- Email: [email protected]
Serum Brain-derived neurotrophic factor levels in post-stroke depression
Journal of Affective Disorders 168 (2014) 373–379
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Serum Brain-derived neurotrophic factor levels in post-stroke depression Jie Li a, Yan-Dong Zhao b, Jun-Wei Zeng c, Xiao-Yan Chen a, Ruo-Dan Wang a, Sai-Yu Cheng a,n a
Department of Neurology, Second Affiliated 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 first 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 (5.6–9.4) vs. 13.7 (10.4–16.5)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(0.72–0.87), P¼ 0.003]. Serum levels of BDNF r10.2 ng/ml were independently associated with post-stroke (OR, 11.5; 95% CI, 5.6–23.4, 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 confirm 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 (Lindén 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, finally, 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
n
Corresponding author. Tel.: þ 86 23 68755613. E-mail address: [email protected] (S.-Y. Cheng).
http://dx.doi.org/10.1016/j.jad.2014.07.011 0165-0327/& 2014 Elsevier B.V. All rights reserved.
neurons in brain circuits (Molendijk et al., 2011). In addition to its importance in learning, studies have revealed BDNF's involvement in cognition as well as mood-related behaviors (Autry and Monteggia., 2012). One study found that some BDNF gene polymorphisms may be contributing factors in the pathogenesis of bipolar disorder (Sears et al., 2011), and several studies reported that blood levels of BDNF were reduced in patients with schizophrenia (Green et al., 2011). Recent evidence supports ‘the neurotrophin hypothesis of depression’ in its prediction that BDNF is involved in depression (Taliaz et al., 2010). Several works have demonstrated decreased levels in depressed patients and a recovery after antidepressants treatment (Gazal et al., 2012; Zhou et al., 2011). It was reported that BDNF could cross the blood–brain barrier, and that BDNF levels in the brain and serum underwent similar changes during the maturation and aging processes in rats, suggesting that serum BDNF levels may reflect BDNF levels in the brain (Hashimoto, 2010). Pikula et al. (2013) found that lower serum BDNF were associated with increased risk of incident stroke/TIA, and higher levels of BDNF were also associated with less white matter hyperintensity
374
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
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 gene–gene 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.
examination. The presence of anhedonia and depressive mood was essential for the diagnosis. 2.4. Laboratory tests Fasting venous blood was collected from all participants in vacutainer tubes and quickly centrifuged to avoid glycolysis. Serum samples were kept at 80 1C until assay. Biomarker concentrations were measured in a central laboratory by investigators blinded to the clinical outcome and neuroimaging findings. BDNF serum levels were measured with sandwich-ELISA, using a commercial kit according to the manufacturer instructions (DuoSet ELISA Development, R&D Systems, Inc., USA). The lower detection limit was 1.6 ng/ml and the line range was 1.6–50 ng/ml. The intra-assay coefficient of variation [CV] and inter-assay CV were 3.5–6.8% and 4.4%–7.5%, respectively.
2. Methods 2.5. Statistical analyses 2.1. Study population Two hundred and ninety-five patients with a first episode of acute ischemic stroke admitted to our hospital within the first 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 inflammatory 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 difficulty 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 classified 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 modified Rankin Scale (mRS) at 3 month (Bonita, 1988). A favorable functional outcome was defined as an mRS score of 0 to 2 points, while an unfavorable functional outcome was defined 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 finish 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. Shapiro–Wilk 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 Mann–Whitney 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 influence 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% confidence 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 significance was defined 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 ¼0.632), gender (P ¼0.803), NIHSS (P ¼0.654) and weight (P ¼0.723)] 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, 2.4–7.5). The number of tissue plasminogen activator-treated patients was 65 (30.1%). 3.2. Main findings Ninety-four patients (43.5%) showed depression (major and minor) at 3 months after admission and in 59 patients (27.3%) this
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
depression was classified as major. The baseline characteristics of 216 stroke patients presented with depression or not are described in Table 1. Patients with depression were older and more frequently were female, living with offspring, widowhood, higher admission stroke severity, higher serum levels of Hs-CRP and lower BDNF. No association was found between etiological subtype or infarct volume and the presence of depression. Similarly, if the minor depression were included, we got the equal conclusion. The results indicated that the median serum BDNF level was 12.4 (IQR, 8.7–15.5) ng/ml. The serum BDNF levels were significantly decreased in PSD patients at the time of admission as compared with stroke patients without depression [8.1 (IQR, 5.6– 9.4) ng/ml and 13.7 (IQR, 10.4–16.5) ng/ml, respectively; P o0.0001], Fig. 1a. Similarly, if the minor depression were included, we also found that serum BDNF levels were significantly decreased in PSD patients [9.3 (IQR, 7.2–12.5) ng/ml and 14.5 (IQR, 11.2–17.4) ng/ml, respectively; P o0.0001], Fig. 1b. Serum BDNF levels decreased with