2024; 22(2): 306-313  https://doi.org/10.9758/cpn.23.1115
Brain Derived Neurotrophic Factor Methylation and Long-term Outcomes after Stroke Interacting with Suicidal Ideation
Hee-Ju Kang1, Ju-Wan Kim1, Joon-Tae Kim2, Man-Seok Park2, Byung Jo Chun3, Sung-Wan Kim1, Il-Seon Shin1, Robert Stewart4,5, Jae-Min Kim1
1Department of Psychiatry, Chonnam National University Medical School, Gwangju, Korea
2Department of Neurology, Chonnam National University Medical School, Gwangju, Korea
3Department of Emergency Medicine, Chonnam National University Medical School, Gwangju, Korea
4King’s College London (Institute of Psychiatry, Psychology and Neuroscience), London, UK
5South London and Maudsley NHS Foundation Trust, London, UK
Correspondence to: Jae-Min Kim
Department of Psychiatry, Chonnam National University Medical School, 160 Baekseo-ro, Dong-gu, Gwangju 61469, Korea
E-mail: jmkim@chonnam.ac.kr
ORCID: https://orcid.org/0000-0001-7409-6306
Received: July 13, 2023; Revised: August 7, 2023; Accepted: August 9, 2023; Published online: September 1, 2023.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective: This study aimed to evaluate the unexplored relationship between BDNF methylation, long-term outcomes, and its interaction with suicidal ideation (SI), which is closely associated with both BDNF expression and stroke outcomes.
Methods: A total of 278 stroke patients were assessed for BDNF methylation status and SI using suicide-related item in the Montgomery–Åsberg Depression Rating Scale at 2 weeks post-stroke. We investigated the incidence of composite cerebro-cardiovascular events (CCVEs) during an 8−14-year period after the initial stroke as long-term stroke outcome. We conducted Cox regression models adjusted for covariates to evaluate the association between BDNF methylation status and CCVEs, as well as its interaction with post-stroke SI at 2 weeks.
Results: Higher methylation status of CpG 1, 3, and 5, but not the average value, predicted a greater number of composite CCVEs during 8−14 years following the stroke. The associations between a higher methylation status of CpGs 1, 3, 5, and 8, as well as the average BDNF methylation value, and a greater number of composite CCVEs, were prominent in patients who had post-stroke SI at 2 weeks. Notably, a significant interaction between methylation status and SI on composite CCVEs was observed only for CpG 8.
Conclusion: The significant association between BDNF methylation and poor long-term stroke outcomes, particularly amplified in individuals who had post-stroke SI at 2 weeks, suggested that evaluating the biological marker status of BDNF methylation along with assessing SI during the acute phase of stroke can help predict long-term outcomes.
Keywords: Stroke; Suicidal ideation; Methylation; Brain-derived neurotrophic factor; Outcome assessment

Stroke is the primary cause of disability imposing a significant burden [1]. There exists considerable inter-subject variability in post-stroke outcomes among encompassing complete recovery, incomplete recoveries with functional deficits, recurrent strokes myocardial infarction and vascular death [1,2]. Therefore, predicting post-stroke outcomes has emerged as crucial area of interest, aiming to provide tailored interventions and maximize recovery [3-5]. Several markers have been evaluated, including age, stroke severity, location and size of lesions and genetic vulnerabilities [2,6-9].

Brain derived neurotrophic factor (BDNF), abundantly present in the brain, plays a critical role in neuronal plasticity and repair [10]. It is involved in neuroprotection [11] and post-injury regeneration [12]. Moreover, physical exercise during rehabilitation has been shown to increase BDNF levels, contributing to improved post-stroke recovery [13]. BDNF modulation has also been suggested to mediate therapeutic effect of treatment by enhancing perilesional cortex excitability [14]. Accordingly, genetic polymorphism of BDNF at nucleotide 196 G/A has been investigated as a marker for predicting stroke outcomes. Meta-analyses have shown that ischemic stroke patients with GA or AA genotypes, which are linked to decreased BDNF secretion [15], are more likely to experience poor outcomes [9].

In addition to genetic factor, BDNF expression is regulated by epigenetic mechanisms, such as DNA methylation of cytosines in cytosine-guanine (CpG) dinucleotides of BDNF genes [16]. Hypermethylation at the BDNF gene has been associated with decreased BDNF levels in the neuron [17]. Based on these mechanism, it can be proposed as potential predictive marker for stroke outcomes. However, previous studies examining the association between BDNF methylation status and stroke outcomes have provided inconclusive results. One study with a small sample size of 48 stroke patients focused solely on stroke outcomes (around 90 days post-stroke) after 6-week rehabilitation and found no significant association between methylation status and stroke outcomes [18].

