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.

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Abstract
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

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