increasing severity of stroke as defined by the NIHSS score. There was a negative correlation between levels of BDNF and the NIHSS (r ¼ 0.286, P o0.0001; Fig. 2a.). Similarly, the lower serum BDNF levels at admission corresponded to the higher HAM-D score at 3 months (r ¼ 0.361, Po 0.0001; Fig. 2b). BDNF was still significantly associated with HAM-D score (β¼ 0.304, P ¼0.009), after controlling for age, gender, body mass index, stroke etiology, the NIHSS score, infarct volume, vascular risk factors and a history of depression. In addition, there was no correlation between level of BDNF and sex (P ¼0.211), and age (P ¼0.326). Based on ROC curves, the optimal cutoff value of serum BDNF levels at admission which predicted the development of depression at 3 months was 10.2 ng/ml, which yielded the highest sensitivity and specificity [80.3% and 81.8%, respectively; area under the curve (AUC) ¼0.854, 95% CI: 0.791–0.917; P o0.0001]. See Fig. 3a. BDNF levels had a higher prognostic accuracy as compared to Hs-CRP [AUC 0.58 (0.47–0.65), P¼ 0.013], HCY [AUC 0.69 (0.51–0.82), P ¼0.008] and NIHSS score at admission [AUC
375
0.66 (0.54–0.77), P¼ 0.007]. In logistic regression analysis, BDNF levels at admission were independently associated with depression (OR, 0.79; 95% CI, 0.72–0.87, P ¼0.003) after adjustment for age, gender, widowhood, living with offspring, NIHSS on admission, serum levels of HS-CRP and HCY. See Table 2. Serum levels of BDNF r10.2 ng/ml were independently associated with poststroke (OR, 11.5; 95% CI, 5.6–23.4, Po 0.0001), after adjustment for above variables. Again, if the minor depression were included, we have produced similar results. Based on ROC curves, the optimal cutoff value of 11.5 ng/ml, which yielded the highest sensitivity and specificity [73.2% and 70.7%, respectively; area under the curve (AUC) ¼ 0.780, 95% CI: 0.717–0.843; P o0.0001]. See Fig. 3b. In logistic regression analysis, BDNF levels at admission were independently associated with depression (OR, 0.85; 95% CI, 0.76–0.93, P¼ 0.006) after adjustment for age, gender, widowhood, living with offspring, NIHSS on admission, serum levels of HS-CRP and HCY. See Table 3. Serum levels of BDNF r11.5 ng/ml were independently associated with post-stroke (OR, 6.93; 95% CI, 3.89– 12.31, Po 0.0001), after adjustment for above variables.
4. Discussion Largely in accord with previous findings 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
Depression patients (n¼ 59)
No depression (n¼ 157)
Pa
Age (years), mean(SD) Female sex, % BMI(kg m 2, IQR) Hypertension, % Diabetes at baseline, % Days of hospitalization, median (IQR) Admission median NIHSS score (IQR) mRS at follow-up, median (IQR) Infarct volume (ml), mean(SD) Widowhood (%) Living with offspring (%) Family history of depression, % TOAST classification (%) a. Large artery b. Small artery c. Cardioembolism d. Other cause e. Unknown Laboratory findings (Median, IQR) White cell count, 109/L Glucose level, mmol/L Hs-CRP, mg/dL HCY, umol/L BDNF, ng/ml
72.8 (11.2) 59.3 26.5 (22.8–28.5) 49.2 32.2 14 (7–18) 8 (4–14) 3 (1–3) 12.5 (1.6) 40.7 32.2 13.6
63.6 (9.1) 40.8 27.2 (23.0–29.2) 51.6 29.3 13 (6–18) 5 (2–8) 2 (1–3) 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 (5.9–8.6) 5.45 (4.79–6.52) 0.80 (0.35–1.88) 18.2 (14,3–23.4) 8.1 (5.6–9.4)
7.6 (5.5–8.4) 5.39 (4.85–6.55) 0.55 (0.26–1.26) 14.9 (11.8–17.8) 13.7 (10.4–16.5)
0.512 0.242 0.013 0.008 o 0.0001
Results are expressed as percentages or as medians (IQR) and means (SD). IQR: interquartile range; SD: standard deviation; Hs-CRP: high-sensitivity C-reactive protein; HCY: homocysteine; BMI: body mass index; BDNF: brain-derived neurotrophic factor; TOAST: Trial of ORG 10172 in Acute Stroke Treatment; mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale. a
Mann–Whitney U test, student's t test or chi-square test were used.
376
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
Fig. 1. Serum BDNF levels in stroke patients with depression and no-depression group. Mann–Whitney U-test. All data are medians and in-terquartile ranges (IQR). (a) Depression patients were defined 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 ¼ 28.992; 95% CI, 8.014–104.891; 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 significant 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 3–6 months after stroke with a range of 9–34% 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 classified 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
subjects (P o6.8 10 8), and that BDNF levels were significantly (P ¼0.003) increased after antidepressant treatment (Sen et al., 2008). The other meta-analysis similarly showed that BDNF levels increased significantly after antidepressant treatment (effect size: 0.62), and that there was a significant (P ¼0.02) correlation between changes in BDNF level and depression score changes (Brunoni et al., 2008). Several lines of evidence suggest that the expression of BDNF may be a downstream target of a variety of antidepressant treatments; BDNF might therefore be an important target for therapeutic recovery from depression, and it might also provide protection against stress-induced neuronal damage (Hashimoto., 2010). The relationship between BDNF and stroke remains not completely understood. There is experimental evidence that neurons and glial cells act as endogenous sources of BDNF after ischemic and other brain injuries (Sandhofer et al., 2009). Dysfunction of cerebral vascular BDNF signaling, therefore, may contribute to disruption of the neurovascular unit, hence to an alteration of tissue responses to vascular injury (Guo et al., 2008). A small molecule BDNF mimetic (LM22A-4) when administered immediately after an ischemic stroke in adult mice lead to increased neurogenesis and improved functional motor recovery (Han et al., 2012). Therefore, BDNF could reduce stroke risk through its neurotrophic or its vascular effect (Pikula et al., 2013).
