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Child's Nervous System

, Volume 24, Issue 3, pp 349–356 | Cite as

Apolipoprotein E genotype and traumatic brain injury in children—association with neurological outcome

Original Paper
First Online:
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Revised:

Abstract

Objective

To determine whether the presence of Apolipoprotein E ε4 genotype (ApoE ε4) is associated with outcomes of traumatic brain injury in children.

Materials and methods

The ApoE genotype was examined in the group of 70 pediatric patients who suffered from traumatic brain injury. The group consists of 48 boys and 22 girls, and the most frequent was the E3 isoform of ApoE. Polymerase chain reaction/restriction fragment length polymorphism method was used for the ApoE genotype assessment. The severity of trauma was assessed by Glasgow Coma Scale and graded into three categories. The presence of focal neurology signs, comparing the admission and dimission status, and duration of hospital care were observed. The neurological outcome after 1 year was assessed by Glasgow Outcome Scale. Trauma severity was compared with the neurological outcome, according to different ApoE genotypes. For statistical processing, t test, nonparametric Wilcoxon test, Fisher, and χ 2 tests were used.

Conclusion

Our results suggest the association between the ApoE genotype and outcome of traumatic brain injury in children. Patients with ApoE ε4 genotype were more likely to have severe clinical symptomatology and unfavorable neurological outcome after traumatic brain injury compared to significantly better outcome with other ApoE genotype.

Keywords

Brain injuries Child Apolipoprotein E4 Association Glasgow Coma Scale Glasgow Outcome Scale 

Introduction

The aim of the study was to assess the possible relation between the ApoE genotype and the severity, clinical course, and outcome of traumatic brain injuries in children. The hypothesis was, that similar to adult patients, the possession of ApoE epsilon 4 allele in children is associated with more serious course and poorer outcome of brain injuries.

Human Apolipoprotien E (ApoE) is produced by glial cells (astrocytes and microglia) and plays a role in transporting lipids in the nervous system by influencing lipoprotein uptake by receptors such as the LDL receptor [9, 19]. This transport system provides nerve cells by the cholesterol and phospholipids needed for the maintenance and repair of neuronal membranes, dendritic remodeling, and synaptogenesis [6]. Generally, ApoE is thought to be responsible for the transportation of lipids, namely, cholesterol, within the brain, maintaining structural integrity of the microtubule within the neuron, assisting with neural transmission, and plays a role in immunology response to cerebral trauma [15].

Astrocytes contained in the blood–brain barrier produce ApoE to injured neurons, so that ApoE may play an isoform-specific role in determining the initial response and the subsequent development to acute brain injury [5, 11, 14]. The impact of injury to the central nervous system is in part to be modulated by the different isoforms of ApoE. ApoE exists in three isoforms named E2, E3, and E4. The gene associated with ApoE influences the construction and regeneration of the neuronal cytoskeleton in allele-specific manner: ApoE ɛ2/ɛ2 may be neuroprotective, whereas ApoE ɛ4/ɛ4 may be neurodestructive [9]. The neuroprotective effect of E3 allele was observed in experimental conditions, whereas E4 allele increased fatalities in closed-head injury in transgenic mice [18].

Previous clinical studies concerning the severities and outcome of traumatic brain injury in adults support the opinion that ApoE ɛ4 allele possession is associated with a poor prognosis and unfavorable outcome after the brain injury [2, 4, 5, 8, 10, 25, 26]. Patients possessing the ApoE ɛ4 allele had a significantly longer hospital stay and unfavorable outcomes after brain injury [2], had a significantly decreased postinjury performance on neuropsychological tests after the mild head injury [25], and had increased risk of late posttraumatic seizures [4]. It was also observed that patients with the ApoE ɛ3/ɛ3 genotype had a better chance of recovery after cardiopulmonary resuscitation than patients with ApoE ɛ4/ɛ4 genotype [22].

Materials and methods

In our study, we examined the ApoE genotype in the group of 70 pediatric patients who suffered from traumatic brain injury and were treated at Clinic of Pediatric Surgery, Orthopedic and Traumatology in Brno Faculty Hospital from 2000 to 2005. The group consists of 48 boys (68.6%) and 22 girls (31.4%). The youngest patient was 1 month old, the oldest 17 years old, the mean age was 9.47 years, SD ± 4.87.

