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Ann Thorac Surg 2004;77:2034-2038
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Tau protein in the cerebrospinal fluid is a marker of brain injury after aortic surgery

^a Department of Cardiovascular Surgery, Hokkaido University Hospital, Sapporo, Japan

Accepted for publication December 17, 2003.

^* Address reprint requests to Dr Shiiya, Department of Cardiovascular Surgery, Hokkaido University Graduate School of Medicine, N14W5, Kita-ku, Sapporo 060-8648, Japan
e-mail: shiyanor{at}med.hokudai.ac.jp

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
BACKGROUND: Tau is a protein localized primarily in neurons, especially in the axonal compartment. Cerebrospinal fluid tau levels are elevated in acute stroke and head traumas. The purpose of this study is to elucidate the alterations of cerebrospinal fluid tau levels in patients with or without neurologic complication after aortic surgery.

METHODS: Twenty-eight patients undergoing descending thoracic (n = 8) or thoracoabdominal (n = 20) aortic surgery were enrolled. Cerebrospinal fluid tau levels were measured before operation and at seven time points up to the 72nd postoperative hour, and were compared with cerebrospinal fluid S100B levels.

RESULTS: Two patients developed brain infarction, including the one with paraplegia. In these patients, 20-fold to 100-fold tau elevation was observed, but S100B elevation was less evident in the patient without paraplegia. Three other patients developed spinal cord injury. Additional three patients suffered from temporary neurologic dysfunction of the brain. Tau levels in the latter three patients showed tenfold elevation and were higher than those in the three patients with spinal cord injury or those in the patients without neurologic complication up to 24 postoperative hours. The S100B levels were also higher in the three patients with temporary neurologic dysfunction of the brain than in the patients without neurologic complication at the conclusion of surgery. From 6 to 24 postoperative hours, they were higher in the three patients with spinal cord injury than in the patients without neurologic complication.

CONCLUSIONS: These preliminary results suggest that cerebrospinal fluid tau levels reflect brain injury. Because tau levels may separate the patients with temporary neurologic dysfunction, they may serve as a useful marker of brain injury.

	Introduction

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S100B proteins in the serum or the cerebrospinal fluid (CSF) have recently been extensively studied during cardiovascular surgery to evaluate various techniques or strategies of brain or spinal cord protection [1]. It has a molecular weight of 21 kDa. As a marker of spinal cord injury, CSF levels have been preferred [2, 3], because influence of contamination from the tissues other than the central nervous system is much less likely, and CSF can easily be collected when CSF drainage (CSFD) is employed to protect the spinal cord. Van Dongen and colleagues [2, 4] were the first to report the correlation between CSF S100B levels and neurologic outcome after aortic operations. We have shown that, in patients with spinal cord injury, CSF S100B levels are from tenfold to 100-fold higher than the serum levels, and can be a highly sensitive marker of spinal cord injury [3].

In our previous study [3] we have also observed small elevations of CSF S100B in those patients without spinal cord injury who underwent deep hypothermic operations. This elevation did not seem due to contamination from the use of the pump suction, because CSF levels were still higher than the serum levels. However, it is not clear whether or not this elevation is due to subclinical neuronal injury, because S100B is derived from the glial and Schwann cells and not from the neurons. Other markers that are directly derived from the neurons may help determine the clinical significance of this observation.

Tau protein in the CSF has been used for the diagnosis of Alzheimer's disease [5]. It is a protein localized primarily in neurons, especially in axonal compartments [6]. Previous studies have demonstrated that CSF tau levels are elevated in acute stroke and head traumas [7, 8]. Therefore, tau levels in CSF may serve as a marker of neurologic injury after aortic operations. The purpose of this study is to evaluate the alterations of CSF tau levels in the patients undergoing descending thoracic or thoracoabdominal aortic surgery, and to elucidate their clinical significance by comparing them with the data of CSF S100B.

	Material and methods

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A total of 28 patients who underwent prosthetic replacement of the descending thoracic or thoracoabdominal aorta and CSFD between April 1997 and June 2000 were enrolled in this study. The study protocol was in accordance with the guide for clinical study by our institutional review board. All patients gave a written informed consent for CSFD and subsequent measurements of the CSF samples. There were 16 males and 12 females, and their age ranged from 26 to 79 (mean, 64 ± 13). Eight patients underwent replacement of the descending thoracic aorta and 20 patients the thoracoabdominal aorta (Crawford type I for 6, type II for 5, and type III for 9 patients). Aortic dissection was present in 10 patients. One patient underwent emergent operation for rupture. Ten patients had a history of previous aortic operation; from the aortic root to the aortic arch in three, the aortic arch in four, the descending thoracic aorta in two, and the abdominal aorta in two patients.