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
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 defined 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
P
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
1.10–2.79 1.04–1.55 1.18–3.09 1.09–1.78 1.04–1.18 1.25–2.89 1.03–1.29 0.72–0.87 5.60–23.40
0.024 0.015 0.002 0.001 0.001 0.013 0.008 0.003 P o0.0001
OR: odds ratio; CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale; mRS: modified Rankin Scale; Hs-CRP: high-sensitivity C-reactive protein; HCY: homocysteine; BDNF: Brain-derived neurotrophic factor. a
The odds ratio corresponds to a unit increase in the explanatory variable.
Table 3 Adjusted OR of depression (minor depression were included) for BDNF levels in the stroke patients. Parameter
ORa
95% CI
P
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
1.08–2.81 1.05–1.56 1.15–3.14 1.11–1.82 1.03–1.22 1.23–2.95 1.04–1.33 0.76–0.93 3.89–12.31
0.019 0.016 0.002 0.001 0.001 0.011 0.007 0.006 P o0.0001
OR: odds ratio; CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale; mRS: Modified Rankin Scale; Hs-CRP: high-sensitivity C-reactive protein; HCY: homocysteine; BDNF: Brain-derived neurotrophic factor. a
The odds ratio corresponds to a unit increase in the explanatory variable.
Many etiologies of PSD have been proposed but it is unlikely that any single hypothesis can explain what appears to be heterogeneous. It is probable that complex interactions between
hormones, neurotransmitters, and environmental factors are involved. In our study, one found that decreased BDNF levels may be important in the pathophysiology of depression. One hypothesis would be that reduced BDNF might reflect a genetic vulnerability in patients with depression. Two studies using mice with a genetic deletion of the BDNF gene have demonstrated that BDNF play a critical role in neuronal differentiation and survival (Ernfors et al., 1994; Jones et al., 1994). Monteggia et al. (2007) showed that conditional BDNF knockout mice also display an increase in depression-like behavior in the forced-swim and sucrose preference tests, suggesting that low production of BDNF may precipitate depressive disorder. Another possible explanation would be that stress-induced BDNF reductions might cause neuronal damage, which would in turn lead to acquired biological vulnerability. Stress, which can precipitate and exacerbate depression, causes neuronal atrophy and death, especially in the hippocampus (Shimizu et al., 2003) proposed that stress-induced changes in the hippocampus may be central to the development of depression in genetically vulnerable individuals (Rajkowska, 2000). Levels in PSD may reflect the collapse of the stress-adaptation system and its failure to protect the brain from stress-induced neuronal degeneration. Third, BDNF has been shown to have antidepressant effects in animal models of depression (Hashimoto., 2010). It has been reported that forced swimming decreased BDNF mRNA in particular regions (CA1, CA3, and the dentate gyrus) of the hippocampus, and that a combination of physical activity and antidepressant treatment increased the level of hippocampal BDNF mRNA to well above the baseline value as well as enhanced swimming time in an animal model (Russo-Neustadt et al., 2001). BDNF signaling appears to be sufficient for antidepressant effects, as direct infusion of BDNF into midbrain areas or the hippocampus induces behavioral responses that are similar to those produced by antidepressants (Rantamäki et al., 2006). This study has a number of limitations. The major limitation of our study was that we were not able to examine the risk factors for depressive episodes including lack of social support, poverty, family violence, and increased life stress. In addition, the study subjects were few and not randomly selected. The study was conducted in only one clinic. Therefore, our findings may not be generalizable to other Chinese stroke patients. Further research is
378
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
needed. Third, the serum levels of BDNF were only measured at the acute stage of stroke in the patients and, hence, this study yielded no data regarding when and how long biomarkers were changed in these patients. Forth, depression assessment was made only once, at the 3-month follow up, whereas the NIHSS was used only at the acute stage. In addition, patients who had more severe stroke died before the 3-month follow up were not included. Some patients who died and had depression might be excluded. Lastly, the depressive status might be influenced by the severity of stroke itself. Schäbitz et al. (2007) found that BDNF may have negative effects on the course and prognosis of stroke. However, in this study, the stroke severity was not evaluated at 3 months. In spite of these limitations, the findings of this study remained important and showed that serum BDNF at admission was significantly reduced and suggested that these alterations might participate in the pathophysiology of depression symptoms in stroke patients. Serum BDNF levels at admission could be seen as one powerful biological marker of risk for developing post-stroke major depression at 3 month. Further studies are necessary to confirm this association. Brunoni et al. (2008) found that that BDNF levels increased significantly after antidepressant treatment, and suggested the applicability of BDNF as an efficient and novel anti-depression tool against depression in patients with ischemic stroke. Future clinical trials with BDNF should be driven.
Role of funding source The funding agencies played no role in the design and conduct of the study.
Conflict of interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm 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 confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm 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 office). He/she is responsible for communicating with other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the corresponding author and which has been configured 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. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24 (1), 35–41. Autry, A.E., Monteggia, L.M., 2012. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol. Rev. 64 (2), 238–258. 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), 871–875.
