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Department of Neurology, Second Afliated Hospital and Xin Qiao Hospital, Third Military Medical University, Chongqing 400037, China
Department of Neurobiology, College of Basic Medical Sciences, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing
400038, China
c
Department of Physiology, Zunyi Medical College, Zunyi, Guizhou province 563000, China
b
art ic l e i nf o
a b s t r a c t
Article history:
Received 1 June 2014
Received in revised form
6 July 2014
Accepted 7 July 2014
Available online 18 July 2014
Background: Depression is a frequent mood disorder that affects around a third of stroke patients and
has been associated with poorer outcome. Our aim was to determine whether there is a relationship
between serum Brain-derived neurotrophic factor (BDNF) levels and post-stroke depression (PSD).
Methods: Two hundred and sixteen ischemic stroke patients admitted to the hospital within the rst
24 h after stroke onset were consecutively recruited and followed up for 3 months. Based on the
symptoms, diagnoses of depression were made in accordance with DSM-IV criteria for post-stroke
depression at day 90. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of
BDNF at admission. Multivariate analyses were performed using logistic regression models.
Results: In our study, 59 patients (27.3%) were diagnosed as having major depression at 3 months.
Patients with major depression showed lower levels of serum BDNF [8.1 (5.69.4) vs. 13.7 (10.416.5)ng/
ml, Po 0.0001] at admission. In multivariate analyses, serum BDNF was an independent predictor of PSD
at 3 months [odds ratio (OR): 0.79(0.720.87), P 0.003]. Serum levels of BDNF r10.2 ng/ml were
independently associated with post-stroke (OR, 11.5; 95% CI, 5.623.4, P o0.0001), after adjustment for
possible variables.
Conclusion: The present study demonstrates a strong relationship between serum BDNF levels at
admission and the development of PSD within 3 months. Further studies are necessary to conrm this
association, which may open the way to the proposal of new therapeutic options.
& 2014 Elsevier B.V. All rights reserved.
Keywords:
Brain-derived neurotrophic factor
Depression
Acute ischemic stroke
Chinese
1. Introduction
Depression is particularly prevalent among stroke survivors,
affecting approximately a third of individuals (Lindn et al., 2007).
Patients with depression experience worse stroke-related outcomes
in the form of greater functional disability and higher mortality
(Ellis et al., 2010), and, nally, with worse rehabilitation outcome.
Early recognition of depression symptoms and introduction of
pharmacological treatment could lead to better functional outcome
(Zavoreo et al., 2009), making the prevention and management of
post-stroke depression an important area of research.
Neurotrophins are an important class of signaling molecules in
the brain responsible for axon targeting, neuron growth, maturation of synapses during development, and synaptic plasticity
(Autry and Monteggia., 2012). Brain-derived neurotrophic factor
(BDNF) is a neurotrophin that has been linked to the viability of
http://dx.doi.org/10.1016/j.jad.2014.07.011
0165-0327/& 2014 Elsevier B.V. All rights reserved.
374
and better visual memory. Kim et al. (2008) reported that the BDNF
val66met polymorphism may modify the association between stroke
and depression. Thus, the role of BDNF in patients with stroke and
depression excited our interest. In a large cohort, Kim et al. (2012)
found evidence for serotonin and BDNF polymorphisms as susceptibility factors and genegene interactions between these systems for
depression at 2 weeks post-stroke. Interestingly, there is rare study on
serum BDNF levels in Chinese patients with post-stroke depression
(PSD). One study reported that serum concentrations of BDNF
decrease in Chinese PSD patients and BDNF may play an important
role in the pathogenesis of PSD. However, only 93 patients were
included (Zhou et al. 2011). Therefore, our aim was to determine
whether there is a relationship between serum BDNF and PSD in a
large cohort.
2. Methods
2.5. Statistical analyses
2.1. Study population
Two hundred and ninety-ve patients with a rst episode of
acute ischemic stroke admitted to our hospital within the rst 24 h
of stroke onset were prospectively included in the study. Patients
with subarachnoid or intracranial hemorrhage, decreased level of
consciousness, severe aphasia or dysarthria, or psychiatric illness,
severe infectious or inammatory diseases, and life expectancy o 3
month were excluded. One hundred and sixty out of 295 patients
(54.2%) were male, with a mean age of 68.9 711.3 years. Seventynine patients were not evaluated at 3 month (38 patients died and
12 refused to attend the follow-up, 10 patients had difculty in
being transported to hospital, and 19 patients were lost to followup); the remaining 216 patients were valid for analysis.
