The association of brain-derived neurotrophic factor Val66Met polymorphism with stroke outcomes: a cross-sectional pilot study

Abstract

Aim: This study investigated the effect of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on post-stroke outcomes, including quality of life, physical fitness, cognitive function, depression, and overall disability.

Methods: The difference between Met carriers and non-Met carriers was analyzed for the entire sample and in pair-matched analysis, using age, sex, time since stroke, and race.

Results: We evaluated 89 stroke participants (mean age, 57 ± 10 years; 58% male; 54% White, and 49% Hispanic). Twelve participants (13%) had one copy of the BDNF Val66Met (Val/Met heterozygotes) and none had two copies (Met/Met homozygotes). Comparing Met (n = 12) and non-Met carriers (n = 77), no significant differences were observed in demographics or clinical characteristics, including motor or cognitive outcomes. In pair-matched analysis, a significant difference was observed for the Center for Epidemiological Studies Depression (CES-D) scale, where Met carriers had significantly greater CES-D scores than non-Met carriers (24 ± 16 vs. 9 ± 9, p = 0.011). Regardless of the chosen CES-D cut-off scores (≥ 16 vs. ≥ 20), more cases of depressive symptomatology were observed among those with the BDNF Val66Met polymorphism than those without it (p values < 0.05).

Conclusions: The BDNF Val66Met polymorphism may be associated with post-stroke depression but not motor or cognitive recovery.

Keywords

stroke / recovery / genetic / polymorphism / BDNF

References

[1] Virani SS,Alonso A,Benjamin EJ,Bittencourt MS,Callaway CW,Carson AP,et al.American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee.Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association.Circulation.2020;141:e139-596.

[2] Chen X,Duan L,Han Y,Tian L,Dai Q,Wang S,et al.Predictors for vascular cognitive impairment in stroke patients.BMC Neurol.2016;16:115.

[3] Alawieh A,Zhao J,Feng W.Factors affecting post-stroke motor recovery: Implications on neurotherapy after brain injury.Behav Brain Res.2018;340:94-101.

[4] Helm EE,Tyrell CM,Pohlig RT,Brady LD,Reisman DS.The presence of a single-nucleotide polymorphism in the BDNF gene affects the rate of locomotor adaptation after stroke.Exp Brain Res.2016;234:341-51.

[5] Shiner CT,Pierce KD,Thompson-Butel AG,Trinh T,Schofield PR,McNulty PA.BDNF Genotype Interacts with Motor Function to Influence Rehabilitation Responsiveness Poststroke.Front Neurol.2016;7:69.

[6] Stanne TM,Tjärnlund-Wolf A,Olsson S,Jood K,Blomstrand C,Jern C.Genetic variation at the BDNF locus: evidence for association with long-term outcome after ischemic stroke.PLoS One.2014;9:e114156.

[7] Greisen MH,Altar CA,Bolwig TG,Whitehead R,Wörtwein G.Increased adult hippocampal brain-derived neurotrophic factor and normal levels of neurogenesis in maternal separation rats.J Neurosci Res.2005;79:772-8.

[8] Egan MF,Kojima M,Callicott JH,Goldberg TE,Kolachana BS,Bertolino A,et al.The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.Cell.2003;112:257-69.

[9] Bath KG,Lee FS.Variant BDNF (Val66Met) impact on brain structure and function.Cogn Affect Behav Neurosci.2006;6:79-85.

[10] Erickson KI,Prakash RS,Voss MW,Chaddock L,Heo S,McLaren M,et al.Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume.J Neurosci.2010;30:5368-75.

[11] Cai X,Shi X,Zhang X,Zhang A,Zheng M,Fang Y.The association between brain-derived neurotrophic factor gene polymorphism and migraine: a meta-analysis.J Headache Pain.2017;18:13.

[12] Fernandes BS,Berk M,Turck CW,Steiner J,Gonçalves CA.Decreased peripheral brain-derived neurotrophic factor levels are a biomarker of disease activity in major psychiatric disorders: a comparative meta-analysis.Mol Psychiatry.2014;19:750-1.

[13] Harrisberger F,Smieskova R,Schmidt A,Lenz C,Walter A,Wittfeld K,et al.BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: A systematic review and meta-analysis.Neurosci Biobehav Rev.2015;55:107-18.

[14] Zuccato C,Cattaneo E.Brain-derived neurotrophic factor in neurodegenerative diseases.Nat Rev Neurol.2009;5:311-22.

[15] Vidović V,Maksimović N,Novaković I,Damnjanović T,Jekić B,Vidović S,et al.Association of the Brain-derived Neurotrophic Factor Val66Met Polymorphism with Body Mass Index, Fasting Glucose Levels and Lipid Status in Adolescents.Balkan J Med Genet.2020;23:77-82.