Bonita, R, Beaglehole, R, 1988. Modification of rankin scale: recovery of motor function after stroke. Stroke 19, 1497–1500. Brunoni, A.R., Lopes, M., Fregni, F., 2008. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int. J. Neuropsychopharmacol. 11, 1169–1180. Cheng, S.Y., Zhao, Y.D., Li, J., et al., 2014. Plasma levels of glutamate during stroke is associated with development of post-stroke depression. Psychoneuroendocrinology 47, 126–135. Ellis, C., Zhao, Y., Egede, L.E., 2010. Depression and increased risk of death in adults with stroke. J. Psychosom. Res. 68, 545–551. Ernfors, P., Lee, K.F., Jaenisch, R., 1994. Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368, 147–150. Gazal, M., Motta, L.S., Wiener, C.D., Fernandes, J.C., Quevedo, L.Á., Jansen, K., Oses, J.P., 2012. Brain-derived neurotrophic factor in post-partum depressive mothers. Neurochem. Res. 37 (3), 583–587. Green, M.J., Matheson, S.L., Shepherd, A., Weickert, C.S., Carr, V.J., 2011. Brainderived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Molecular psychiatry 16 (9), 960–972. Guo, S., Kim, W.J., Lok, J., Lee, S.R., Besancon, E., Luo, B.H., Lo, E.H., 2008. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Proc. Natl. Acad. Sci. 105 (21), 7582–7587. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23 (1), 56–62. Han, J., Pollak, J., Yang, T., Siddiqui, M.R., Doyle, K.P., Taravosh-Lahn, K., Buckwalter, M.S., 2012. Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic–ischemic stroke. Stroke 43 (7), 1918–1924. Hashimoto, K., 2010. Brain‐derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin. Neurosci. 64 (4), 341–357. Jones, K.R., Fariñas, I., Backus, C., Reichardt, L.F., 1994. Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell 76 (6), 989–999. Kim, J.M., Stewart, R., Bae, K.Y., Kim, S.W., Kang, H.J., Shin, I.S., Yoon, J.S., 2012. Serotonergic and BDNF genes and risk of depression after stroke. J. Affect. Disord. 136 (3), 833–840. Kim, J.M., Stewart, R., Kim, S.W., Yang, S.J., Shin, I.S., Kim, Y.H., Yoon, J.S., 2008. BDNF genotype potentially modifying the association between incident stroke and depression. Neurobiol. Aging 29 (5), 789–792. Lindén, T., Blomstrand, C., Skoog, I., 2007. Depressive disorders after 20 months in elderly stroke patients a case-control study. Stroke 38 (6), 1860–1863. Molendijk, M.L., Bus, B.A., Spinhoven, P., Penninx, B.W., Kenis, G., Prickaerts, J., Elzinga, B.M., 2011. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment. Mol. Psychiatry 16 (11), 1088–1095. Monteggia, L.M., Luikart, B., Barrot, M., Theobold, D., Malkovska, I., Nef, S., Nestler, E.J., 2007. Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol. Psychiatry 61 (2), 187–197. Pikula, A., Beiser, A.S., Chen, T.C., Preis, S.R., Vorgias, D., DeCarli, C., Seshadri, S., 2013. Serum brain–derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury framingham study. Stroke 44 (10), 2768–2775. Rajkowska, G., 2000. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol. Psychiatry 48 (8), 766–777. Rantamäki, T., Knuuttila, J.E., Hokkanen, M.E., Castrén, E., 2006. The effects of acute and long-term lithium treatments on trkB neurotrophin receptor activation in the mouse hippocampus and anterior cingulate cortex. Neuropharmacology 50 (4), 421–427. Russo-Neustadt, A., Ha, T., Ramirez, R., Kesslak, J.P., 2001. Physical activity– antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model. Behav. Brain Res. 120 (1), 87–95. Sears, C., Markie, D., Olds, R., Fitches, A., 2011. Evidence of associations between bipolar disorder and the brain‐derived neurotrophic factor (BDNF) gene. Bipolar Disord. 13 (7–8), 630–637. Sandhofer, A., Tatarczyk, T., Kirchmair, R., Iglseder, B., Paulweber, B., Patsch, J.R., Schratzberger, P., 2009. Are plasma VEGF and its soluble receptor sFlt-1 atherogenic risk factors? Cross-sectional data from the SAPHIR study. Atherosclerosis 206 (1), 265–269. Schäbitz, W.R., Steigleder, T., Cooper-Kuhn, C.M., Schwab, S., Sommer, C., Schneider, A., Kuhn, H.G., 2007. Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 38 (7), 2165–2172. Sen, S., Duman, R., Sanacora, G., 2008. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol. Psychiatry 64 (6), 527–532. Shimizu, E., Hashimoto, K., Okamura, N., Koike, K., Komatsu, N., Kumakiri, C., Iyo, M., 2003. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol. Psychiatry 54 (1), 70–75. Sims, J.R., Gharai, L.R., Schaefer, P.W., Vangel, M., Rosenthal, E.S., Lev, M.H., Schwamm, L.H., 2009. ABC/2 for rapid clinical estimate of infarct, perfusion, and mismatch volumes. Neurology 72 (24), 2104–2110. Taliaz, D., Stall, N., Dar, D.E., Zangen, A., 2010. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol. Psychiatry 15 (1), 80–92.
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
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), 153–156. Whyte, E.M., Mulsant, B.H., 2002. Post stroke depression: epidemiology, pathophysiology, and biological treatment. Biol. Psychiatry 52, 253–264. 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), 495–502.
379
Zavoreo, I., Bašić-Kes, V., Bosnar-Puretić, M., Demarin, V., 2009. Post-stroke depression. Acta Clin. Croat. 48 (3), 329–333. 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), 347–352. 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), 185–189.