Informed consent was obtained after having provided verbal
and written information to participants or nearest relatives when
relevant. Ethics approval was granted by The Ethics Committee for
Medical Research at the Xin Qiao Hospital, Third Military Medical
University.
2.2. Clinical variables
At baseline, age, sex, body mass index and history of risk factors
were obtained. Stroke subtype was classied according to TOAST
(Trial of ORG 10172 in Acute Stroke Treatment) criteria (Adams et
al., 1993). Routine blood and biochemical tests, brain CT/MRI scan
were performed in all patients at admission. MRI with diffusionweighted imaging (DWI) was available in some patients. The
infarct volume was calculated by using the formula 0.5 a b c
(Sims et al., 2009). Stroke severity was evaluated by trained
neurologists using the NIHSS at admission (Brott et al., 1989).
Functional outcome was evaluated by the modied Rankin Scale
(mRS) at 3 month (Bonita, 1988). A favorable functional outcome
was dened as an mRS score of 0 to 2 points, while an unfavorable
functional outcome was dened as an mRS score of 3 to 6 points.
2.3. Psychological measurement
Depression assessments were conducted by a neurologist/
psychiatrist who was unaware of the type, size and location of
the index stroke at the time of 3 months after stroke onset.
Previous history of psychiatric disease and depression, educational
level and people living with the patient were recorded at admission. Patients should nish the Hamilton Rating Scale for Depression
(HAM-D) at 3 months follow-up (Hamilton., 1960). Clinical depression was diagnosed according to DSM-III-R criteria using algorithms based on psychiatric interview and neuropsychiatric
The results are expressed as percentages for categorical variables and as mean (standard deviation, S.D.) or median (interquartile range, IQR) for the continuous variables depending on
their normal distribution. ShapiroWilk tests were used for
normal distribution test. Proportions were compared using the
Chi-square test. Two-group comparison of not normally distributed data was performed using MannWhitney U test, and a twotailed Student's unpaired t-test was used for normally distributed
continuous variables. Spearman's Rank correlation was used
for bivariate correlations. Associations between the severity
of depression evaluated by HAM-D scale and the serum levels of
BDNF were also assessed by using ordered logistic regression
models with multivariate adjustment for possible confounders,
for instance, age, sex, body mass index, stroke syndrome, stroke
etiology, the NIHSS score, infarct volume, vascular risk factors and
a history of depression. The inuence of serum BDNF levels on PSD
was performed by binary logistic regression analysis, which allows
adjustment for above confounding factors. The results are
expressed as adjusted odds ratios (ORs) with the corresponding
95% condence intervals (CIs). Receiver operating characteristic
(ROC) curves were utilized to evaluate the accuracy of serum BDNF
to predict PSD. Area under the curve (AUC) was calculated as
measurements of the accuracy of the test. All statistical analysis
was performed with SPSS for Windows, version 19.0 (SPSS Inc.,
Chicago, IL, USA). Statistical signicance was dened as P o0.05.
3. Results
3.1. Baseline characteristics of study samples
The study cohort consisted of 295 patients at baseline (stroke
admission). By the time of follow-up at 3 months, leaving 216
individuals were included in our study. However, these 216
patients were similar in terms of baseline characteristics [age
(P 0.632), gender (P 0.803), NIHSS (P 0.654) and weight
(P 0.723)] compared to the overall cohort. In the study population, 45.8% were females and the average age was 66.5 710.2
years. The median (quartiles) NIHSS score on admission was 6 (3,
12), and the median time from symptom recognition to admission
to hospital was 4.8 h (IQR, 2.47.5). The number of tissue plasminogen activator-treated patients was 65 (30.1%).
3.2. Main ndings
Ninety-four patients (43.5%) showed depression (major and
minor) at 3 months after admission and in 59 patients (27.3%) this
375
4. Discussion
Largely in accord with previous ndings and with the neurotrophin
hypothesis of depression (Autry and Monteggia., 2012; Molendijk et
al., 2011; Hashimoto., 2010; Shimizu et al., 2003), our data showed that
serum BDNF levels were low in PSD patients compared with stroke
patients without depression. Our results mainly suggested that serum
BDNF level was a powerful biological marker of risk of developing
post-stroke major depression at 3 month after adjustment by variables, and serum BDNF levelsr10.2 ng/ml were associated with 11.5fold increase in risk of post-stroke depression. Similarly, Yang et al.