We ascertained the presence of focal neurological signs in patients during hospital admission and dimission and the severity of neurological status according to Glasgow Coma Scale (GCS). The neurological outcome after 1 year was assessed according to Glasgow Outcome Scale (GOS), and these data were compared and processed statistically.

All of the patients in our study underwent clinical neurological examination comparing the hospital admission and dimission status, skull X ray, and brain CT scan. The most common diagnosis was cerebral contusion, present in 45 patients (64.3%), from that in 32 boys (71.1%) and 13 girls (28.9%). Traumatic subdural hematoma was diagnosed in 11 cases (15.7%), epidural hematoma in 30 cases (42.8%), traumatic subarachnoideal hemorrhage in 19 cases (27.1%), hemocephalus in 3 cases (4.2%), traumatic brain edema in 19 cases (27.1%), and diffuse axonal injury in 6 cases (8.6%). Impressive skull fracture was diagnosed in 11 patients (15.7%) and fractura baseos cranii in 17 patients (24.3%). The structure of the diagnoses and the predominance of epidural hematomas and cerebral contusions are shown in Fig. 1.
Fig. 1

Diagnosis structure

In cooperation with Molecular Biology and Gene Therapy Center Brno, Faculty Hospital Brno, Czech Republic, all of the patients were examined as to the ApoE genotype. Genotyping of ApoE, genomic deoxyribonucleic acid (DNA) was extracted from 5 ml of ethylenediaminetetraacetic acid—anticoagulated blood using standard methods. A rapid polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP)-based DNA analysis was used to identify ApoE alleles ɛ2, ɛ3, and ɛ4 that create or abolish the given natural Hin6I restriction sites (G↓CGC). Genomic DNA (500 ng) was amplified in a 50 μl reaction mixture containing 10 mM Tris–HCl (pH 8.8), 50 mM KCl, 0.8% Nonidet P40, 1.5 mM MgCl2, 0.2 mM of each dNTP, 0.5 μM of each primer, 5% of DMSO, and 1.25 U of Taq DNA polymerase (MBI, Fermentas) in a Termal Cycler PTC-200 (MJ Research, USA). The primer sequences were 5′ ACA GAA TTC GCC CCG GCC TGG TAC AC for the forward primer (ApoE–F4) and 5′TAA GCT GG CAC GGC TGT CCA AGG A (ApoE–F6) for the reverse primer. The cycling profile included an initial 95°C denaturation step for 5 min and was followed by 30 cycles of denaturation at 95°C (1 min), annealing at 68°C (1 min), and extension at 72°C (1 min 15 s), with a final extension step of 7 min at 72°C. Enzymatic digestion of PCR products and analysis of obtained fragments in 5% MetaPhor agarose (BMA, USA) were performed (see Fig. 2).
Fig. 2

Agarose DNA analysis

The group of 70 patients was divided into four subgroups, according to the ApoE genotypes: ɛ2/ɛ3, ɛ3/ɛ3, ɛ2/ɛ4, and ɛ3/ɛ4. ApoE ɛ2/ɛ3 genotype was established in 7 patients (10.0%, from that four boys and three girls), genotype ɛ3/ɛ3 was established in 52 patients (74.4%, from that 38 boys and 14 girls), genotype ɛ2/ɛ4 was found out in 2 boys (2.9%), and genotype ɛ3/ɛ4 was found out in 9 patients (12.7%, from that 4 boys and 5 girls). The most frequent was the E3 isoform of ApoE, presented in 52 patients (74.4%). The findings are shown in Fig. 3.
Fig. 3

Distribution of ApoE genotype

We analyzed the presence of diagnoses and the way of treatment (neurosurgery vs conservative) in defined four ApoE genotype subgroups. Diagnoses spectrum is shown in Table 1 and the treatment options in Fig. 4. Overall, in our group of 70 children, 34 (48.6%) patients were treated by surgery, and 36 (51.4%) patients were treated conservatively (without surgery).
Fig. 4