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Serum Brain-derived neurotrophic factor levels in post-stroke depression Jie Li a, Yan-Dong Zhao b, Jun-Wei Zeng c, Xiao-Yan Chen a, Ruo-Dan Wang a, Sai-Yu Cheng a,n a
Department of Neurology, Second Affiliated 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 first 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 (5.6–9.4) vs. 13.7 (10.4–16.5)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(0.72–0.87), P¼ 0.003]. Serum levels of BDNF r10.2 ng/ml were independently associated with post-stroke (OR, 11.5; 95% CI, 5.6–23.4, 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 confirm 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 (Lindén 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, finally, 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
n
Corresponding author. Tel.: þ 86 23 68755613. E-mail address: [email protected] (S.-Y. Cheng).
http://dx.doi.org/10.1016/j.jad.2014.07.011 0165-0327/& 2014 Elsevier B.V. All rights reserved.
neurons in brain circuits (Molendijk et al., 2011). In addition to its importance in learning, studies have revealed BDNF's involvement in cognition as well as mood-related behaviors (Autry and Monteggia., 2012). One study found that some BDNF gene polymorphisms may be contributing factors in the pathogenesis of bipolar disorder (Sears et al., 2011), and several studies reported that blood levels of BDNF were reduced in patients with schizophrenia (Green et al., 2011). Recent evidence supports ‘the neurotrophin hypothesis of depression’ in its prediction that BDNF is involved in depression (Taliaz et al., 2010). Several works have demonstrated decreased levels in depressed patients and a recovery after antidepressants treatment (Gazal et al., 2012; Zhou et al., 2011). It was reported that BDNF could cross the blood–brain barrier, and that BDNF levels in the brain and serum underwent similar changes during the maturation and aging processes in rats, suggesting that serum BDNF levels may reflect BDNF levels in the brain (Hashimoto, 2010). Pikula et al. (2013) found that lower serum BDNF were associated with increased risk of incident stroke/TIA, and higher levels of BDNF were also associated with less white matter hyperintensity
374
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
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 gene–gene 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.
examination. The presence of anhedonia and depressive mood was essential for the diagnosis. 2.4. Laboratory tests Fasting venous blood was collected from all participants in vacutainer tubes and quickly centrifuged to avoid glycolysis. Serum samples were kept at 80 1C until assay. Biomarker concentrations were measured in a central laboratory by investigators blinded to the clinical outcome and neuroimaging findings. BDNF serum levels were measured with sandwich-ELISA, using a commercial kit according to the manufacturer instructions (DuoSet ELISA Development, R&D Systems, Inc., USA). The lower detection limit was 1.6 ng/ml and the line range was 1.6–50 ng/ml. The intra-assay coefficient of variation [CV] and inter-assay CV were 3.5–6.8% and 4.4%–7.5%, respectively.
2. Methods 2.5. Statistical analyses 2.1. Study population Two hundred and ninety-five patients with a first episode of acute ischemic stroke admitted to our hospital within the first 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 inflammatory 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 difficulty 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 classified 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 modified Rankin Scale (mRS) at 3 month (Bonita, 1988). A favorable functional outcome was defined as an mRS score of 0 to 2 points, while an unfavorable functional outcome was defined 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 finish 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. Shapiro–Wilk 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 Mann–Whitney 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 influence 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% confidence 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 significance was defined 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 ¼0.632), gender (P ¼0.803), NIHSS (P ¼0.654) and weight (P ¼0.723)] 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, 2.4–7.5). The number of tissue plasminogen activator-treated patients was 65 (30.1%). 3.2. Main findings Ninety-four patients (43.5%) showed depression (major and minor) at 3 months after admission and in 59 patients (27.3%) this
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
depression was classified as major. The baseline characteristics of 216 stroke patients presented with depression or not are described in Table 1. Patients with depression were older and more frequently were female, living with offspring, widowhood, higher admission stroke severity, higher serum levels of Hs-CRP and lower BDNF. No association was found between etiological subtype or infarct volume and the presence of depression. Similarly, if the minor depression were included, we got the equal conclusion. The results indicated that the median serum BDNF level was 12.4 (IQR, 8.7–15.5) ng/ml. The serum BDNF levels were significantly decreased in PSD patients at the time of admission as compared with stroke patients without depression [8.1 (IQR, 5.6– 9.4) ng/ml and 13.7 (IQR, 10.4–16.5) ng/ml, respectively; P o0.0001], Fig. 1a. Similarly, if the minor depression were included, we also found that serum BDNF levels were significantly decreased in PSD patients [9.3 (IQR, 7.2–12.5) ng/ml and 14.5 (IQR, 11.2–17.4) ng/ml, respectively; P o0.0001], Fig. 1b. Serum BDNF levels decreased with increasing severity of stroke as defined by the NIHSS score. There was a