All operations were performed through a left posterolateral thoracotomy combined with or without thoracoabdominal incision. As an adjunct, distal aortic perfusion by partial cardiopulmonary bypass and mild hypothermia was employed in 22 patients, while deep hypothermic total cardiopulmonary bypass was used in six patients. In the patients with deep hypothermia, proximal aortic perfusion was maintained throughout the operation in two patients, while the remaining four patients underwent brain circulatory arrest (32 to 64 minutes). Distal aortic perfusion was maintained in three patients, while the remaining three patients underwent open distal aortic anastomosis.

Cerebrospinal fluid drainage and measurement of S100B and tau
Lumbar CSFD was performed through a 16G indwelling catheter, which was inserted through the L4/5 intervertebral space after induction of the anesthesia. Cerebrospinal fluid was allowed to freely drain if CSF pressure exceeded 13 cm H₂O. Cerebrospinal fluid drainage was discontinued from 12 hours to 72 hours after surgery according to the patients' condition. The samples of CSF were collected just before and immediately after the operation, and at 6, 12, 18, 24, 48, and 72 postoperative hours. Samples were centrifuged and the supernatant was immediately frozen at –80°C for the later measurements. A two-site immunoradiometric assay kit (Sangtec Medical, Bromma, Sweden) was used to measure S100B, and an enzyme linked immunosorbent assay kit (Innogenetics, Gent, Belgium) was used to measure tau. Both kits were purchased. The manner of storage does not influence the measurements of either S100B or tau (manufacturer's information). The minimum detectable level was 0.2 µg/L for S100B and 75 pg/mL for tau.

Statistical analysis
All values are expressed as mean ± standard deviation. Statistical analyses were performed using the StatView 5.0 program (SAS Institute Inc., Cary, NC). The repeated measures analysis of variance test was used to evaluate the difference among groups, time-related differences, and their interaction for each protein. The relationship between CSF S100B and tau was analyzed by the linear regression model. One way analysis of variance, followed by Scheffe's post hoc test, was used to compare the difference at each time point. For comparisons of other continuous variables, one way analysis of variance was used. The ² test was used to compare prevalence among the groups. A p value less than 0.05 was considered significant.

	Results

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Clinical results
There was one hospital death due to mesenteric necrosis, which occurred one month after surgery and was caused by isolated dissection of the superior mesenteric artery that was not involved in the extent of aortic reconstruction. Postoperative spinal cord injury occurred in four patients, two paraplegia in the patients with nondissecting descending thoracic aneurysms and two paraparesis in the patients with nondissecting thoracoabdominal aneurysms (type I and III). Spinal cord functions of the two patients with paraparesis recovered almost completely within two months. In these four patients, distal aortic perfusion was used as an adjunct. One of the paraplegic patients who underwent emergent operation for rupture, and another patient who underwent deep hypothermic operation with brain circulatory arrest, had multiple embolic brain infarction as evidenced by brain computed tomographic scan. Postoperative temporary neurologic dysfunction of the brain (TND), as defined by Ergin and colleagues [9], occurred in three patients who underwent deep hypothermic operation, two of whom underwent brain circulatory arrest. These patients also underwent brain computed tomography or magnetic resonance imaging, and were evaluated by neurologists for diagnosis and treatment.

Changes in CSF tau and S100B

View larger version (22K): [in this window] [in a new window]   Fig 1. Changes in cerebrospinal fluid tau levels. (T group = patients with temporary neurologic dysfunction of the brain; S group = patients with spinal cord injury without brain infarction; N group = patients without neurologic complication; B patient = patient with brain infarction; BS patient = patient with both brain infarction and paraplegia; Pre. = just before the operation; Postop. hour = postoperative hour.)

View larger version (21K): [in this window] [in a new window]   fig 2. Changes in cerebrospinal fluid S100B levels. (T group = patients with temporary neurologic dysfunction of the brain; S group = patients with spinal cord injury without brain infarction; N group = patients without neurologic complication; B patient = patient with brain infarction; BS patient = patient with both brain infarction and paraplegia.)

