and neuron-specific enolase (NSE) are released systemically in a variety of neurological diseases, but S100β levels sometimes rise in the absence of neuronal damage, suggesting that S100β is a marker of BBB rather than neuronal damage. Methods: We measured both proteins in the serum of patients undergoing iatrogenic BBB disruption with intrarterial mannitol, followed by …chemotherapy. Results: Serum S100β increased significantly after mannitol infusion (p<0.05) while NSE did not. Furthermore, in a model of intracerebral hemorrhage, S100β increases in CSF did not lead to serum changes at a time when the BBB was intact. Modeling of S100β release from the CNS suggested that low (<0.34 ng/ml) serum levels of S100β are consistent with BBB opening without CNS damage, while larger increases imply synthesis and release from presumable damaged glia. Conclusions: Thus, S100β in serum is an early marker of BBB openings that may precede neuronal damage and may influence therapeutic strategies. Secondary, massive elevations in S100β are indicators of prior brain damage and bear clinical significance as predictors of poor outcome or diagnostic means to differentiate extensive damage from minor, transient impairment. Show more

Keywords: S100β, cerebrovascular disease, diagnostics, endothelium, magnetic resonance imaging, neurological disorders, cerebral ischemia

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 109-121, 2003

Authors: Snyder-Ramos, Stephanie A. | Böttiger, Bernd W.

Article Type: Research Article

Abstract: Although 25–50% of patients suffering from cardiac arrest can be stabilised haemodynamically, the hospital discharge rate is only 2–14%. One of the major causes of this discrepancy is persistent brain damage. Studies to assess the prognostic value of early prediction of neurologic and overall outcome in patients with cardiac arrest have not yet produced precise and generally accepted diagnostic rules. As apparative diagnostic methods often fail to predict neurologic outcome, the role of molecular markers has …come a focus of common interest for early outcome prediction. This systematic review article aims to give an overview on the most important molecular markers for neurologic and overall outcome prediction and outline the advantages, clinical implications and ethical issues in patients undergoing cardiopulmonary resuscitation after cardiac arrest. For this purpose, the traditional marker for brain damage, the neuron-specific enolase, a gamma gamma isomer of enolase and cytoplasmatic enzyme of glycolysis, and the astroglial protein S100, a calcium-binding protein regulating neuronal differentiation, outgrowth, and apoptosis, are analysed and their role discussed as a marker for brain damage in general and recovery after cardiopulmonary resuscitation following cardiac arrest. Neuron-specific enolase has been investigated as a neuro-marker after brain damage and for outcome prediction in unconscious patients. Whereas the protein S100 has proven to be a good marker for neuronal damage after isolated brain injury, its role in cardiac surgery is not as clear: at least, in the early postoperative phase S100 is not a sole marker for neurologic damage, as release of S100 from cardiac tissue and other sources has also been demonstrated. However, the persistent elevation of S100 after cardiac surgery is specific for neurologic impairment. Most interestingly, after cardiac arrest the protein S100 has shown to be a good survival marker for overall outcome prediction. Although it cannot be absolutely determined whether cerebral or cardiac release of S100 is predominant in this clinical setting, recent studies have revealed that S100 serum levels are a useful diagnostic tool for outcome prediction. In contrast, after cardiac arrest serum levels of protein S100 did not reach a 100% specificity and sensitivity in clinical studies, and, therefore, elevated S100 in these patients has to be interpreted with caution. Nonetheless, low S100 serum levels have been correlated with good outcome and, therefore, even if all other diagnostic tests indicate poor outcome, all therapeutic efforts must be undertaken, as no single study has shown that normal S100 serum levels were associated with poor prognosis. Show more

Keywords: molecular neuro-marker of brain damage (S100, NSE), cardiac arrest, cardiopulmonary resuscitation, neurologic and overall outcome, prognosis

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 123-139, 2003

Authors: Abdul-Khaliq, Hashim | Schubert, Stephan | Stoltenburg-Didinger, Gisela | Huebler, Michael | Troitzsch, Dirk | Wehsack, Anke | Boettcher, Wolfgang | Schwaller, Beat | Crausaz, Michel | Celio, Marco | Schröter, Matthias L. | Blasig, Ingolf E. | Hetzer, Roland | Lange, Peter E.

