Article, Neurology

The value of serum tau protein for the diagnosis of intracranial injury in minor head trauma

Original Contribution

The value of serum tau protein for the diagnosis of Intracranial injury in minor head trauma

Cemil Kavalci MDa, Murat Pekdemir MDa,*, Polat Durukan MDa, Necip Ilhan PhDb,

Mustafa Yildiz MDa, Selami Serhatlioglu MDc, Dilara Seckin MDb

aDepartment of Emergency Medicine, Firat University Faculty of Medicine, ElazVg?/Turkey

bDepartment of Biochemistry and Clinical Biochemistry, Firat University Faculty of Medicine, ElazVg?/Turkey

cDepartment of Radiodiagnostic, Firat University Faculty of Medicine, ElazVg?/Turkey

Received 16 June 2006; revised 25 July 2006; accepted 14 October 2006

Abstract

Objective: Tau protein localizes in the axons of neuron cells, and it is released secondarily from the central nervous system because of hypoxia and trauma. In the present study, it was aimed to investigate the value of serum tau protein levels in diagnosing intracranial pathologies in minor head trauma.

Methods: Patients were categorized into 2 groups: those without intracranial lesions in head CTs (group 1) and those with lesions in head CTs (group 2). Serum tau protein levels were determined.

Results: Group 1 (n = 55) median serum tau protein level was 16.29 pg/mL (2.12-215.97 pg/mL) and group 2 (n = 33) median serum tau protein level was 18.39 pg/mL (2.19-714.47 pg/mL). Statistical analysis revealed no significant difference between the 2 groups for tau protein values, sex, age, mechanism of trauma, and Glasgow Coma Scale score.

Conclusion: It is suggested that serum tau protein has limited value in minor head trauma.

D 2007

Introduction

Head injury is one of the major health problems in emergency medicine. There are approximately 1 million emergency department (ED) visits annually for traumatic brain injury in the United States [1], or an incidence of 56.4/ 100000 of US population [2].

This study was presented at Turkiye Acil TVp Sempozyumu & 3. Acil Hemsirelig?i ve Paramedik Sempozyumu, 24-27 KasVm 2004, Gaziantep.

* Corresponding author. Department of Emergency Medicine, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey. Tel.: +90 262 3038547; fax: +90 262 3038003.

E-mail address: [email protected] (M. Pekdemir).

Minor or mild Traumatic brain injuries (defined as loss of consciousness b30 minutes, amnesia b24 hours, or peri- injury confusion/disorientation in a patient with a Glasgow Coma Scale [GCS] score of 13-15) constitute nearly 70% to 90% of traumatic brain injuries that occur worldwide [3-5]. Ruling out pathology is essential for patients with closed head injury because it may require immediate intervention or cause rapid deterioration. At present, the ED workup of intracranial hemorrhage, Brain edema, and impending herni- ation is predominantly limited to clinical evaluation and computed tomography (CT) [6]. However, the routine use of CT in Screening patients with minor head trauma (MHT) for intracranial lesions is expensive. It is estimated that even a 10% reduction in the number of CT scans in patients with MHT would save more than $20 million per year [7].

0735-6757/$ – see front matter D 2007 doi:10.1016/j.ajem.2006.10.008

Emergency physicians have sought for the development of a clinical decision rule, which is essential for more standard- ized and efficient use of cranial CT in MHT [8]. Moreover, to standardize and improve the emergency management of patients with MHT, diagnostic and prognostic use of serum markers such as Neuron-specific enolase, creatine kinase-BB, myelin basic protein, and S-100b for traumatic brain injury have also been intensely investigated. Tau protein is also one of these serum markers; however, to date, it has not been extensively studied in patients with MHT.

Tau protein has a microtubule structure and is localized in the axons of central nervous system (CNS) neurons. [9-11]. It is expressed from a single gene that undergoes alternate splicing resulting in 6 tau isoforms with apparent molecular masses between 48 and 68 kd [12]. It binds to axonal microtubules and forms axonal microtubule bundles. These bundles form important structural elements in the axonal cytoskeleton, and they are also critical elements in the axoplasmic flow of proteins between the nerve terminal and neuronal cell body [13]. Tau also stabilizes the microtubules and arranges the internal cell vesicular transport and interacts with actins in neuronal formation and cell skeleton. Hypoxic or traumatic Axonal injury causes tau protein to be released extracellularly by CNS neurons [14].

The aim of our study was to evaluate the role of serum tau protein concentrations in patients with MHT. We also investigated the concordance between cranial CT findings and serum Tau levels. The relationship between other demographic and diagnostic clinical factors and serum tau level was also investigated.