(2011) reported that serum BDNF on day 1 after admission may
predict the risk of subsequent PSD, and serum BDNF o 5.86 ng/ml
was independently associated with incident PSD at the acute stage of
Table 1
Basal characteristic of stroke patients with depression and no depression.
Baseline characteristics
No depression (n 157)
Pa
72.8 (11.2)
59.3
26.5 (22.828.5)
49.2
32.2
14 (718)
8 (414)
3 (13)
12.5 (1.6)
40.7
32.2
13.6
63.6 (9.1)
40.8
27.2 (23.029.2)
51.6
29.3
13 (618)
5 (28)
2 (13)
12.2 (1.5)
19.7
12.1
5.7
15.3
16.9
33.9
18.6
15.3
19.1
22.3
38.2
10.8
9.6
0.024
0.015
0.214
0.762
0.624
0.627
0.011
0.221
0.424
0.002
0.001
0.085
0.126
7.8 (5.98.6)
5.45 (4.796.52)
0.80 (0.351.88)
18.2 (14,323.4)
8.1 (5.69.4)
7.6 (5.58.4)
5.39 (4.856.55)
0.55 (0.261.26)
14.9 (11.817.8)
13.7 (10.416.5)
0.512
0.242
0.013
0.008
o 0.0001
376
Fig. 1. Serum BDNF levels in stroke patients with depression and no-depression group. MannWhitney U-test. All data are medians and in-terquartile ranges (IQR).
(a) Depression patients were dened as major depression; (b) patients with minor depression were also included.
Fig. 2. Correlation between serum BDNF levels and other predictors. (a) Correlation between serum BDNF levels and the National Institutes of Health Stroke Scale (NIHSS)
score; (b) Correlation between serum BDNF levels and HAM-D score.
stroke (OR 28.992; 95% CI, 8.014104.891; po 0.001 after adjustment). Thus, it may open the way to the proposal of new therapeutic
options in patients with ischemic stroke. In addition, our results also
indicated a signicant negative correlation between HAM-D score, the
severity of depressive symptoms, and serum BDNF levels. Several
studies showed a negative correlation between BDNF levels and
severity of depressive symptoms (Shimizu et al., 2003).
The prevalence of PSD varies over time with an apparent peak 36
months after stroke with a range of 934% during this time-frame and
subsequently decline reaching about 50% of the initial rates at one year
(Whyte and Mulsant., 2002). In our study, we found that 27.3% of
stroke patients were classied as major depression at 3 month, while
the depression prevalence was reported to be ranging from 17 to 62.2%
among Chinese stroke patients (Zhang et al., 2010; Tang et al., 2004;
Cheng et al., 2014). In addition, low circulating BDNF concentrations
have been observed in patients with coronary artery disease, type
2 diabetes mellitus, metabolic syndrome, stroke and physical inactivity
(Autry and Monteggia., 2012; Pikula et al., 2013). Consistent with those
results, in our study, we found low serum BDNF levels in stroke
patients and depression patients. Depression had been widely documented to reduce the expression of BDNF in both animal and clinical
studies (Gazal et al., 2012).
One meta-analysis study demonstrated strong evidence that
BDNF levels were lower in depressed subjects than healthy control
377
Fig. 3. Receiver operating characteristic (ROC) curves were utilized to evaluate the accuracy of serum BDNF levels to predict PSD. (a) Depression patients were dened as
major depression; (b) patients with minor depression were also included.
Table 2
Adjusted OR of depression for BDNF levels in stroke patients.
Parameter
ORa
95% CI
Age
Females
Widowhood
Living with offspring
NIHSS on admission
Hs-CRP
HCY
BDNF levels at admission
BDNF levels at admission( r10.2 ng/ml)
1.74
1.22
1.83
1.33
1.11
1.76
1.16
0.79
11.50
1.102.79
1.041.55
1.183.09
1.091.78
1.041.18
1.252.89
1.031.29
0.720.87
5.6023.40
0.024
0.015
0.002
0.001
0.001
0.013
0.008
0.003
P o0.0001
OR: odds ratio; CI: condence interval; NIHSS: National Institutes of Health Stroke
Scale; mRS: modied Rankin Scale; Hs-CRP: high-sensitivity C-reactive protein;
HCY: homocysteine; BDNF: Brain-derived neurotrophic factor.
a
Table 3
Adjusted OR of depression (minor depression were included) for BDNF levels in the
stroke patients.