negative correlation between levels of BDNF and the NIHSS (r ¼ 0.286, P o0.0001; Fig. 2a.). Similarly, the lower serum BDNF levels at admission corresponded to the higher HAM-D score at 3 months (r ¼ 0.361, Po 0.0001; Fig. 2b). BDNF was still significantly associated with HAM-D score (β¼ 0.304, P ¼0.009), after controlling for age, gender, body mass index, stroke etiology, the NIHSS score, infarct volume, vascular risk factors and a history of depression. In addition, there was no correlation between level of BDNF and sex (P ¼0.211), and age (P ¼0.326). Based on ROC curves, the optimal cutoff value of serum BDNF levels at admission which predicted the development of depression at 3 months was 10.2 ng/ml, which yielded the highest sensitivity and specificity [80.3% and 81.8%, respectively; area under the curve (AUC) ¼0.854, 95% CI: 0.791–0.917; P o0.0001]. See Fig. 3a. BDNF levels had a higher prognostic accuracy as compared to Hs-CRP [AUC 0.58 (0.47–0.65), P¼ 0.013], HCY [AUC 0.69 (0.51–0.82), P ¼0.008] and NIHSS score at admission [AUC
375
0.66 (0.54–0.77), P¼ 0.007]. In logistic regression analysis, BDNF levels at admission were independently associated with depression (OR, 0.79; 95% CI, 0.72–0.87, P ¼0.003) after adjustment for age, gender, widowhood, living with offspring, NIHSS on admission, serum levels of HS-CRP and HCY. See Table 2. Serum levels of BDNF r10.2 ng/ml were independently associated with poststroke (OR, 11.5; 95% CI, 5.6–23.4, Po 0.0001), after adjustment for above variables. Again, if the minor depression were included, we have produced similar results. Based on ROC curves, the optimal cutoff value of 11.5 ng/ml, which yielded the highest sensitivity and specificity [73.2% and 70.7%, respectively; area under the curve (AUC) ¼ 0.780, 95% CI: 0.717–0.843; P o0.0001]. See Fig. 3b. In logistic regression analysis, BDNF levels at admission were independently associated with depression (OR, 0.85; 95% CI, 0.76–0.93, P¼ 0.006) after adjustment for age, gender, widowhood, living with offspring, NIHSS on admission, serum levels of HS-CRP and HCY. See Table 3. Serum levels of BDNF r11.5 ng/ml were independently associated with post-stroke (OR, 6.93; 95% CI, 3.89– 12.31, Po 0.0001), after adjustment for above variables.
4. Discussion Largely in accord with previous findings 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
Depression patients (n¼ 59)
No depression (n¼ 157)
Pa
Age (years), mean(SD) Female sex, % BMI(kg m 2, IQR) Hypertension, % Diabetes at baseline, % Days of hospitalization, median (IQR) Admission median NIHSS score (IQR) mRS at follow-up, median (IQR) Infarct volume (ml), mean(SD) Widowhood (%) Living with offspring (%) Family history of depression, % TOAST classification (%) a. Large artery b. Small artery c. Cardioembolism d. Other cause e. Unknown Laboratory findings (Median, IQR) White cell count, 109/L Glucose level, mmol/L Hs-CRP, mg/dL HCY, umol/L BDNF, ng/ml
72.8 (11.2) 59.3 26.5 (22.8–28.5) 49.2 32.2 14 (7–18) 8 (4–14) 3 (1–3) 12.5 (1.6) 40.7 32.2 13.6
63.6 (9.1) 40.8 27.2 (23.0–29.2) 51.6 29.3 13 (6–18) 5 (2–8) 2 (1–3) 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 (5.9–8.6) 5.45 (4.79–6.52) 0.80 (0.35–1.88) 18.2 (14,3–23.4) 8.1 (5.6–9.4)
7.6 (5.5–8.4) 5.39 (4.85–6.55) 0.55 (0.26–1.26) 14.9 (11.8–17.8) 13.7 (10.4–16.5)
0.512 0.242 0.013 0.008 o 0.0001
Results are expressed as percentages or as medians (IQR) and means (SD). IQR: interquartile range; SD: standard deviation; Hs-CRP: high-sensitivity C-reactive protein; HCY: homocysteine; BMI: body mass index; BDNF: brain-derived neurotrophic factor; TOAST: Trial of ORG 10172 in Acute Stroke Treatment; mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale. a
Mann–Whitney U test, student's t test or chi-square test were used.
376
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
Fig. 1. Serum BDNF levels in stroke patients with depression and no-depression group. Mann–Whitney U-test. All data are medians and in-terquartile ranges (IQR). (a) Depression patients were defined 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 ¼ 28.992; 95% CI, 8.014–104.891; 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 significant 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 3–6 months after stroke with a range of 9–34% 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 classified 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
subjects (P o6.8 10 8), and that BDNF levels were significantly (P ¼0.003) increased after antidepressant treatment (Sen et al., 2008). The other meta-analysis similarly showed that BDNF levels increased significantly after antidepressant treatment (effect size: 0.62), and that there was a significant (P ¼0.02) correlation between changes in BDNF level and depression score changes (Brunoni et al., 2008). Several lines of evidence suggest that the expression of BDNF may be a downstream target of a variety of antidepressant treatments; BDNF might therefore be an important target for therapeutic recovery from depression, and it might also provide protection against stress-induced neuronal damage (Hashimoto., 2010). The relationship between BDNF and stroke remains not completely understood. There is experimental evidence that neurons and glial cells act as endogenous sources of BDNF after ischemic and other brain injuries (Sandhofer et al., 2009). Dysfunction of cerebral vascular BDNF signaling, therefore, may contribute to disruption of the neurovascular unit, hence to an alteration of tissue responses to vascular injury (Guo et al., 2008). A small molecule BDNF mimetic (LM22A-4) when administered immediately after an ischemic stroke in adult mice lead to increased neurogenesis and improved functional motor recovery (Han et al., 2012). Therefore, BDNF could reduce stroke risk through its neurotrophic or its vascular effect (Pikula et al., 2013).
