Neurochem Res (2012) 37:819825
DOI 10.1007/s11064-011-0677-x
ORIGINAL PAPER
Role of a Neural Cell Adhesion Molecule Found in Cerebrospinal
Fluid as a Potential Biomarker for Epilepsy
Wei Wang Liang Wang Jing Luo
Zhiqin Xi Xuefeng Wang Guojun Chen
Lan Chu
Received: 1 September 2011 / Revised: 6 December 2011 / Accepted: 15 December 2011 / Published online: 5 January 2012
Springer Science+Business Media, LLC 2012
Abstract The neural cell adhesion molecule (NCAM-1)
plays an important role in cell adhesion and synaptic
plasticity. We designed this study to evaluate NCAM-1 as a
potential biomarker for epilepsy. We performed a quanti-
tative evaluation of the levels of NCAM-1 in cerebrospinal
fluid (CSF) and serum and noted differences in patients
with epilepsy compared to control subjects. We used
sandwich enzyme-linked immunosorbent assays to mea-
sure NCAM-1 concentrations in CSF and serum samples of
76 epileptic patients (subdivided into the following sub-
groups: drug-refractory epilepsy, DRE; first-diagnosis
epilepsy, FDE; and drug-effective epilepsy, DEE) and 44
control subjects. Our results show that cerebrospinal fluid
NCAM-1 (CSFNCAM-1) concentrations and NCAM-1
Indices in the epileptic group were lower than in the control
group. Both the CSFNCAM-1 concentration and the
NCAM-1 Indices in the drug-refractory epilepsy group
were lower than in the drug-effective epilepsy group. These
differences were statistically significant (P \ 0.05). How-
ever, serumNCAM-1 levels were not statistically different
when comparing the epilepsy group to the control group
(P [ 0.05). Our results indicate that CSFNCAM-1 is a
potential biomarker for drug-effective epilepsy and drug-
refractory epilepsy.
W. Wang
L. Chu (&)
Department of Neurology, The Affiliated Hospital of Guiyang
Medical College, 28 Gui Yi Street, Guiyang 550004, Guizhou
Province, China
e-mail: chulan8999@sohu.com
L. Wang
J. Luo
Z. Xi
X. Wang
G. Chen
Department of Neurology, The First Affiliated Hospital of
Chongqing Medical University, 1 You Yi Road, Chongqing
400016, China
Keywords NCAM-1
Epilepsy
Cerebrospinal fluid

Serum
ELISA
Biomarker
Introduction
Epilepsy is a chronic brain dysfunction syndrome that is
characterized by repeated and excessive abnormal neuronal
activity. It affects approximately 50 million people all over
the world, representing approximately 5% of the worldwide
population [1, 2]. Although electroencephalogram (EEG),
Magnetic Resonance Imaging (MRI) and 18F-FDG positron
emission tomography (18F-FDG PET) have been used in
clinical practice [37], the diagnosis of epilepsy is primarily
based on a detailed examination of clinical manifestations
and a detailed medical history. However, often clinical
manifestations and history provided by patients or their
families are not sufficient. It has been estimated that the rate
of misdiagnosis remains relatively high, at approximately
2030% [8, 9]. Therefore, biomarkers may serve as a new
diagnostic tool, leading to the correct clinical diagnosis and
facilitating the appropriate treatment. In our previous stud-
ies, we listed some of the potential biomarkers, which are
specific to epilepsy and are present in CSF and serum, such as
Tetranectin (TN), Talin 2, Vitamin D-binding protein
(DBP), Superoxide dismutase 1 (SOD1) [1012]. Regarding
the neural cell adhesion molecule (NCAM-1), our lab has
demonstrated altered expression of the molecule in temporal
lobe neocortex of patients with intractable temporal lobe
epilepsy [13]. Therefore, we hypothesized that NCAM-1 is
also a potential biomarker for epilepsy. Due to ethical con-
siderations, affected brain tissues are difficult to obtain.
However, collection of cerebrospinal fluid (CSF) is rela-
tively easy and it is well known that biochemical changes in
the brain are reflected in CSF [12]. In previous proteomics
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studies, low NCAM-1 levels were observed in the CSF
samples of patients suffering from multiple sclerosis (MS),
Alzheimer disease (AD) and meningitis patients [1416].