Article Type: Research Article

Abstract: Objective: Brain injury and altered psychomotor development in infants, children and adults after cardiac surgery using cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) is still a matter of concern. Early diagnosis and identification of brain injury that has occurred or is ongoing by measurement of biochemical markers in serum may have diagnostic and prognostic value. The aim of the experimental studies in an animal model was therefore to investigate the release patterns of astroglial …and neuronal markers in serum and to determine the morphological and immunohistochemical changes in the brain of animals undergoing similar perfusion conditions of CPB and a period of DHCA. Methods: Fourteen New Zealand rabbits, (weight, 3.1 ± 0.25 kg) were anesthetized, intubated and mechanically ventilated. Four animals were sham operated and served as controls. After median sternotomy the animals were connected to CPB by cannulation of the aorta and right atrium. Full flow CPB (200–250 ml/kg/min) was initiated to achieve homogeneous systemic cooling. Circulatory arrest of 60 minutes was induced when rectal and nasopharyngeal temperature of 14°C was achieved. After rewarmed reperfusion and establishment of stable cardiac ejection the animals were weaned from CPB and monitored for 6 hours. Then the animals were killed, the brain was immediately removed and cut in standardized sections. These were fixated, embedded in paraffin and stained for further quantitative histological studies. In the brain astrocyte reactivity for S-100B was assessed immunocytochemically (DPC® Immustain Los Angeles, USA). Monoclonal mouse anti-human neurospecific enolase (NSE) antibody was used for the localization of NSE in the fixed and paraffin embedded brain (NSE-DAKO, H14). The concentrations of S-100B protein and neurospecific enolase (NSE) in the serum were analyzed using a commercially available immunoluminometric assay (LIA-mat®, Sangtec® 100, Byk-Sangtec). Immunospecific monoclonal anti-parvalbumin antibody was used for the detection of parvalbumin in the brain. Serum concentrations of parvalbumin were analyzed using a newly developed ELISA method. Results: In all experimental animals a significant increase of the serum concentration of the astroglial protein S-100B was found immediately after reperfusion and the termination of CPB. In contrast the serum levels of the neuronal proteins parvalbumin and NSE were not increased, but rather decreased. Light microscopy and electron microscopy revealed perivascular astrocytic swelling and minor neuronal cell injury. In comparison to the sham operated animals, increased immunohistochemical staining of S-100B was found. This increased reactivity of S100B antibody was found in the astrocytic processes with immediate connection to the perivascular space and around the perivascular oedema. The immunocytochemical stainings for NSE and parvalbumin in the neuronal cells was not different from that of sham-operated animals and indicated well preserved neurons. Show more

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 141-150, 2003

Authors: Jönsson, Henrik

Article Type: Research Article

Abstract: Serum determinations of the glial protein S100B has been found to correlate with brain damage after cardiac surgery. Forty-eight hours and later after surgery, increased S100B levels correlates with the presence of brain infarction, and the extent of infracted brain tissue. S100B at this time-point has been shown to predict long-term outcome, higher S100B levels correlated with decreased survival. Early levels (2–8 hours after surgery) of S100B have shown disparate results when trying to correlate it …with postoperative cognitive decline. One reason for the lack of strong correlation could be the contamination of S100B from shed blood the first hours after surgery. Show more

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 151-157, 2003

Authors: Raabe, Andreas | Kopetsch, Olaf | Woszczyk, Alina | Lang, Josef | Gerlach, Rüdiger | Zimmermann, Michael | Seifert, Volker