Treatment options in ApoE genotype subgroups

Table 1

Diagnosis spectrum in ApoE genotype subgroups

 

ApoE ɛ2/ɛ3

ApoE ɛ3/ɛ3

ApoE ɛ2/ɛ4

ApoE ɛ3/ɛ4

Subdural hematoma

3

4

0

4

Epidural hematoma

1

25

1

3

Subarach. Hemorrhage

2

14

1

2

Hemocephalus

0

3

0

0

Contusio cerebri

4

32

1

8

Edema cerebri

4

11

1

3

Diffuse axonal injury

1

3

0

1

Fractura impressiva

0

9

0

2

Fractura baseos cranii

4

10

1

3

The severity of trauma was assessed by GCS and graded into three categories. In addition, the presence of focal neurology signs was observed, comparing the admission and dimission status. According to GCS value, the injuries were graded as slight (GCS 15–13), medium (GCS 12–9), and severe (GCS 8–3). After 1 year, the neurological outcome was assessed by GOS, and the residual deficit was graded as slight or no deficit (GOS 5), medium (GOS 4), and severe (GOS 1, GOS 2, and GOS 3). We compared the trauma severity and the presence of focal neurological signs with the neurological outcome, in each of defined ApoE genotype subgroup. To assess the significance of differences between GCS and GOS in each genotype subgroup, t test, nonparametric Wilcoxon test, Fisher, and χ 2 tests were used.

Results

Among the patients from ApoE ɛ2/ɛ3 subgroup, six (85.7%) were ranked among the severe (GCS 8–3) injuries and one patient (14.3%) among the slight injuries (GCS 15–13). In the ApoE ɛ3/ɛ3 subgroup, 34 patients (65.4%) were classified as severe (GCS 8–3), 9 patients (17.3%) as medium (GCS 12–9), and 9 patients (17.3%) as slight (GCS 15–13) injuries. In the ApoE ɛ2/ɛ4 subgroup, one patient (50%) was ranked among severe (GCS 8–3) and the other (50%) among slight (GCS 15–13) injuries. In the ApoE ɛ3/ɛ4 subgroup, four patients (44.4%) were classified as severe (GCS 8–3), one patient (11.1%) as medium (GCS 12–9), and four patients (44.4%) as slight (GCS 15–13) injuries. The severity of trauma assessed by GCS in ApoE genotype subgroups is shown in Table 2.
Table 2

The severity of trauma in ApoE genotype subgroups

 

ApoE ɛ2/ɛ3

ApoE ɛ3/ɛ3

ApoE ɛ2/ɛ4

ApoE ɛ3/ɛ4

GCS 15–13

1

9

1

4

GCS 12–9

0

9

0

1

GCS 8–3

6

34

1

4

The presence of focal neurology signs in the time of hospital admission and dimission was observed. In the ApoE ɛ2/ɛ3 subgroup, six patients (85.7%) possessed focal neurology signs in admission and three patients (42.9%) in dimission. In the ApoE ɛ3/ɛ3 subgroup, 22 patients (42.3%) possessed focal neurology signs in admission and 6 patients (11.5%) in dimission. No focal neurology signs were observed in the ApoE ɛ2/ɛ4 subgroup. In the ApoE ɛ3/ɛ4 subgroup, six patients (66.6%) possessed focal neurology signs in admission and four patients (44.4%) in dimission. The presence of focal neurology signs, comparing the admission and dimission status in ApoE genotype subgroups, is shown in Fig. 5.
Fig. 5

Focal neurology signs observed in ApoE genotype subgroups

After 1 year, the neurological outcome was assessed by GOS. In the ApoE ɛ2/ɛ3 subgroup, three patients (42.8%) were ranked GOS 5, two patients (28.6%) were ranked GOS 4, one patient (14.3%) ranked GOS 3, no patient in GOS 2, and one patient (14.3%) in GOS 1. In the ApoE ɛ3/ɛ3 subgroup, 42 patients (80.7%) were classified as GOS 5, four patients (7.7%) as GOS 4, five patients (9.6%) as GOS 3, one patient (1.9%) as GOS 2, and no patient in GOS 1. In the ApoE ɛ2/ɛ4 subgroup, all two patients (100%) were assessed as GOS 5. In the ApoE ɛ3/ɛ4 subgroup, six patients (66.6%) were ranked GOS 5 and three patients (33.3%) GOS 3; no patient in GOS 4, GOS 2, and GOS 1. Table 3 represents the neurological outcome after 1 year, assessed by GOS, in defined ApoE genotype subgroups.
Table 3