Moreover, the concentration of NCAM-1 in CSF is increased
in patients with schizophrenic and mood disorders [1720].
These studies suggest that NCAM-1 may participate in the
development of neurological disorders. However, whether or
not concentrations of CSFNCAM-1 and serumNCAM-1
are changed in epilepsy remains unknown. In this study, we
measured the concentration of NCAM-1 in CSF and serum
samples of epileptic patients and studied the changes of
NCAM-1 levels after epileptic seizures using sandwich
enzyme-linked immunosorbent assay (ELISA).
Materials and Methods
Subjects
A total of 76 patients (40 males and 36 females), aged
1273 years old (35.21 1.64 years), were recruited by the
Neurology departments of the First Affiliated Hospital of
Chongqing Medical University and the Affiliated Hospital of
Guiyang Medical College. All patients, who were accepted
to the study, had undergone a comprehensive clinical
examination including a detailed medical history, a neuro-
logical examination, neuropsychological testing, an EEG
and neuroradiological studies. Epilepsy was diagnosed and
classified according to the definition and classification cri-
teria proposed by the International League Against Epilepsy
in 2001 [21]. The drug-refractory epilepsy (DRE) subgroup
consisted of 28 patients (13 males and 15 females), who had
suffered from epilepsy for more than 4 years, and who had
been on a treatment regimen which included at least three
types of commonly used antiepileptic drugs (AEDs). Their
seizures were not controlled. The first-diagnosis epilepsy
(FDE) subgroup consisted of 17 patients (10 males and 7
females) who had suffered at least one seizure before diag-
nosis and did not take any AEDs. The drug-effective epilepsy
(DEE) subgroup consisted of 31 patients (17 males and 14
females) who had stayed seizure-free for more than 2 years
after previously taking one type of AED. A total of 44 con-
trols subjects (24 males and 20 females), aged 1474 years
(39.27 2.19 years) were recruited. The control population
consisted of patients suffering from primary headache,
neurosis (primary headache accompanied by a number of
somatization symptoms such as fatigue, weakness and
insomnia), dizziness and neuralgia with normal neurological
and neuropsychological findings. Brain MRI scans or com-
puted tomography (CT) were negative for progressive
lesions in the central nervous system. Table 1 shows the
clinical information of epilepsy patients and control subjects.
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Neurochem Res (2012) 37:819825
The study was approved by the ethics committee at the
First Affiliated Hospital of Chongqing Medical University
and the Affiliated Hospital of Guiyang Medical College. It
was conducted in accordance with the Helsinki Declara-
tion. Informed written consent was obtained from patients
or their relatives regarding the use of data and tissue
specimens for research purposes.
Sample Collection and Storage
First, 2 ml of CSF and 5 ml of venous blood samples were
collected from each subject. Albumin concentrations and
biochemical profiles were analyzed for all CSF and serum
samples by the laboratory department at the First Affiliated
Hospital of Chongqing Medical University. The remainder
of the blood samples was centrifuged at 3,0009g for 15 min
to collect the serum, which was then aliquoted and stored at
-80C for further analysis. CSF samples were centrifuged at
2,0009g for 10 min at 4C and stored at -80C.
Measurement of NCAM-1
The concentrations of CSFNCAM-1 and serumNCAM-1
were determined using a sandwich ELISA NCAM-1
ELISA Kit (R&D systems, USA, Catalog Number:
DY2408). Sample manipulations were performed accord-
ing to the manufacturers protocol. Dilutions of the CSF
and serum samples were 1:100 and 1:80, respectively.