Methods

This prospective cross-sectional study was approved by the local ethics committee of Firat University. Informed consent was obtained from every patient.

The patients with diagnosis of MHT admitted to the ED of the university hospital between January 8 and June 26, 2003, were prospectively analyzed. Patients with Blunt head trauma in the first 24 hours requiring screening with cranial CT were included in the study. The inclusion and exclusion criteria are shown in Table 1.

Demographic features of the patients, mechanisms of the trauma, presence accompanying injuries, time passed after

Table 1 Inclusion and exclusion criteria of study in patients with MHT

Inclusion criteria Exclusion criteria

Blunt head trauma Penetrating head trauma patients with cranial CT coagulation disorder or use

of anticoagulants

Presentation at first History of brain operation 24 hours of trauma

Old neurologic deficit Presentation after 24 hours after trauma

group (n = 55)

group (n = 33)

Brain edema

26

Linear fracture

6

6

Depressed fracture

4

Pneumocephalus

5

Cerebral contusion

3

Intraparenchymal

2

hemorrhage

SAH

1

epidural hematoma

1

trauma, GCS scores, physical examination findings, cranial CT results, and ED outcomes were also gathered.

Table 2 Pathologic findings in cranial CT

Findings Head CT (–) Head CT (+)

SAH indicates subarachnoid hemorrhage.

Venous blood samples taken from each patient were centrifuged for 15 minutes at 4000g. After the centrifuga- tion, each sample and serum was stored at –808C while awaiting assay for tau protein. Human tau immunoassay kit (BioSource International, Camarillo, CA) with sandwich enzyme-linked immunosorbent assay method was used in the analysis. Sensitivity of enzyme-linked immunosorbent assay assessment was less than 12 pg/mL [14].

All of the cranial CT studies done in the study were evaluated by the same radiologist.

The patients were divided into 2 groups. Group 1 consisted of patients with normal cranial CT findings and linear fracture, whereas the patients in group 2 had intracranial lesions such as brain edema, epidural hemato- ma, subdural hematoma, subarachnoid bleeding, cerebral contusion, intraparenchymal bleeding, and depressed frac- ture on cranial CT.

SPSS 11.0 software (SPSS Inc, Chicago, Ill) was used for the statistical analysis. demographic and clinical features of the patients were examined according to mean F SD, median, range, and percentage. The normal distributions were tested with Shapiro-Wilk test. Kruskal-Wallis test was used for multiple continuous group comparisons, whereas Student t test and Mann-Whitney U test were used for 2 continuous group comparisons. v2 Test was used for the categorical variables. Linear regression was used to examine the influence of independent variables (GCS score, pathol- ogy in cranial CT, sex, age, injury mechanism, presence accompanying injuries, and time from the trauma to blood sampling) on serum tau protein levels. P b .05 was considered to be statistically significant. Power of the study was determined as 0.23.

Results

Eighty-eight patients fitting the inclusion criteria were included in the study. There were 55 patients (63%) in group 1 and 33 patients (37%) in group 2.

group (n = 55)

group (n = 33)

Age (mean F SD)

24.36 F 20.4

24.91 F 16.8

.892

Admission time, min

160 (30-1080)

180 (60-840)

.474

(median [range])

Sex (male/female)

40/15

22/11

.717

Children/adult

24/31

10/23

.309

Mechanism of

trauma

Motor vehicle

17

12

accidents

Pedestrian accidents

10

3

.892

Falls from height

25

17

Violent assaults

3

1

Concomitant injury

16 (29%)

17 (51%)

.061

SBP (mean F SD)

109.82 F 21.5

120.91 F 26.3

.045

DBP (mean F SD)

67.45 F 13.8

72.42 F 14.8

.123

Pulse rate

95.44 F 18.1

93.64 F 16.1

.630

(mean F SD)

RR (mean F SD)

20.07 F 2

21.12 F 2.9

.077

Fifty-five patients (62.5%) had isolated head injuries, and

Table 3 Demographic and clinical features of patients

Features Head CT (–) Head CT (+) P

SBP indicates systolic blood pressure; DBP, diastolic blood pressure; RR, respiration rate.

33 patients (37.5%) had accompanying injuries. These injuries were extremity fracture (13 patients), pneumothorax (3 patients), vertebrae fracture (3 patients), splenic rupture (2 patients), Liver laceration (1 patient), and pelvic fracture (1 patient). Pathologic findings in cranial CT are shown in Table 2.