To address these gaps, our study aimed to investigate the independent effect of the BDNF gene methylation status on long-term stroke outcomes, specifically composite cerebro-cardiovascular events (CCVEs), during 8−14 years after the initial stroke. Numerous preceding publications have indicated that the suicide risk is higher in stroke survivors and stroke is strongly correlated with suicide mortality [19]. Suicidal behaviors including suicidal ideation (SI) can adversely impact long-term stroke outcomes through biological mechanisms involving dysregulated inflammatory process and neuroplasticity [20] as well as through behavioral mechanisms such as poor compliance with medical recommendations. However, the impact of suicidal behaviors on the long-term stroke outcomes has been investigated to a limited extent. A study conducted by our research team evaluated the association between long-term stroke outcomes and SI at 2 weeks after stroke, as a precursor to suicidal attempt and/or death. In that study, stroke patients experiencing SI at 2 weeks post-stroke were more likely to have a higher occurrence of CCVEs during 8−14 years after stroke, even after adjusting for depression diagnosis [21]. Similar associations were also identified in patients with acute coronary syndrome (ACS), where SI within 2 weeks of ACS was significantly linked to poor long-term cardiac outcomes during 5−12 year after ACS [22]. Given the well-established association between BDNF and suicidality [23,24], we also examined the interactive effects of BDNF gene methylation status with SI at 2 weeks post-stroke on outcomes over an 8−14-year period following the index stroke.


Study Overview and Participants

The current study utilized a subset of data from a prospective cohort of stroke patients to investigate psychiatric comorbidity using a naturalistic study design [25]. The recruitment process (Fig. 1) involved consecutively enrolling 465 patients with recent ischemic stroke between 2005 and 2011 at the Department of Neurology, Chonnam National University Hospital (CNUH), Gwangju, South Korea. From these patients, 423 stroke patients who met the eligibility criteria (full criteria described in the Supplementary Materials; available online) and willingly participated underwent baseline assessments, including the assessment of SI at 2 weeks after stroke. Blood samples for measuring BDNF methylation status were obtained from 286 (67.6%) baseline participants. The study followed up with all baseline participants in 2019 to estimate the long-term stroke outcomes, specifically CCVEs occurring 8−14 years after the initial stroke. Ultimately, the present analyses included 278 patients (97.2%) who completed both the blood test and follow-up evaluation. The data from the same participants was previously published [22]. The study received approval from the CNUH Institutional Review Board (CNUH-2018-006) and written informed consent was obtained from all participants.

Assessment of SI and Clinical Covariates at 2 Weeks of Stroke

The evaluation of SI status was performed based on the suicide-related item of the Montgomery–Åsberg Depression Rating Scale (MADRS) [26]. Two research nurses, who received training and supervision from the project psychiatrist and were blind to the results of the diagnostic interview, administered the MADRS. The participants were asked about their feelings regarding the worthiness of life and the presence of suicide plans, and their responses were rated on a scale of 1 (satisfied with life) to 6 (explicit suicidal plans). The presence of SI was determined by a score of 2 (fleeting suicidal thoughts) or higher on this item, in accordance with a previous study on SI following stroke [27].

The study assessed several covariates that have the potentials to be associated with both SI and long-term stroke outcomes [2,28,29] including sociodemographic and clinical characteristics data including stroke-related characteristics and depression (detailed variables in the Supplementary Materials; available online).

Measurement of BDNF Gene Methylation Status

The extraction of genomic DNA (1 mg) was performed from 200 ml of whole blood, using the QIAamp DNA Blood Mini Kit (Qiagen) at the laboratory of Chonnam National University Hwasun Hospital. The technicians conducting the measurement process were blinded to the clinical data to minimize potential bias. Methylation status was measured using the PSQ 96M Pyrosequencing System (Biotage AB), and Pyro Q-CpG software (ver. 1.0.9; Biotage AB), in accordance with methods described in previous study [30].

The BDNF gene’s methylation status was measured in a CpG-rich region located between −612 and −463 from the transcriptional start site in exon VII, which included nine CpG sites (Supplementary Fig. 1; available online). The measured site has been submitted in GenBank with the accession number BankIt1568919 BDNF JX848620. The choice of this CpG region was based on the evidence from previous studies showing that a corresponding region in rat BDNF gene is differentially methylated and associated with BDNF messenger RNA expression [31], as well as its association with depression and suicidal outcomes in different patients population [30,32,33]. To ensure accurate analysis, three CpG sites (2, 4, 6) were excluded from the present analyses due to observation that all participants showed 100% methylation at these sites. The analyses focused on the methylation percentage of the remaining six individual CpG sites and average value.