Parameter
ORa
95% CI
Age
Females
Widowhood
Living with offspring
NIHSS on admission
Hs-CRP
HCY
BDNF levels at admission
BDNF levels at admission( r11.5 ng/ml)
1.77
1.22
1.87
1.37
1.13
1.79
1.18
0.85
6.93
1.082.81
1.051.56
1.153.14
1.111.82
1.031.22
1.232.95
1.041.33
0.760.93
3.8912.31
0.019
0.016
0.002
0.001
0.001
0.011
0.007
0.006
P o0.0001
OR: odds ratio; CI: condence interval; NIHSS: National Institutes of Health Stroke
Scale; mRS: Modied Rankin Scale; Hs-CRP: high-sensitivity C-reactive protein;
HCY: homocysteine; BDNF: Brain-derived neurotrophic factor.
a
378
Conict of interest
We wish to conrm that there are no known conicts of interest associated
with this publication and there has been no signicant nancial support for this
work that could have inuenced its outcome.
We conrm that the manuscript has been read and approved by all named
authors and that there are no other persons who satised the criteria for authorship but are not listed. We further conrm that the order of authors listed in the
manuscript has been approved by all of us.
We conrm that we have given due consideration to the protection of
intellectual property associated with this work and that there are no impediments
to publication, including the timing of publication, with respect to intellectual
property. In so doing we conrm that we have followed the regulations of our
institutions concerning intellectual property.
We further conrm that any aspect of work covered in this manuscript that has
involved either experimental animals or human patients has been conducted with
the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript.
We understand that the corresponding author is the sole contact for the
editorial process (including Editorial Manager and direct communications with the
ofce). He/she is responsible for communicating with other authors about progress,
submissions of revisions and nal approval of proofs. We conrm that we have
provided a current, correct email address which is accessible by the corresponding
author and which has been congured to accept emails.
Acknowledgment
This research was supported by the fundamental and advanced research
projects of Chongqing (No: cstc2013jcyjA10147). We express our gratitude to all
the patients, the nurses and physicians who participated in this study, and thereby
made this work possible. Authors also acknowledge the contribution of the
reviewers who have helped us to improve the manuscript.
References
Adams, H.P., Bendixen, B.H., Kappelle, L.J., Biller, J., Love, B.B., Gordon, D.L., Marsh, E.,
1993. Classication of subtype of acute ischemic stroke. Denitions for use in a
multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.
Stroke 24 (1), 3541.
Autry, A.E., Monteggia, L.M., 2012. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol. Rev. 64 (2), 238258.
Brott, T., Marler, J.R., Olinger, C.P., Adams, H.P., Tomsick, T., Barsan, W.G., Walker, M.,
1989. Measurements of acute cerebral infarction: lesion size by computed
tomography. Stroke 20 (7), 871875.
Tang, W.K., Chan, S.S., Chiu, H.F., Wong, K.S., Kwok, T.C., Mok, V., Ungvari, G.S., 2004.
Can the geriatric depression scale detect poststroke depression in Chinese
elderly? J. Affect. Disord. 81 (2), 153156.
Whyte, E.M., Mulsant, B.H., 2002. Post stroke depression: epidemiology, pathophysiology, and biological treatment. Biol. Psychiatry 52, 253264.
Yang, L., Zhang, Z., Sun, D, Xu, Z., Yuan, Y., Zhang, X., Li, L., 2011. Low serum BDNF
may indicate the development of PSD in patients with acute ischemic stroke.
Int. J. Geriatr. Psychiatry 26 (5), 495502.
379
Zavoreo, I., Bai-Kes, V., Bosnar-Pureti, M., Demarin, V., 2009. Post-stroke
depression. Acta Clin. Croat. 48 (3), 329333.
Zhang, T., Wang, C., Liu, L., Zhao, X., Xue, J., Zhou, Y., Wang, Y., 2010. A prospective
cohort study of the incidence and determinants of post-stroke depression
among the mainland Chinese patients. Neurol. Res. 32 (4), 347352.
Zhou, Z., Lu, T., Xu, G., Yue, X., Zhu, W., Ma, M., Liu, X., 2011. Decreased serum brainderived neurotrophic factor (BDNF) is associated with post-stroke depression
but not with BDNF gene Val66Met polymorphism. Clin. Chem. Lab. Med. 49 (2),
185189.