Demographic and clinical features

Sixty-two patients (70.5%) were male, and 54 (61.4%) were adults. The mean age was 24.57 F 19.0 years (3 months-80 years). The demographic and clinical features of the patients are presented in Table 3. No significant difference was found between the groups in terms of demographic and clinical features except for mean systolic blood pressure.

Falling from height was the most frequent trauma mechanism in the study (47.7%). The most frequently seen symptoms were drowsiness (47.7%), headache (40.9%),

amnesia (23.9%), unconsciousness (10.2%), and seizure (4.5%). The most frequently observed findings in physical

examinations were scalp laceration (56.8%), scalp hemato- ma (20.5%), depressed fracture (4.5%), periorbital hemato- ma (3.4%), focal neurologic findings (2.3%), otorrhea (1.1%), and rhinorrhea (1.1%).

Tau protein

The median serum tau protein level was 16.29 pg/mL (2.12-215.97 pg/mL) in group 1, whereas it was 18.39 pg/ mL (2.19-714.47 pg/mL) in group 2, with no significant difference between the groups ( P = .515).

The median serum tau protein levels were 16.62 pg/mL (2.12-215.97 pg/mL) and 17.60 pg/mL (3.42-714.47 pg/ mL) for the male and female patients, respectively, also with no statistically significant difference ( P = .714).

There was also no significant difference in serum tau protein levels between children and adults (18.61 vs 16.62 pg/mL, P = .377).

Median serum tau protein levels also showed no significant difference according to the mechanism of injury (Table 4).

Serum levels of tau protein according to GCS scores are also shown in Table 5. There was no statistically significant difference in serum tau protein levels according to GCS scores ( P = .408).

A multiple regression model was constructed to inves- tigate the influence of the variables on tau protein levels. Glasgow Coma Scale score, pathology in cranial CT, sex, age, injury mechanism, presence of accompanying injuries, and the time from the trauma to blood sampling were examined by multiple regression analysis. Glasgow Coma Scale score was the only influential variable on tau protein levels (b = –0.301, P = .004).

Discussion

Serum tau protein levels were increased in patients with MHT who had intracranial lesions demonstrated in cranial CT; however, the increase was not statistically significant. In addition, there was no difference in serum tau protein levels between subgroups (age, sex, mechanism of injury, and GCS scores).

Traditionally, GCS score has been used to determine the category of brain injury. The term MHT is usually used for patients with a GCS score of 13 or higher. However, some

Table 4 Tau protein levels according to Trauma mechanisms

Mechanism

Head CT (–) group* (median)

Patients (n)

Head CT (+) group**median)

Patients (n)

P

MVA

19.76 (3.57-215.97)

17

15.82 (2.19-37.79)

12

.479

Pedestrian

24.55 (5.91-201.09)

10

24.35 (9.59-50.29)

3

.866

Falls

15.07 (2.12-175.82)

25

23.72 (3.42-714.47)

17

.163

Violent assault

14.76 (6.13-17.99)

3

19.94

1

MVA indicates motor vehicle accident.

* P = .694, v2 = 1.447; Kruskal-Wallis test.

** P = .564, v2 = 2.039; Kruskal-Wallis test.

Table 5 The patients’ tau protein levels according to GCS scores

GCS score

Head CT (–) group* (median)

Patients (n)

Head CT (+) group**median)

Patients (n)

P

13

25.06 (6.23-714.47)

7

14

14.47 (3.17-175.82)

9

66.57 (10.96-197.21)

6

.099

15

16.67 (2.12-215.97)

46

16.98 (2.19-125.21)

20

.586

* P = .838, v2 = .042; Kruskal-Wallis test.

** P = .101, v2 = 4.579; Kruskal-Wallis test.

authors have suggested that patients with a GCS score of 13 could be excluded from the mild category and could be placed in the moderate-risk group because of their high incidence of lesions requiring neurosurgical intervention [15]. As a limitation in the study, patients with a GCS score of 13 were also included; however, the results show that there was no significant difference between the serum tau protein levels of patients with a GCS score of 13 and those of patients with GCS score of 14 and 15.

The tau protein level that can be measured in serum is released from CNS neurons secondarily because of trauma and hypoxia. Previous studies suggest that measuring the levels of the microtubule-associated protein tau in cerebro- spinal fluid (CSF) may provide an alternative method to assessing axonal injury in traumatic brain injury. Tau is a protein localized primarily in neurons and demonstrates selective axonal stabilization as well, resulting in tau sequestration in the axonal compartment [9,16].