Neurological outcome after 1 year in ApoE genotype subgroups

 

ApoE ɛ2/ɛ3

ApoE ɛ3/ɛ3

ApoE ɛ2/ɛ4

ApoE ɛ3/ɛ4

GOS 5

3

42

2

6

GOS 4

2

4

0

0

GOS 3

1

5

0

3

GOS 2

0

1

0

0

GOS 1

1

0

0

0

For statistical processing, because of the data characteristic, nonparametric Wilcoxon pair test was used. The limitation for nonparametric pair test is the data shortage in ɛ2/ɛ4 group, which is the main disadvantage here for statistics at all. For only two specimens, it is not possible to count. On the p < 0.05 level, significant difference between the trauma severity and outcome was observed for ApoE ɛ2/ɛ3 and ApoE ɛ3/ɛ3 genotype subgroups. These results are shown in Table 4.
Table 4

Statistics—results of Wilcoxon pair test

 

Number of patients

t

z

p value

ɛ2/ɛ4 GCS_ɛ2/ɛ4 GOS

2

0.00000

–

–

ɛ2/ɛ3 GCS_ɛ2/ɛ3 GOS

7

0.00000

2.0226

0.043115*

ɛ3/ɛ4 GCS_ɛ3/ɛ4 GOS

9

10.00000

0.6761

0.498963

ɛ3/ɛ3 GCS_ɛ3/ɛ3 GOS

52

0.00000

5.2316

<0.001*

*p<0.05

To assess the differences between Glasgow Scales in each category and genotype subgroup, we also used Fisher and χ 2 tests in 2 × 2 table. The most significant differences for non-ɛ4 genotypes were found in GCS 13–15 (slight symptomatology) and GOS 1 + 2 + 3 category (severe deficit), as seen in Table 5.
Table 5

Statistics—results of 2 × 2 correlation table

 

Severe symptom (GCS 3–8)

Medium symptom (GCS 9–12)

Slight symptom (GCS 13–15)

Severe deficit (GOS 1 + 2 + 3)

Medium deficit (GOS 4)

Slight or no deficit (GOS 5)

ApoE ɛ2/ɛ4

1

0

1

0

0

2

ApoE ɛ2/ɛ3

6

0

1

2

2

3

χ 2

p = 0.284

 

p = 0.284

p = 0.392

p = 0.392

p = 0.152

Fisher p

p = 0.417

 

p = 0.417

p = 0.583

p = 0.583

 

ApoE ɛ3/ɛ4

4

1

4

3

0

6

ApoE ɛ3/ɛ3

34

9

9

6

4

42

χ 2

p = 0.232

p = 0.643

p = 0.067

p = 0.089

p = 0.390

p = 0.341

Fisher p

p = 0.203

p = 0.543

p = 0.087

p = 0.120

p = 0.519

p = 0.289

We decided to use t test for dependent specimens then. On the p < 0.05 level, there is the significant difference between GCS and GOS for ɛ3/ɛ3 genotype; also significant is the difference for ɛ2/ɛ3 genotype. These results are shown in Table 6 and Fig. 6.
Fig. 6

t test diagram

Table 6

Statistics—results of t test

 

Mean

SD

Number

Mean diff.