Long-term Stroke Outcomes

To comprehensively evaluate long-term stroke outcomes, we assessed recurrent stroke, myocardial infarction (MI), and vascular death (VD) during a period of 8−14 years after the initial stroke. The detailed criteria of recurrent stroke, MI, and VD were described in Supplementary Materials. To estimate long-term outcomes, we followed up with all participants who agreed to blood sampling and completed baseline assessments. Follow-up was conducted until 2019, or until death. We obtained information on the above outcomes by checking the electronic medical records and asking participants whether they had ever received management for stroke or myocardial infarction in a hospital. For deceased patients, we contacted caregivers or physicians to gather outcome information through structured questionnaires and we also collected death certifi-cates. Due to limited occurrence of individual outcome events, the primary endpoint was a combined measure called composite CCVEs, which included recurrent stroke, myocardial infarction, and vascular death (Supplementary Table 1; available online). An impartial committee of neurologists, who were unaware of the participants’ psychiatric status, evaluated all CCVEs.

Statistical Analyses

In line with a methodology used in a previous study [34], methylation status of BDNF gene was categorized into two groups, low and high based on the median value (Supplementary Table 2; available online). Additionally, baseline demographic and clinical characteristics were selected as covariates for adjustment analyses, which were compared according to methylation and SI status using appropriate statistical test such as t tests, χ2 tests, or Fisher’s exact test. Covariates showing a significant association with methylation and SI status (p < 0.05), and other potential factors influencing long-term stroke outcomes were included in subsequent analyses [2,33].

To evaluate the independent associations between BDNF methylation status and long-term stroke outcomes, Cox proportional hazards models were employed. The effect of the methylation status at individual CpG sites and the average BDNF methylation value on the occurrence of composite CCVEs was compared. The models were adjusted for the selected covariates. Moreover, the interactive effect of BDNF methylation status and SI on composite CCVEs was examined using stratified Cox proportional hazards models based on SI status. SPSS statistic (v. 21.0; SPSS Inc.) was used and a two-sided p value less than 0.05 was considered statistically significant.


BDNF Methylation Status and Baseline Characteristics

There was no significant differences identified among the participants who agreed to undergo blood sampling and those who declined, regarding factors affecting attrition (all p values > 0.1). Out of the 278 patients who completed baseline and follow-up assessment, 45 (16.2%) experienced post-stroke SI at 2 weeks. Supplementary Tables 3 and 4 (available online) provide information on the association of BDNF methylation status with stroke hemisphere while SI at 2 weeks was associated with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) depression diagnosis, and higher National Institutes of Health Stroke Scale (NIHSS) scores immediately after the stroke. Therefore, NIHSS score, diagnosis of depression, stroke hemisphere, age, presence of cardiac disease and previous stroke history were selected as covariates.

The Supplementary Table 2 (available online) presents the median (interquartile range, IQR) and mean (standard deviation, SD) values of BDNF methylation percentage for six individual CpG sites, as well as the average value. Strong correlations were observed between the methylation values of the individual CpG sites and the average value (Spearman’s rho correlation coefficients > 0.175, p ≤ 0.003). Therefore, the average value was chosen as the primary outcome.

Average BDNF Methylation Status and SI Status with Long-term Stroke Outcomes

Follow-up assessments were conducted for all participants, approximately 8−14 years after initial stroke, until 2019 or until their death. The median follow-up period was 12.0 years (IQR: 9.8−13.1 years) with a mean of 10.3 years (SD, 4.1 years) after stroke. Among the participants, 76 (27.3%) stroke patients experienced composite CCVEs during the 8−14 years of follow-up, as shown in Supplementary Table 1 (available online). The independent association between average BDNF methylation status and composite CCVEs was analyzed using Cox proportional hazards models adjusting for covariates. The interactive associations between average BDNF methylation status and SI status on composite CCVEs were calculated using the same Cox proportional hazards models with adjustment, stratified by SI status (Fig. 2). Although, average BDNF methylation status was not independently associated with composite CCVEs, a statistically significant association was found between higher BDNF methylation status and more CCVEs during the 8−14 years of follow-up, particularly in patients who experienced SI at 2 weeks post-stroke. However, the interactive effect between average BDNF methylation status and SI was not significant (p = 0.121).