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
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 defined 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
P
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
1.10–2.79 1.04–1.55 1.18–3.09 1.09–1.78 1.04–1.18 1.25–2.89 1.03–1.29 0.72–0.87 5.60–23.40
0.024 0.015 0.002 0.001 0.001 0.013 0.008 0.003 P o0.0001
OR: odds ratio; CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale; mRS: modified Rankin Scale; Hs-CRP: high-sensitivity C-reactive protein; HCY: homocysteine; BDNF: Brain-derived neurotrophic factor. a
The odds ratio corresponds to a unit increase in the explanatory variable.
Table 3 Adjusted OR of depression (minor depression were included) for BDNF levels in the stroke patients. Parameter
ORa
95% CI
P
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
1.08–2.81 1.05–1.56 1.15–3.14 1.11–1.82 1.03–1.22 1.23–2.95 1.04–1.33 0.76–0.93 3.89–12.31
0.019 0.016 0.002 0.001 0.001 0.011 0.007 0.006 P o0.0001
OR: odds ratio; CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale; mRS: Modified Rankin Scale; Hs-CRP: high-sensitivity C-reactive protein; HCY: homocysteine; BDNF: Brain-derived neurotrophic factor. a
The odds ratio corresponds to a unit increase in the explanatory variable.
Many etiologies of PSD have been proposed but it is unlikely that any single hypothesis can explain what appears to be heterogeneous. It is probable that complex interactions between
hormones, neurotransmitters, and environmental factors are involved. In our study, one found that decreased BDNF levels may be important in the pathophysiology of depression. One hypothesis would be that reduced BDNF might reflect a genetic vulnerability in patients with depression. Two studies using mice with a genetic deletion of the BDNF gene have demonstrated that BDNF play a critical role in neuronal differentiation and survival (Ernfors et al., 1994; Jones et al., 1994). Monteggia et al. (2007) showed that conditional BDNF knockout mice also display an increase in depression-like behavior in the forced-swim and sucrose preference tests, suggesting that low production of BDNF may precipitate depressive disorder. Another possible explanation would be that stress-induced BDNF reductions might cause neuronal damage, which would in turn lead to acquired biological vulnerability. Stress, which can precipitate and exacerbate depression, causes neuronal atrophy and death, especially in the hippocampus (Shimizu et al., 2003) proposed that stress-induced changes in the hippocampus may be central to the development of depression in genetically vulnerable individuals (Rajkowska, 2000). Levels in PSD may reflect the collapse of the stress-adaptation system and its failure to protect the brain from stress-induced neuronal degeneration. Third, BDNF has been shown to have antidepressant effects in animal models of depression (Hashimoto., 2010). It has been reported that forced swimming decreased BDNF mRNA in particular regions (CA1, CA3, and the dentate gyrus) of the hippocampus, and that a combination of physical activity and antidepressant treatment increased the level of hippocampal BDNF mRNA to well above the baseline value as well as enhanced swimming time in an animal model (Russo-Neustadt et al., 2001). BDNF signaling appears to be sufficient for antidepressant effects, as direct infusion of BDNF into midbrain areas or the hippocampus induces behavioral responses that are similar to those produced by antidepressants (Rantamäki et al., 2006). This study has a number of limitations. The major limitation of our study was that we were not able to examine the risk factors for depressive episodes including lack of social support, poverty, family violence, and increased life stress. In addition, the study subjects were few and not randomly selected. The study was conducted in only one clinic. Therefore, our findings may not be generalizable to other Chinese stroke patients. Further research is
378
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
needed. Third, the serum levels of BDNF were only measured at the acute stage of stroke in the patients and, hence, this study yielded no data regarding when and how long biomarkers were changed in these patients. Forth, depression assessment was made only once, at the 3-month follow up, whereas the NIHSS was used only at the acute stage. In addition, patients who had more severe stroke died before the 3-month follow up were not included. Some patients who died and had depression might be excluded. Lastly, the depressive status might be influenced by the severity of stroke itself. Schäbitz et al. (2007) found that BDNF may have negative effects on the course and prognosis of stroke. However, in this study, the stroke severity was not evaluated at 3 months. In spite of these limitations, the findings of this study remained important and showed that serum BDNF at admission was significantly reduced and suggested that these alterations might participate in the pathophysiology of depression symptoms in stroke patients. Serum BDNF levels at admission could be seen as one powerful biological marker of risk for developing post-stroke major depression at 3 month. Further studies are necessary to confirm this association. Brunoni et al. (2008) found that that BDNF levels increased significantly after antidepressant treatment, and suggested the applicability of BDNF as an efficient and novel anti-depression tool against depression in patients with ischemic stroke. Future clinical trials with BDNF should be driven.
Role of funding source The funding agencies played no role in the design and conduct of the study.
Conflict of interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm 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 confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm 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 office). He/she is responsible for communicating with other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the corresponding author and which has been configured 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. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24 (1), 35–41. Autry, A.E., Monteggia, L.M., 2012. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol. Rev. 64 (2), 238–258. 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), 871–875.