Diff. SD

t

sv

p value

ɛ2/ɛ4 GCS

2.00000

1.41421

      

ɛ2/ɛ4 GOS

1.00000

0.00000

2

1.00000

1.41421

1.00000

1

0.5000

ɛ2/ɛ3 GCS

2.71429

0.75593

      

ɛ2/ɛ3 GOS

1.85714

0.89974

7

0.85714

0.89974

2.5205

6

0.0453*

ɛ3/ɛ4 GCS

2.00000

1.00000

      

ɛ3/ɛ4 GOS

1.66667

1.00000

9

0.33333

1.58113

0.63246

8

0.5447

ɛ3/ɛ3 GCS

2.46154

0.80346

      

ɛ3/ɛ3 GOS

1.30769

0.67267

52

1.15385

0.87188

9.54313

51

<0.001*

*p < 0.05

Discussion

Evidence from previous studies indicates that ApoE plays a defined role in the response of the brain to injury and implicates the possession of the Apo ɛ4 allele as a genetic determinant in recovery from head injury. Published studies already demonstrated the correlation between ApoE ɛ4 expression and the unfavorable outcome of traumatic brain injury in adult patients, with higher risk of long-term posttraumatic coma [23], more than five times higher probability of unconsciousness for more than 7 days [5], worsening of cognitive functions, learning disturbances, and worsening of memory [21]. More recent evidence indicates an association with poor outcome after intracerebral hemorrhage. APOE gene polymorphism also influences the risk of hemorrhage in cerebral amyloid angiopathy [22], and expression of ApoE ɛ4 allele was associated with more severe hypoxic damage and with higher cerebral contusion index [23].

In addition, the possible neuroprotective properties of ApoE ɛ3 allele were described [18]. The pattern of geographical distribution of ApoE ɛ3 and ɛ4 in Europe [13] and ApoE ɛ2 and ɛ4 ethnical predominancies in Africans and Australian aborigines was described too, all concerning the adult population. As mentioned before, the relationship between poor neuropsychological outcome after mild head injury and possession of ApoE ɛ4 was published. Possession of the ApoE ɛ4 allele has also been shown to influence neuropathological findings in patients who die from traumatic brain injury, including the accumulation of amyloid beta protein [12, 15, 16, 17]. The presence of ApoE ɛ4 genotype is also mentioned in relation with increased risk of late onset Alzheimer’s disease and cardiovascular disorders [6, 7, 19, 20, 27].

The way of action of ApoE is not fully understood. In experimental conditions, the neurodegenerative properties of ApoE ɛ4 allele can be attenuated by calcium channel blockers [28]. Diverse brain disorders associated with ApoE indicate the multiple roles of ApoE within the central nervous system.

Published data concerning the expression of ApoE genotype and distribution of ApoE genotype in children are rare, and this specific field is not explored in detail yet in the pediatric age. Based on previously published studies in adult patients, we postulated the work hypothesis that is similar to adults, the possession of ApoE epsilon 4 allele in children is associated with more serious course and poorer outcome of brain injuries. So the aim of this study was to compare the trauma severity and outcome with regard to ApoE genotype in the group of 70 pediatric patients.

Using the Wilcoxon nonparametric test, significant difference between the trauma severity and outcome was observed for ApoE ɛ2/ɛ3 and ApoE ɛ3/ɛ3 genotype subgroups. Patients in subgroups containing the ApoE ɛ4 allele showed no statistical difference. The similar results were obtained by using the t test for the assessment of GCS/GOS differences. On the p < 0.05 level, there is the significant difference between GCS and GOS in ApoE ɛ3/ɛ3 genotype subgroup; also significant is the difference for ApoE ɛ2/ɛ3 genotype.

Based on the analysis above, our results suggest the association between the ApoE genotype and outcome of traumatic brain injury also in children. In the group of 70 pediatric patients, children with ApoE ɛ4 genotype had unfavorable neurological outcome when compared with significantly better outcome in children with other (ɛ3/ɛ3, ɛ2/ɛ3) ApoE genotypes.

The presented results can be of clinical use by predicting the outcome of traumatic brain injury in children. Implementation of the ApoE genotyping to a routine clinical management of pediatric head trauma can improve the initial assessment and treatment of traumatic brain injury in children. Also in less severe head injuries [1, 3, 24], the ApoE ɛ4 genotype can indicate possible neuropsychological deficit and thus allow to establish early neuropsychological care.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Clinic of Pediatric Surgery, Orthopaedics and TraumatologyBrno Faculty HospitalBrnoCzech Republic
  2. 2.Molecular biology and gene therapy centerBrno Faculty HospitalBrnoCzech Republic

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