The remaining 26 patients were divided into the following three groups according to the neurologic complications. The T group consisted of three patients with TND, the S group consisted of three patients with spinal cord injury, and the N group consisted of 20 patients without neurologic complication. Changes in CSF S100B and tau levels in these three groups were summarized in Table 1.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The present study evaluates CSF tau as a marker of neurologic injury after aortic operations. Although the number of patients was small, the striking elevation of CSF tau in the patients with brain infarction and the marked difference observed between the patients with TND and those without it suggest that it may be used as a marker of brain injury including TND. Cerebrospinal fluid tau, on the other hand, failed to detect spinal cord injury in this study, while S100B seemed to reflect both brain and spinal cord injury.

These results are surprising, because tau is abundantly present in neurons, and is not specific to the brain. Tau is a microtubule-associated protein that serves to stabilize the microtubular network in axons. It has multiple isoforms, and the low molecular weight isoforms of 45 to 68 kDa are widely distributed in the central nervous system, including the spinal cord [10]. In the brain they are more abundant in the white matter than in the gray matter [6]. In the spinal cord the high molecular weight isoforms of 110 to 130 kDa, which contain the entire sequence present in the low molecular weight isoforms, is also abundant [11]. The enzyme linked immunosorbent assay kit used in the current study is based on the anti-tau antibody AT120 [5], which reacts with both the low and high molecular weight isoforms (manufacturer's information). Therefore, elevated CSF tau levels are also expected, at least theoretically, in the patients with spinal cord injury.

One possible explanation for this surprising result is the difference in the relative volume of the gray and white matter between the brain and the spinal cord. Because the white matter that is rich in tau proteins occupies a larger part in the brain than in the spinal cord, brain injury is more likely to be associated with elevated CSF tau levels than the spinal cord injury. In addition, because motor neurons in the anterior horn are more susceptible to ischemia than the surrounding motor tract fibers, transient spinal cord ischemia may result in selective motor neuron death. This type of injury has been reported in the model of spinal cord ischemia [12], and may not be reflected in the CSF tau levels because axons of the spinal cord motor neurons are located in the peripheral nerve.

These considerations, however, may not explain the behavior of the S100B proteins in the present study, which were elevated both in the patients with brain injury and in those with spinal cord injury. S100B proteins are derived from Schwann cells and glial cells, which predominantly exist in the white matter. Therefore, if the difference in the relative volume of the gray and white matter between the brain and the spinal cord or selective motor neuron death in the spinal cord was the reason for the relative brain-specificity of CSF tau, S100B should equally be brain-specific. S100B, however, may be influenced by contamination from the use of pump suction even though CSF levels are used, because the blood brain barrier may be deteriorated when neurologic injury is present. In addition, S100B is released not only after astrocyte death but also after its activation. Because simultaneous measurements of serum levels in our previous study revealed that CSF levels were higher than the serum levels in these patients [3], the influence of contamination is not likely. Therefore, S100B release through astrocyte activation that occurs after ischemic insult may be the key to understanding the difference between the behavior of S100B and that of tau.

Use of CSFD in the presence of total heparinization for cardiopulmonary bypass has been concerned with the risk of intracranial hemorrhage. We used 2 mg/kg of heparin for partial cardiopulmonary bypass and 3 mg/kg for deep hypothermic operations, and have so far not experienced any such complications. However, experiences with such complications in other centers (personal communication) led us to abandon the use of CSFD in patients undergoing deep hypothermic brain circulatory arrest. Because TND is a problem that is frequently seen in this particular group of patients, and measurements of CSF samples are not practical in the patients who do not undergo CSFD, the clinical value of CSF tau measurements may be limited. This also means that further clinical studies with larger numbers of patients are difficult in the same setting. In the experimental studies that evaluate the various brain protection strategies, however, measurement of CSF tau may still have a role once our finding that it effectively separated the patients with TND from those without it early after surgery is validated. In addition, measurements of the serum tau levels may be an interesting study. In the present study, we did not measure the serum tau levels because the assay kit used in this study is not specific for cleaved tau and tau is not normally detectable in the serum by this kit. However, recent studies using anti-tau antibodies that react with cleaved tau and are not commercially available, have suggested that tau may be detected in the serum after head traumas [13, 14]. Therefore, further studies in animal models or those using serum samples and different antibodies are warranted to validate our results.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We thank Professor Naoki Mafune, MD, PhD, Rakuno Gakuen University, for help in the measurement of CSF tau levels.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Norihiko Shiiya Takashi Kunihara Tsukasa Miyatake Keishu Yasuda Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shiiya, N. Articles by Yasuda, K. Search for Related Content PubMed PubMed Citation Articles by Shiiya, N. Articles by Yasuda, K. Related Collections Cerebral protection