Schunk and colleagues [17] have shown that there is a positive correlation between high serum and CSF tau protein levels and intracranial pressure, but a negative correlation with poor Clinical prognosis. Few postmortem studies have reported that tau protein levels were high in oligodendrogliocytes of people who died after sustaining head injuries [18]. It has also been suggested that it is clinically useful to measure CSF tau protein levels in axonal injuries by head traumas [19]. Furthermore, there is a relationship between serum tau protein levels and intracra- nial injury, disability, and death only in the Closed head injuries [20]. The discrepancy between findings in this study and those in aforementioned studies may be attributed to larger sample sizes and the inclusion of patients with only MHT [21-25].

Bulut and colleagues [26] have reported that serum tau

protein levels of patients with mild traumatic brain injury were relatively higher than those of healthy volunteers; however, the difference was not statistically significant. Our study also revealed that serum tau protein levels in patients with intracranial lesions increased in correspondence to their cranial CT, although there was no statistically significant difference. The lack of statistical significance may be due to the poor power of the study.

The GCS score negatively relates with serum tau protein level. The correlation between severity of head injury and serum tau protein level appears to be consistent with the literature. The GCS score has also a negative relationship with both CNS degeneration and serum tau protein level.

To date, there is no report in the literature showing a relationship between serum tau protein level and trauma mechanism, presence of other injuries, age, and sex. Similarly, there was also no significant correlation between serum tau protein levels and these variables in our study.

Some researchers have investigated S-100b protein as an indicator of CNS injury. Woertgen and colleagues [27] have demonstrated that serum S-100b levels might be useful in reflecting clinical conditions of patients with Severe head injuries. High serum levels of S-100b related to intracranial pathologies in magnetic resonance imaging have also been reported [28]. Yamazaki and colleagues [29] have reported that the sensitivity and specificity of neuron-specific enolase levels higher than 20 ng/mL are 87% and 82%, respectively, in intracranial pathologies demonstrated in cranial CT. However, in our study, no significant correlation was found between tau protein levels and pathologic findings in cranial CT.

Limitations of the study

The statistical power of the study is poor because of the relatively small number of patients. Secondly, a small number of patients (7 patients, 8%) with a GCS score of 13 were also included in the study. However, although all these patients had intracranial pathologies demonstrated in cranial CT, the results showed that there was no significant difference between the serum tau protein levels of patients with a GCS score of 13 and those of patients with GCS score of 14 and 15.

In conclusion, our study showed that there was a relationship between serum tau protein concentration and severity of trauma, although it did not achieve statistical significance. However, serum tau protein concentration does not seem to be useful in indicating the intracranial lesions in patients with MHT. There was also no significant correlation between serum tau protein levels and cranial CT, age, sex, trauma mechanism, presence of other injuries, GCS score, symptoms, and physical examination findings. Although the results of this study should be viewed with caution because of the relatively small number of patients, they still provide an evidence for the significance of serum tau protein concentrations in patients with MHT. Tau can assist physicians in deciding whether cranial CT is necessary for patients with MHT. Further studies with higher number of patients can provide better information about the relationship between tau protein and head trauma.