Individual Methylation Status of CpG Site in BDNF Gene and SI Status with Long-term Stroke Outcomes

Similarly, the independent and interactive associations of individual methylation status of CpG sites in the BDNF gene and SI status with long-term stroke outcomes were examined. Cox proportional hazards models were employed for the analysis, adjusting for relevant factors and stratifying by SI status (Supplementary Fig. 2; available online). Regarding the independent associations, higher methylation status of CpG 1 and CpG 5 at the initial stroke were found to be associated with a higher incidence of composite CCVEs (p = 0.044 and p = 0.043, respectively). In terms of the interactive associations, higher methylation status at CpG 1, CpG 3, CpG 5, and CpG 8 were significantly associated with higher incidence of composite CCVEs, but only in patients who experienced SI at 2 weeks after stroke (p = 0.025 for CpG 1, p = 0.014 for CpG 3, p = 0.027 for CpG 5 and p = 0.007 for CpG 8, respectively). Notably, CpG 8 was the only site that exhibited a statistically significant interactive effect between methylation and SI on long-term stroke outcomes (p = 0.010).


Mainly, higher methylation status of CpG 1 and 5, rather than the average BDNF methylation value, were found to be predictive of poor long-term stroke outcomes, specifically composite CCVEs during 8−14 years following the stroke. These associations remained significant even after adjusting covariates. Furthermore, the associations of between higher methylation status at specific CpG sites (CpGs 1, 3, 5, and 8) and the average BDNF methylation value with composite CCVEs were more prominent in patients who had post-stroke SI at 2 weeks. Interestingly, we observed a significant interaction effect between methylation status and SI on long-term stroke outcomes specifically in CpG site 8.

Higher methylation status of specific CpG sites in the BDNF gene, rather than average methylation value at the initial stroke, was associated with worse long-term stroke outcomes. Specifically, CpG sites 1 and 5 showed an association with composite CCVEs. The link between elevated methylation status of specific CpG sites in the BDNF gene and poor long-term stroke outcomes can be attributed to the known effects of methylation, which result in the reduced transcription and gene expression [17,24]. Decreased levels of expressed BDNF, in turn, impede neurogenesis and neuronal repair after stroke and indirectly leads to platelet aggregation and promote inflammation through interactions with the serotonin system and inflammatory processes [35-37]. These mechanisms hinder stroke recovery and increase the risk of CCVEs. However, further investigation is required to fully comprehend the underlying mechanisms linking the methylation status of specific sites, BDNF levels, and stroke outcomes.

In this study, we revealed that higher methylation status of CpGs 1, 3, 5, and 8, as well as the average BDNF methylation value, were associated with an increased risk of worse stroke outcomes (composite CCVEs) during 8−14 years following the stroke, particularly in patients who had SI immediately after stroke. Although we did not find a significant interactive effect, except CpG 8, it is noteworthy that it is the firstly reported findings of a significant association between BDNF methylation and SI on long-term stroke outcomes. Our previous study found that SI at 2 weeks following stroke was associated with worse long-term outcomes during 8−14 years after stroke, even after adjusting for depression [22]. Suicidality, including SI, can potentially impair cerebro-cardiovascular function through various biological mechanisms. These mechanisms may involve neuroendocrine dysregulation, heightened inflammatory and autonomic responses, and impaired neuroplasticity [21]. Additionally, behavioral factors also play a role, as individuals experiencing suicidality may face challenges in handling the stressful events associated with the stroke and following doctors’ advice to promote physical conditions such as regular exercise and adherence to medical treatment. These combined factors underlying SI may be exacerbated in stroke patient with higher methylation status of BDNF genes, particularly at CpG site 8. Based on our finding, SI in stroke patients with higher BDNF methylation status has effects on long-term cerebro-cardiovascular outcomes. Therefore, it is recommended to conduct thorough evaluation and implement appropriate treatment strategies for stroke patients who exhibit higher BDNF methylation and experience SI, especially within the first 2 weeks following stroke.