Article Type: Research Article

Abstract: Purpose: There is growing evidence that S-100B protein may be used as a novel biochemical marker of brain cell damage, measured by a simple blood test. In this paper, we summarize the current knowledge about S-100B serum measurements in severe head injury and address actual controversies. Methods: The material of the present analysis consists of a MEDLINE literature search for S-100 and severe head injury from 1966 to 2003. Studies of S-100B in severe head injury were reviewed for …their information about the potential clinical value of this marker. Results: A total of 18 clinical studies were identified and reviewed. Peak values of serum S-100B were demonstrated to have the highest correlation to any endpoint parameter. Admission values also have a significant correlation to injury severity and outcome but show a highly time dependent temporal course. There is extracranial release of S-100B in multitrauma patients in the first 48 hours, but the impact is limited as many studies have found a clear relationship between S-100B and injury severity, imaging findings and outcome. Conclusion: S-100B belongs to a new generation of molecular serum markers of brain damage. These markers will have potential as a surrogate outcome marker or monitoring parameters for both clinical and experimental settings. Show more

Keywords: S-100 protein, severe head injury, prognosis, outcome

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 159-169, 2003

Authors: Ingebrigtsen, Tor | Romner, Bertil

Article Type: Research Article

Abstract: Purpose. To provide an overview of clinical research on the use of biochemical serum markers for traumatic brain injury (TBI) in the evaluation of patients with mild head injuries (MHI). Methods. The MEDLINE database was searched for publications on biochemical serum markers of TBI until August 2002. Clinical studies addressing their use in MHI were reviewed. Results. Desirable characteristics for biochemical serum markers of TBI were identified. Creatine kinase isoenzyme BB (CK-BB), neuron specific …enolase (NSE) and S-100B protein have been most extensively studied. The sensitivity and specificity of CK-BB is inadequate for use as an indicator of traumatic brain injury. Serum levels of NSE do not correspond to the amount of TBI, probably because of its long (20 h) half-life. S-100B serum levels are correlated to both clinical measures of injury severity, neuroradiological findings and outcomes in several studies from different authors. Conclusion. Currently, S-100B protein is the most promising marker for evaluation of TBI in patients with MHI. Show more

Keywords: head injury, biochemical markers, creatine kinase, neuron specific enolase, S-100B protein, glial fibrillary acidic protein

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 171-176, 2003

Authors: Herrmann, Manfred | Ehrenreich, Hannelore

Article Type: Research Article

Abstract: Purpose: Ischemic stroke is associated with a variety pathophysiological changes affecting both glial and neuronal brain tissue. These changes are mirrored in the release of specific proteins into peripheral blood. Neurone-specific enolase (NSE), protein S100B and glial fibrillary acidic protein (GFAP) are those proteins investigated most often as peripheral surrogate markers of brain damage after stroke in humans. Methods and results: In the present article we present data which show that the release patterns of …neuronal and glial tissue derived proteins after acute stroke are associated with the neuroradiological and neurobehavioral consequences of ischemic brain lesions and, additionally, may be useful in short-term outcome prediction. Kinetics of protein serum concentrations, however, are highly dependent on subtype of stroke lesions and do not merely reflect the degree of brain damage. They rather express complex neuronal-glial interactions as a (patho-)physiological consequence of ischemic brain lesions. We further demonstrate that S100B release patterns do reflect successful neuroprotective drug treatment with recombinant human erythropoietin (EPO) in acute stroke patients. Conclusions: The analysis of poststroke serum concentrations of glial tissue derived proteins might be a promising strategy to monitor and evaluate neuroprotective approaches in stroke treatment. Show more

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 177-190, 2003

Authors: Otto, Markus | Wiltfang, Jens

Article Type: Research Article

Abstract: In principle, two research approaches can be considered for the laboratory diagnosis of transmissible spongiform encephalopathies (TSE): (i) the direct detection of PrP^{Sc} and (ii) the detection of surrogate markers in biological materials that show an altered pattern of expression in early stages of the disease or are used in the differential diagnosis of other dementias and thus enable an exclusion diagnosis. This review concentrates on the second approach. It was shown …that a single determination of just a few markers (tau-protein, S-100B, 14-3-3-protein) was already sufficient to achieve a high degree of diagnostic certainty in the diagnosis of CJD. On the basis of the available data, it is to be expected that a combination of these markers will bring improved diagnostic strength with regard to the differential diagnosis of dementias as a whole. This especially applies to some of the subtypes of CJD and Alzheimer's dementia (AD). Show more

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 191-209, 2003