Then, 96-well microtiter plates were coated overnight at
25C with 100 ll per well of mouse anti-human NCAN-1
antibody (2 lg/ml, R&D Systems, Part 842183). Solutions
were aspirated and washed four times with Washing Buffer
(0.05% Tween-20 in PBS, pH 7.2). Subsequently, micro-
plates were blocked at 25C for 1 h with 1% BSA in PBS
(PH 7.2). After washing, 100 ll of CSF, serum samples
and recombinant human NCAM-1 standards (R&D Sys-
tems, Part 842185) were added to the corresponding plate
wells. Before further washing, the plates were covered with
an adhesive strip and incubated for 2 h at 25C. Then,
100 ll of the biotinylated goat anti-human NCAM-1
(Detection Antibody, R&D Systems, Part 842184) was
added to each well and incubated for 2 h at 25C. After
four washes, 100 ll of streptavidin conjugated to horse-
radish-peroxidase (200 ng/ml streptavidin-HRP, R&D
Systems, Part 890803) was added to each well and incu-
bated in the dark for 20 min at 25C. After the final four
washes, 100 ll of Substrate Solution (R&D Systems,
Catalog number DY995) was placed into each well and
incubated in the dark for 20 min at 25C. Finally, 50 ll of
2 M H2SO4 was added into each well to stop the reaction.
Optical densities were determined using a Multiskan
Spectrum Microplate Spectraphotometer microplate reader
set at 450 nm (Thermo Fisher Scientific, USA).
Neurochem Res (2012) 37:819825 821

Table 1 Clinical materials of

Patients no. Gender Age Patients no. Gender Age Patients no. Gender Age
the epilepsy patients and
controls in the study DRE group 41 M 34 81 M 36
1 F 40 42 M 42 82 M 34
2 M 36 43 F 25 83 M 27
3 F 16 44 M 24 84 M 38
4 F 26 45 F 49 85 M 46
5 M 56 DEE group 86 F 14
6 F 54 46 F 35 87 M 17
7 F 40 47 M 21 88 F 40
8 F 44 48 M 22 89 M 31
9 M 26 49 F 40 90 F 18
10 F 21 50 F 36 91 M 39
11 F 60 51 M 17 92 F 31
12 M 65 52 M 39 93 F 41
13 M 22 53 M 63 94 F 46
14 M 21 54 F 34 95 F 47
15 F 24 55 M 54 96 M 40
16 F 40 56 M 31 97 M 40
17 M 12 57 F 37 98 F 47
18 M 16 58 M 45 99 F 52
19 F 21 59 F 44 100 M 45
20 F 40 60 M 55 101 M 28
21 M 17 61 F 37 102 M 30
22 F 15 62 F 16 103 M 33
23 M 31 63 F 36 104 F 54
24 M 26 64 M 51 105 F 44
25 M 24 65 M 73 106 F 23
26 F 28 66 F 33 107 F 33
27 M 55 67 M 26 108 M 33
28 F 20 68 M 60 109 F 45
FDE group 69 F 54 110 M 36
29 M 22 70 M 42 111 F 35
30 M 27 71 M 21 112 F 66
31 M 61 72 M 25 113 M 22
32 M 42 73 F 28 114 F 27
33 M 47 74 M 19 115 F 67
34 M 44 75 F 40 116 M 53
35 F 15 76 F 41 117 M 74
36 F 48 Control group 118 M 73
37 M 46 77 M 14 119 M 63
DRE drug-refractory epilepsy
subgroup, FDE first-diagnosis 38 F 24 78 F 40 120 M 29
epilepsy subgroup, DEE drug- 39 F 21 79 M 30
effective epilepsy subgroup, 40 F 42 80 F 41
M male, F female

Calibration Curve Statistical Analysis

A seven point calibration curve with two-fold serial dilu-
tions was used, which detected maximum and minimum
concentrations of 5,000 and 78.625 pg/ml, respectively.
Calibration curves were fitted to the polynomial model,
with adjusted R2 = 0.9998.
All statistical analyses were performed using Statistical
Product and Service Solutions (SPSS), version 17.0.
Descriptive data were computed using means standard
error (SE). Differences between two groups were assessed
using the independent-sample t tests, and one-way analysis

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822 Neurochem Res (2012) 37:819825

of variance (ANOVA) was used to assess differences NCAM-1 and serumNCAM-1) in the epilepsy and control
among groups. The level of statistical significance was set groups were 0.92 0.05 and 1.23 0.08, respectively.
at 0.05 (P \ 0.05). The independent-sample t test showed that CSFNCAM-1
concentrations and NCAM-1 Indices were significantly
lower in epileptic patients than in the control group
Results (P \ 0.05). CSFNCAM-1 levels were significantly lower
than serumNCAM-1 in the epileptic group (P \ 0.05).