The present study possesses several strengths. One of the strength lies in the consecutive recruitment of all eligible patients who recently experienced a stroke, which enhanced the homogeneity or the sample. Additionally, the study gathered comprehensive data on psychiatric and stroke-related variables using validated scales. However, there are several limitations to consider when interpreting our findings. Firstly, the study only measured BDNF methylation in peripheral blood, and it did not investigate the functional significance of BDNF hypermethylation, such as the expression level of BDNF mRNA and BDNF protein. Although, methylation status is known to be tissue specific, there is a potential relationship between BDNF methylation in the brain and peripheral blood due to BDNF’s ability to cross the blood-brain barrier [38]. Future research is necessary to understand the relationship between methylation status in peripheral blood and brain tissue, as well as the functional relevance of BDNF methylation. Secondly, caution should be exercised when interpreting the significant findings regarding the association between BDNF methylation status and long-term outcomes such as individual recurrent stroke, MI, VD. The analyses for individual stroke outcomes were not computed due to modest sample size, and the limited numbers of individual CCVEs during the 8−14-year after stroke, which hindered the identification of statistical dif-ferences. Thirdly, although the present study investigated SI as suicide-related variable, it did not assess suicide attempts or suicidal death. While there is a close relationship between SI and suicidal behavior [39], generalizing our findings to overall suicidal behavior in stroke patients can be challenging. Lastly, instead of using an exclusive instrument for assessing suicidality, we utilized the suicide-related item of MADRS to determine SI status. How-ever, the validity of suicide-related item of MADRS has been demonstrated in previous suicide study [40] and randomized controlled trial [41].

In summary, our finding indicate that stroke patients with a high methylation status of BDNF gene, particularly in those experiencing post-stroke SI at 2 weeks are more likely to have worse stroke outcomes in terms of composite CCVEs, during an 8−14 years follow-up period after stroke. These results suggest that epigenetic susceptibility of BDNF could be a valuable predictor of long-term stroke prognosis. Furthermore, the potential impact of BDNF methylation on long-term stroke prognosis is accentuated when stroke patients experienced a psychologically unstable condition such as SI at 2 weeks following stroke. This highlight the importance for physicians treating stroke patients to assess not only the biological marker for stroke outcomes but also the psychological status, including SI, in an integrated manner. It is crucial to replicate our findings in a larger stroke population and further investigation whether factors that influence decreased DNA methylation levels [42] including BDNF gene, and improvement of SI can enhance the long-term stroke prognosis. Nevertheless, evaluating the methylation status of BDNF gene and assessing SI can aid in identifying stroke patients at high risk of poor long-term outcomes. This identification enables frequent monitoring and intensive treatment to improve outcomes in high-risk stroke patients.


The results of this study were partly presented at 34th CINP World Congress of Neuropsychopharmacology, 7−10 May 2023, Montreal, Canada.


This study was supported by a grant of National Research Foundation of Korea Grant (NRF-020M3E5D9080733) to J-M Kim and by a grant (BCRI-22072) of Chonnam National University Hospital Biomedical Research Institute to Hee-Ju Kang.

Conflicts of Interest

Jae-Min Kim declares research support in the last 5 years from Janssen and Lundbeck. Sung-Wan Kim declares research support in the last 5 years from Janssen, Boehringer Ingelheim, Allergan and Otsuka. All other authors report no biomedical financial interests or potential conflicts of interest.

Author Contributions

Concenptualization: Hee-Ju Kang, Jae-Min Kim. Design and methodology: Hee-Ju Kang, Jae-Min Kim. Conduction of study: Hee-Ju Kang, Joon-Tae Kim, Man-Seok Park, Jae-Min Kim. Statistical analysis and interpretation: Hee-Ju Kang, Jae-Min Kim. Writing−original draft preparation: Hee-Ju Kang, Jae-Min Kim. Writing−review and editing: Hee-Ju Kang, Ju-Wan Kim, Joon-Tae Kim, Man-Seok Park, Byung Jo Chun, Sung-Wan Kim, Il-Seon Shin, Robert Stewart, Jae-Min Kim. Resources: Jae-Min Kim. Supervision: Robert Stewart, Jae-Min Kim.

Fig. 1. Study outline and participant recruitment process.
Fig. 2. Association of the average BDNF methylation value with the cumulative incidence (%) of composite cerebro-cardiovascular events, stratified by SI status immediately after stroke (within 2 weeks). Cox proportional hazards models were used for analyses of the overall cohort, and for analyses stratified by SI after adjustment for age, NIHSS score, stroke hemisphere, previous history of stroke, presence of cardiac disease, and depression (according to the DSM-IV criteria) within 2 weeks after stroke. The interaction effect between average BDNF methylation value and SI on composite CCVEs was not significant (p = 0.121).
SI, suicidal ideation; NIHSS, National Institutes of Health Stroke Scale; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition; BDNF, brain derived neurotrophic factor; CCVEs, cerebro-cardiovascular events.
*Represents statistical significance (p value < 0.05).
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