References

  1. Jager TE, Weiss HB, Coben JH, et al. Traumatic brain injuries evaluated in U.S. emergency departments, 1992-1994. Acad Emerg Med 2000;7:134 – 40.
  2. Bazarian JJ, McClung J, Cheng YT, et al. Emergency department management of mild traumatic brain injury in the USA. Emerg Med J 2005;22:473 – 7.
  3. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. Report to Congress. Mild traumatic brain injury in the United States: steps to prevent a serious Public health problem. Atlanta (Ga)7 Centers for Disease Control and Prevention; 2003.
  4. Cassidy JD, Carroll LJ, Peloso PM, et al. Incidence, risk factors and prevention of mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on mild traumatic brain injury. J Rehabil Med 2004;(Suppl 43):28 – 60.
  5. von Holst H, Cassidy JD. Mandate of the WHO Collaborating Centre Task Force on mild traumatic brain injury. J Rehabil Med 2004; (Suppl 43):8 – 10.
  6. Neumar RW. Rule out TBI? Serum markers for traumatic brain injury. Ann Emerg Med 2002;39:342 – 3.
  7. Reinus WR, Wippold II FJ, Erickson KK. Practical selection criteria for noncontrast cranial computed tomography in patients with head trauma. Ann Emerg Med 1993;22:1148 – 55.
  8. Stiell IG, Wells GA, Vandemheen K, et al. Variation in ED use of computed tomography for patient with Minor head injury. Ann Emerg Med 1997;30:14 – 22.
  9. Binder LI, Frankfurter A, Rebhun LI. The distribution of tau in the mammalian central nervous system. J Cell Biol 1985;101:1371 – 8.
  10. Kosik KS, Finch EA. MAP2 and tau segregate into dendritic and axonal domains after the elaboration of morphologically distinct neurites. J Neurosci 1987;7:3142 – 53.
  11. Litman P, Barg J, Rindzoonski L, et al. Subcellular localization of tau mRNA in differentiating neuronal culture: implications for neuronal polarity. Neuron 1993;10:627 – 38.
  12. Goedert M, Spillantini MG, Jakes R, et al. Multiple isoforms of human microtubule-associated protein tau: sequence and localization in neuro- fibrillary tangles and Alzheimer’s disease. Neuron 1989;3:519 – 26.
  13. Zemlan FP, Rosenberg WS, Luebbe PA, et al. Quantification of axonal damage in traumatic brain injury: affinity purification and charac- terization of cerebrospinal fluid tau proteins. J Neurochem 1999;72: 741 – 50.
  14. Human Tau (total) Biosource Immunoassay Kit Catalog #KHB0042/ KHB0041. Biosite website available at: http://www.biosource.com/ content/catalogContent/tds3/moreinfo/KHO0631%20pr328%20revA1% 20mar2706%20(Hu%20Tau%20[pT181]).pdf [Accessed: 1.06.2006].
  15. Dietrich AM, Bowman MJ, Ginn-Pease ME, et al. Pediatric head injuries: can clinical factors reliably predict an abnormality on computed tomography? Ann Emerg Med 1993;22:1535 – 40.
  16. Gruskin KD, Schutzman SA. Head trauma in children younger than 2 years: are there predictors for complications? Arch Pediatr Adolesc Med 1999;153:15 – 20.
  17. Schunk JE, Rodgerson JD, Woodward GA. The utility of head computed tomographic scanning in pediatric patients with normal neurologic examination in the emergency department. Pediatr Emerg Care 1996;12:160 – 5.
  18. Quayle KS, Jaffe DM, Kuppermann N, et al. Diagnostic testing for acute head injury in children: when are head computed tomography and skull radiographs indicated? Pediatrics 1997;99:11 – 23.
  19. Ingebrigtsen T, Romner B, Kock-Jensen C. Scandinavian guidelines for initial management of minimal, mild and moderate head injuries. J Trauma 2000;18:760 – 6.
  20. Jagoda AS, Cantrill SV, Wears RL, et al. Clinical policy: neuro- imaging and decision-making in adult mild traumatic brain injury in the acute setting. Ann Emerg Med 2002;40:231 – 49.
  21. Kanai Y, Hirokawa N. Sorting mechanisms of tau and MAP2 in neurons: suppressed axonal transit of MAP2 and locally regulated microtubule binding. Neuron 1995;14:421 – 32.
  22. Zemlan FP, Jauch EC, Mulchahey JJ, et al. C-tau biomarker of neuronal damage in severe brain injured patients: association with Elevated intracranial pressure and clinical outcome. Brain Res 2002;947:131 – 9.
  23. Irving EA, Nicoll J, Graham DI, et al. Increased tau immunoreactivity in oligodendrocytes following human stroke and head injury. Neurosci Lett 1996;213:189 – 92.
  24. Raabe A, Grolms C, Keller M, et al. Correlation of computed tomography findings and serum brain damage markers following severe head injury. Acta Neurochir 1998;140:787 – 92.
  25. Shaw GJ, Jauch EC, Zemlan FP. Serum cleaved tau protein levels and clinical outcome in adult patients with closed head injury. Ann Emerg Med 2002;39:254 – 7.
  26. Bulut M, Koksal O, Dogan S, et al. Tau protein as a serum marker of brain damage in mild traumatic brain injury: preliminary results. Adv Ther 2006;23:12 – 22.
  27. Woertgen C, Rothoerl RD, Metz C, et al. Comparison of clinical, radiologic and serum marker as prognostic factors after severe head injury. J Trauma 1999;47:1126 – 30.
  28. Ingebrigtsen T, Romner B. Serial S-100 protein measurements related to early magnetic resonance imaging after minor head injury. J Neurosurg 1996;85:945 – 8.
  29. Yamazaki Y, Yada K, Morii S, et al. Diagnostic significance of serum neuron specific enolase and myelin basic protein assay in patients with acute head injury. Surg Neurol 1995;43:267 – 71.