Table 2 summarizes the concentrations of NCAM-1 in CSF However, there were no significant differences between the
and serum in both the epilepsy and control groups. Figure 1 epilepsy and control groups in serumNCAM-1 concen-
is a histogram of CSF and serumNCAM-1 concentration trations, albumin levels in CSF and serum, and the CSF
in the epilepsy and control groups. The concentrations of Indices (the ratio of levels of CSF-albumin and serum-
CSFNCAM-1 in the epilepsy and the control groups were albumin) (P [ 0.05).
234.68 10.85 and 318.31 14.27 ng/ml, respectively. Table 3 summarizes the levels of CSFNCAM-1 and
The NCAM-1 Indices (the ratio of concentrations of CSF serumNCAM-1 in the different epilepsy subgroups. Figure 2
shows a histogram of CSFNCAM-1 and serumNCAM-1
Table 2 The concentrations of NCAM-1 in CSF and serum in epi- concentrations in the epilepsy subgroups. CSFNCAM-1
lepsy and control groups and the NCAM-1 Indices were significantly lower in the
Epilepsy Control P (independent- DRE subgroup than in the DEE subgroup (P \ 0.05).
t test) value CSFNCAM-1 concentration in the FDE subgroup was not
CSFNCAM- 234.68 10.85 318.31 14.27 \0.01 significantly different from that in the other two subgroups
1 (ng/ml) (P [ 0.05). The One-Way ANOVA analysis showed that,
Serum 277.95 6.89 270.80 8.41 [0.05 unlike CSFNCAM-1 concentrations, serumNCAM-1
NCAM-1 concentrations were not significantly different between the
(ng/ml) epilepsy subgroups (P [ 0.05).
NCAM-1 0.92 0.05 1.23 0.08 \0.05
Indices
CSF-albumin 202.39 32.22 253.62 40.21 [0.05
(mg/l)
Discussion
Serum- 41.33 1.14 42.78 1.21 [0.05
albumin In this study, we have demonstrated that CSFNCAM-1
(g/l) concentrations are decreased in epileptic patients, and are
CSF Indices 5.03 1.06 5.94 0.92 [0.05 particularly low in DRE patients. In contrast, concentra-
(910-3) tions of serumNCAM-1 in epilepsy and control groups
NCAM-1 Indices the ratio of the concentrations of CSFNCAM-1 were not statistically different.
over serumNCAM-1 (CSFNCAM-1/serumNCAM-1) NCAM-1 is a cell adhesion molecule that belongs to the
CSF Indices the ratio of CSF-albumin over serum-albumin (CSF- immunoglobulin superfamily. It is a cell membrane surface
albumin/serum-albumin) glycoprotein that appears to mediate cell-to-cell and cell-to-
extracellular matrix adhesions. NCAM-1 has three main
polypeptide isoforms with molecular weights of 180, 140 and
120 kD [22]. It interacts mainly with polysialic acid (PSA),
which adjusts the morphological interaction between cells.
NCAM-1 not only plays an important role in the development
of neurons and synaptic plasticity but also participates in the
axonal outgrowth and neuronal repair [2325].
Soluble forms of NCAM-1 have been identified in brain
homogenates, neuronal cell culture media, serum and CSF
[26, 27]. In previous studies, a decrease in serum NCAM-1
levels has been observed in some cancers, including pan-
creatic cancer, colon carcinoma and astrocytoma [2831].
Elevated expressions of NCAM-1 have also been observed
in various cancers, including acute myeloid leukemia,
breast cancer, small cell lung carcinoma, glioma and
Fig. 1 Histogram of CSF and serumNCAM-1 concentrations in the
epilepsy and control groups. It shows that the CSFNCAM-1 in malignant melanomas [3238]. These results suggest that
epilepsy group is significantly lower than that in control soluble forms of NCAM-1 may be an important biomarker

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Neurochem Res (2012) 37:819825
Table 3 The concentrations of NCAM-1 in CSF and serum in each epilepsy subgroups
DRE
Number of samples 28
Age (years) 32.04 2.86
CSFNCAM-1 (ng/ml) 202.27 16.59*
SerumNCAM-1 (ng/ml) 265.05 15.38
NCAM-1 Indices 0.72 0.08#
DRE drug-refractory epilepsy, FDE first-diagnosis epilepsy, DEE drug-effective epilepsy, NCAM-1 Indices the ratio of the concentrations of
CSFNCAM-1 over serumNCAM-1 (CSFNCAM-1/serumNCAM-1)
* DRE versus DEE; P \ 0.05
#
DRE versus DEE; P \ 0.05
Fig. 2 Histogram of CSF and serumNCAM-1 concentrations in the
epilepsy subgroups. It shows that the CSFNCAM-1 in DRE
subgroup is significantly lower than that in DEE subgroup. DRE
drug-refractory epilepsy, FDE first-diagnosis epilepsy, DEE drug-
effective epilepsy
that can be used to monitor the relapse of cancers, and may
be associated with therapeutic reaction and survival time
[36, 37, 39].