[16] Tsai S.Critical Issues in BDNF Val66Met Genetic Studies of Neuropsychiatric Disorders.Front Mol Neurosci.2018;11:156.

[17] Braun RG,Kittner SJ,Ryan KA,Cole JW.Effects of the BDNF Val66Met polymorphism on functional status and disability in young stroke patients.PLoS One.2020;15:e0237033.

[18] French MA,Morton SM,Pohlig RT,Reisman DS.The relationship between BDNF Val66Met polymorphism and functional mobility in chronic stroke survivors.Top Stroke Rehabil.2018;25:276-80.

[19] Lee NT,Ahmedy F,Mohamad Hashim N,Yin KN,Chin KL.Brain-Derived Neurotrophic Factor Polymorphism and Aphasia after Stroke.Behav Neurol.2021;2021:8887012.

[20] Kim JM,Stewart R,Kang HJ,Kim SY,Kim SW,Shin IS,et al.A longitudinal study of BDNF promoter methylation and genotype with poststroke depression.J Affect Disord.2013;149:93-9.

[21] Shen T,You Y,Joseph C,Mirzaei M,Klistorner A,Graham SL,et al.BDNF Polymorphism: A Review of Its Diagnostic and Clinical Relevance in Neurodegenerative Disorders.Aging Dis.2018;9:523-36.

[22] Koch S,Tiozzo E,Simonetto M,Loewenstein D,Wright CB,Dong C,et al.Randomized Trial of Combined Aerobic, Resistance, and Cognitive Training to Improve Recovery From Stroke: Feasibility and Safety.J Am Heart Assoc.2020;9:e015377.

[23] Shinar D,Gross CR,Price TR,Banko M,Bolduc PL,Robinson RG.Screening for depression in stroke patients: the reliability and validity of the Center for Epidemiologic Studies Depression Scale.Stroke.1986;17:241-5.

[24] Vilagut G,Forero CG,Barbaglia G,Alonso J.Screening for Depression in the General Population with the Center for Epidemiologic Studies Depression (CES-D): A Systematic Review with Meta-Analysis.PLoS One.2016;11:e0155431.

[25] Towfighi A,Ovbiagele B,El Husseini N,Hackett ML,Jorge RE,Kissela BM,et al.American Heart Association Stroke Council;Council on Cardiovascular and Stroke Nursing;Council on Quality of Care and Outcomes Research.Poststroke Depression: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association.Stroke.2017;48:e30-43.

[26] Kutlubaev MA,Hackett ML.Part II: predictors of depression after stroke and impact of depression on stroke outcome: an updated systematic review of observational studies.Int J Stroke.2014;9:1026-36.

[27] Bartoli F,Lillia N,Lax A,Crocamo C,Mantero V,Carrà G,et al.Depression after stroke and risk of mortality: a systematic review and meta-analysis.Stroke Res Treat.2013;2013:862978.

[28] Hackett ML,Yapa C,Parag V,Anderson CS.Frequency of depression after stroke: a systematic review of observational studies.Stroke.2005;36:1330-40.

[29] Agrell B,Dehlin O.Comparison of six depression rating scales in geriatric stroke patients.Stroke.1989;20:1190-4.

[30] Liang J,Yue Y,Jiang H,Geng D,Wang J,Lu J,et al.Genetic variations in the p11/tPA/BDNF pathway are associated with post stroke depression.J Affect Disord.2018;226:313-25.

[31] Verhagen M,van der Meij A,van Deurzen PA,Janzing JG,Arias-Vásquez A,Buitelaar JK,et al.Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity.Mol Psychiatry.2010;15:260-71.

[32] Zhou JX,Li HC,Bai XJ,Chang BC,Li CJ,Sun P,et al.Functional Val66Met polymorphism of Brain-derived neurotrophic factor in type 2 diabetes with depression in Han Chinese subjects.Behav Brain Funct.2013;9:34.

[33] Czira ME,Wersching H,Baune BT,Berger K.Brain-derived neurotrophic factor gene polymorphisms, neurotransmitter levels, and depressive symptoms in an elderly population.Age (Dordr).2012;34:1529-41.

[34] Surtees PG,Wainwright NW,Willis-Owen SA,Sandhu MS,Luben R,Day NE,et al.No association between the BDNF Val66Met polymorphism and mood status in a non-clinical community sample of 7389 older adults.J Psychiatr Res.2007;41:404-9.