Bonita, R, Beaglehole, R, 1988. Modification of rankin scale: recovery of motor function after stroke. Stroke 19, 1497–1500. Brunoni, A.R., Lopes, M., Fregni, F., 2008. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int. J. Neuropsychopharmacol. 11, 1169–1180. Cheng, S.Y., Zhao, Y.D., Li, J., et al., 2014. Plasma levels of glutamate during stroke is associated with development of post-stroke depression. Psychoneuroendocrinology 47, 126–135. Ellis, C., Zhao, Y., Egede, L.E., 2010. Depression and increased risk of death in adults with stroke. J. Psychosom. Res. 68, 545–551. Ernfors, P., Lee, K.F., Jaenisch, R., 1994. Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368, 147–150. Gazal, M., Motta, L.S., Wiener, C.D., Fernandes, J.C., Quevedo, L.Á., Jansen, K., Oses, J.P., 2012. Brain-derived neurotrophic factor in post-partum depressive mothers. Neurochem. Res. 37 (3), 583–587. Green, M.J., Matheson, S.L., Shepherd, A., Weickert, C.S., Carr, V.J., 2011. Brainderived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Molecular psychiatry 16 (9), 960–972. Guo, S., Kim, W.J., Lok, J., Lee, S.R., Besancon, E., Luo, B.H., Lo, E.H., 2008. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Proc. Natl. Acad. Sci. 105 (21), 7582–7587. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23 (1), 56–62. Han, J., Pollak, J., Yang, T., Siddiqui, M.R., Doyle, K.P., Taravosh-Lahn, K., Buckwalter, M.S., 2012. Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic–ischemic stroke. Stroke 43 (7), 1918–1924. Hashimoto, K., 2010. Brain‐derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin. Neurosci. 64 (4), 341–357. Jones, K.R., Fariñas, I., Backus, C., Reichardt, L.F., 1994. Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell 76 (6), 989–999. Kim, J.M., Stewart, R., Bae, K.Y., Kim, S.W., Kang, H.J., Shin, I.S., Yoon, J.S., 2012. Serotonergic and BDNF genes and risk of depression after stroke. J. Affect. Disord. 136 (3), 833–840. Kim, J.M., Stewart, R., Kim, S.W., Yang, S.J., Shin, I.S., Kim, Y.H., Yoon, J.S., 2008. BDNF genotype potentially modifying the association between incident stroke and depression. Neurobiol. Aging 29 (5), 789–792. Lindén, T., Blomstrand, C., Skoog, I., 2007. Depressive disorders after 20 months in elderly stroke patients a case-control study. Stroke 38 (6), 1860–1863. Molendijk, M.L., Bus, B.A., Spinhoven, P., Penninx, B.W., Kenis, G., Prickaerts, J., Elzinga, B.M., 2011. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment. Mol. Psychiatry 16 (11), 1088–1095. Monteggia, L.M., Luikart, B., Barrot, M., Theobold, D., Malkovska, I., Nef, S., Nestler, E.J., 2007. Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol. Psychiatry 61 (2), 187–197. Pikula, A., Beiser, A.S., Chen, T.C., Preis, S.R., Vorgias, D., DeCarli, C., Seshadri, S., 2013. Serum brain–derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury framingham study. Stroke 44 (10), 2768–2775. Rajkowska, G., 2000. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol. Psychiatry 48 (8), 766–777. Rantamäki, T., Knuuttila, J.E., Hokkanen, M.E., Castrén, E., 2006. The effects of acute and long-term lithium treatments on trkB neurotrophin receptor activation in the mouse hippocampus and anterior cingulate cortex. Neuropharmacology 50 (4), 421–427. Russo-Neustadt, A., Ha, T., Ramirez, R., Kesslak, J.P., 2001. Physical activity– antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model. Behav. Brain Res. 120 (1), 87–95. Sears, C., Markie, D., Olds, R., Fitches, A., 2011. Evidence of associations between bipolar disorder and the brain‐derived neurotrophic factor (BDNF) gene. Bipolar Disord. 13 (7–8), 630–637. Sandhofer, A., Tatarczyk, T., Kirchmair, R., Iglseder, B., Paulweber, B., Patsch, J.R., Schratzberger, P., 2009. Are plasma VEGF and its soluble receptor sFlt-1 atherogenic risk factors? Cross-sectional data from the SAPHIR study. Atherosclerosis 206 (1), 265–269. Schäbitz, W.R., Steigleder, T., Cooper-Kuhn, C.M., Schwab, S., Sommer, C., Schneider, A., Kuhn, H.G., 2007. Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 38 (7), 2165–2172. Sen, S., Duman, R., Sanacora, G., 2008. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol. Psychiatry 64 (6), 527–532. Shimizu, E., Hashimoto, K., Okamura, N., Koike, K., Komatsu, N., Kumakiri, C., Iyo, M., 2003. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol. Psychiatry 54 (1), 70–75. Sims, J.R., Gharai, L.R., Schaefer, P.W., Vangel, M., Rosenthal, E.S., Lev, M.H., Schwamm, L.H., 2009. ABC/2 for rapid clinical estimate of infarct, perfusion, and mismatch volumes. Neurology 72 (24), 2104–2110. Taliaz, D., Stall, N., Dar, D.E., Zangen, A., 2010. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol. Psychiatry 15 (1), 80–92.
J. Li et al. / Journal of Affective Disorders 168 (2014) 373–379
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), 153–156. Whyte, E.M., Mulsant, B.H., 2002. Post stroke depression: epidemiology, pathophysiology, and biological treatment. Biol. Psychiatry 52, 253–264. 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), 495–502.
379
Zavoreo, I., Bašić-Kes, V., Bosnar-Puretić, M., Demarin, V., 2009. Post-stroke depression. Acta Clin. Croat. 48 (3), 329–333. 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), 347–352. 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), 185–189.