In this study, we observed that concentrations of CSF
NCAM-1 were lower in epileptic patients than in the
control group. This result conflicts with previous findings
in which brain tissues showed elevated NCAM-1 expres-
sion [4345]. NCAM-1 is known to promote synaptic
remodeling and maintenance of synaptic structure, thereby
affecting adhesion of cells and regulating neuronal activi-
ties. NCAM-1 also promotes synaptic plasticity by
adjusting the concentration of Ca2?. NCAM-1 mediated
synaptic growth (growth cone) relies on intracellular and
extracellular Ca2? [41, 42]. However, it was found that
NCAM-1 combines with PSA to form a PSANCAM
complex. An increase in PSANCAM level is considered
to lead to a decrease in cell adhesion and promote synaptic
growth [40]. Although we do not know whether levels of
PSANCAM complexes are elevated in epileptic brain
tissues, it is possible that an increase in NCAM-1 binding
to PSA will result in a reduction in free NCAM-1 circu-
lating in CSF.
823
FDE DEE P (ANOVA) value
17 31
36.06 3.14 37.90 2.55 [0.05
224.80 23.18 268.31 16.65* \0.05
281.19 10.91 282.59 11.02 [0.05
0.78 0.06 0.98 0.06# \0.05
Our current study failed to show a significant decreased
in levels of serumNCAM-1 in patients with epilepsy.
Evidence indicates that the bloodbrain barrier (BBB) is
impaired and permeability is increased after an acute epi-
leptic seizure [46, 47]. Therefore, CSF changes of NCAM-
1 should also be reflected in the blood. We noticed that
sampling of blood and CSF was performed at least 3 days
after the last seizure attack. During that time, the damaged
BBB may have undergone a self-repair process. Another
reason may be that blood NCAM-1 originates from not
only the central nervous system but also from a variety of
other organs; Therefore, a change in concentration may not
be reflective of changes in the central nervous system
(CNS) alone. Consequently, we suggest that the sensitivity
of CSFNCAM-1 is higher than the sensitivity of serum
NCAM-1 in reflecting changes in neuronal activity after
epilepsy.
In the epileptic patient group, the difference in CSF
NCAM-1 levels between the DRE group and the DEE group
was statistically significant. Although mechanisms underly-
ing DRE are relatively unknown, which distinguishes it from
DEE, the decreased CSFNCAM-1 concentration might
indicate a sustained neuronal hyperactivity and potential
molecular changes. The possible binding of NCAM-1 to PSA
may represent a biomarker in drug-resistant epilepsy. It also
suggests that changes in CSFNCAM-1 levels are likely to
predict the progress and prognosis of epilepsy. However,
follow-up studies with larger sample sizes and additional
types of epilepsy are needed. The potential significance of the
PSANCAM-1 complex, found in CSF, as a reliable bio-
marker for epilepsy also requires further investigation.
Conclusion
In conclusion, our present study demonstrates that CSF
NCAM-1 concentrations are decreased in epileptic patients
and lowest in DRE patients. Based on this study, we sug-
gest that CSFNCAM-1 may play an important role in the
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diagnosis of DEE and DRE. However, further research is
required to validate NCAM-1 as an epilepsy-specific bio-
marker. Moreover, the role of NCAM-1 in epileptogenesis
remains to be explored.
Acknowledgments This work was supported by funds from the
National Natural Science of China (No. 81071039). We thank the
patients and their families for their participation in this study. We also
sincerely thank the First Affiliated Hospital of Chongqing Medical
University and the Affiliated Hospital of Guiyang Medical College for
support and assistance in CSF and serum procurement.
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