[35] Gyekis JP,Yu W,Dong S,Wang H,Qian J,Kota P,et al.No association of genetic variants in BDNF with major depression: a meta- and gene-based analysis.Am J Med Genet B Neuropsychiatr Genet.2013;162B:61-70.

[36] Gujral S,Manuck SB,Ferrell RE,Flory JD,Erickson KI.The BDNF Val66Met polymorphism does not moderate the effect of self-reported physical activity on depressive symptoms in midlife.Psychiatry Res.2014;218:93-7.

[37] Domschke K,Lawford B,Laje G,Berger K,Young R,Morris P,et al.Brain-derived neurotrophic factor ( BDNF) gene: no major impact on antidepressant treatment response.Int J Neuropsychopharmacol.2010;13:93-101.

[38] Mojtabavi H,Shaka Z,Momtazmanesh S,Ajdari A,Rezaei N.Circulating brain-derived neurotrophic factor as a potential biomarker in stroke: a systematic review and meta-analysis.J Transl Med.2022;20:126.

[39] Groves JO.Is it time to reassess the BDNF hypothesis of depression?Mol Psychiatry.2007;12:1079-88.

[40] Yu H,Chen ZY.The role of BDNF in depression on the basis of its location in the neural circuitry.Acta Pharmacol Sin.2011;32:3-11.

[41] Tramontina J,Frey BN,Andreazza AC,Zandona M,Santin A,Kapczinski F.Val66met polymorphism and serum brain-derived neurotrophic factor levels in bipolar disorder.Mol Psychiatry.2007;12:230-1.

[42] Lang UE,Hellweg R,Sander T,Gallinat J.The Met allele of the BDNF Val66Met polymorphism is associated with increased BDNF serum concentrations.Mol Psychiatry.2009;14:120-2.

[43] Shimizu E,Hashimoto K,Okamura N,Koike K,Komatsu N,Kumakiri C,et al.Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.Biol Psychiatry.2003;54:70-5.

[44] Fan J,Chen D,Wang N,Su R,Li H,Ma H,et al.Negative relationship between brain-derived neurotrophic factor (BDNF) and attention: A possible elevation in BDNF level among high-altitude migrants.Front Neurol.2023;14:1144959.

[45] Aljuhni R,Cleland BT,Roth S,Madhavan S.Genetic polymorphisms for BDNF, COMT, and APOE do not affect gait or ankle motor control in chronic stroke: A preliminary cross-sectional study.Top Stroke Rehabil.2021;28:72-80.

[46] Di Pino G,Pellegrino G,Capone F,Assenza G,Florio L,Falato E,et al.Val66Met BDNF Polymorphism Implies a Different Way to Recover From Stroke Rather Than a Worse Overall Recoverability.Neurorehabil Neural Repair.2016;30:3-8.

[47] Liu X,Fang JC,Zhi XY,Yan QY,Zhu H,Xie J.The Influence of Val66Met Polymorphism in Brain-Derived Neurotrophic Factor on Stroke Recovery Outcome: A Systematic Review and Meta-analysis.Neurorehabil Neural Repair.2021;35:550-60.

[48] Han Z,Qi L,Xu Q,Xu M,Cai L,Wong J,et al.BDNF Met allele Is Associated With Lower Cognitive Function in Poststroke Rehabilitation.Neurorehabil Neural Repair.2020;34:247-59.

[49] Parsian A,Sinha R,Racette B,Zhao JH,Perlmutter JS.Association of a variation in the promoter region of the brain-derived neurotrophic factor gene with familial Parkinson's disease.Parkinsonism Relat Disord.2004;10:213-9.

[50] Fukumoto N,Fujii T,Combarros O,Kamboh MI,Tsai SJ,Matsushita S,et al.Sexually dimorphic effect of the Val66Met polymorphism of BDNF on susceptibility to Alzheimer's disease: New data and meta-analysis.Am J Med Genet B Neuropsychiatr Genet.2010;153B:235-42.

[51] Pivac N,Kim B,Nedić G,Joo YH,Kozarić-Kovacić D,Hong JP,et al.Ethnic differences in brain-derived neurotrophic factor Val66Met polymorphism in Croatian and Korean healthy participants.Croat Med J.2009;50:43-8.

[52] Rodier M,Quirié A,Prigent-Tessier A,Béjot Y,Jacquin A,Mossiat C,et al.Relevance of Post-Stroke Circulating BDNF Levels as a Prognostic Biomarker of Stroke Outcome. Impact of rt-PA Treatment.PLoS One.2015;10:e0140668.

[53] Arboix A.Lacunar infarct and cognitive decline.Expert Rev Neurother.2011;11:1251-4.