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Brain-derived neurotrophic factor Val66Met variant on brain volumes in infants

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Abstract

The brain-derived neurotrophic factor (BDNF) has many important roles in neurogenesis and neuronal health. BDNF is also involved in learning and memory. Individuals with BDNF-Val66Met variant (Met +) are at higher risk for neuropsychiatric disorders and have smaller hippocampi and amgydalae compared to those without this variant (Met −). Whether these smaller brain volumes are already present at birth is unknown and were evaluated. 66 newborn infants were genotyped for BDNF-rs6265 and had brain MRI scans. The T1-weighted images were automatically parcellated for hippocampus and amygdala, as well as the intracranial volume (ICV), total brain volume, total gray and white matter, using a multi-atlas label fusion method implemented in the MRICloud (https://braingps.anatomyworks.org). The segmented brain volumes were normalized to the ICV for group comparisons. The two infant groups were not different in their demographics and birth characteristics. However, compared to Met − infants, the Met + infants had smaller hippocampi (p = 0.013), smaller amygdalae (p = 0.041), and less steep age-related declines in total brain volume and % white matter volume. The smaller relative hippocampal and amygdala volumes in Met + infants suggest that the Met + genotype affected prenatal developmental processes. In addition, the slower age-dependent declines in the relative total brain and white matter volumes of the Met + group in this cross-sectional dataset suggest the BDNF-Val66Met variant might have an ongoing negative influence on the postnatal developmental processes.

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Fig. 1
Fig. 2

Data availability

Data are available upon request to corresponding author.

References

  • Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta JK (2006) BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 59:812–815

    Article  CAS  Google Scholar 

  • Chang L, Oishi K, Skranes J, Buchthal S, Cunningham E, Yamakawa R, Hayama S, Jiang CS, Alicata D, Hernandez A, Cloak C, Wright T, Ernst T (2016) Sex-specific alterations of white matter developmental trajectories in infants with prenatal exposure to methamphetamine and tobacco. JAMA Psychiatry 73:1217–1227

    Article  Google Scholar 

  • Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, Herrera DG, Toth M, Yang C, McEwen BS, Hempstead BL, Lee FS (2006) Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314:140–143

    Article  CAS  Google Scholar 

  • Chen L, Lawlor DA, Lewis SJ, Yuan W, Abdollahi MR, Timpson NJ, Day IN, Ebrahim S, Smith GD, Shugart YY (2008) Genetic association study of BDNF in depression: finding from two cohort studies and a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 147b:814–821

    Article  CAS  Google Scholar 

  • Chen L et al (2015) Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism influences the association of the methylome with maternal anxiety and neonatal brain volumes. Dev Psychopathol 27:137–150

    Article  CAS  Google Scholar 

  • Cunha C, Brambilla R, Thomas KL (2010) A simple role for BDNF in learning and memory? Front Mol Neurosci 3:1

    PubMed  PubMed Central  Google Scholar 

  • Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269

    Article  CAS  Google Scholar 

  • Giedd JN, Rapoport JL (2010) Structural MRI of pediatric brain development: what have we learned and where are we going? Neuron 67:728–734

    Article  CAS  Google Scholar 

  • Hajek T, Kopecek M, Höschl C (2012) Reduced hippocampal volumes in healthy carriers of brain-derived neurotrophic factor Val66Met polymorphism: meta-analysis. World J Biol Psychiatry 13:178–187

    Article  Google Scholar 

  • Harrisberger F, Spalek K, Smieskova R, Schmidt A, Coynel D, Milnik A, Fastenrath M, Freytag V, Gschwind L, Walter A, Vogel T, Bendfeldt K, de Quervain DJ, Papassotiropoulos A, Borgwardt S (2014) The association of the BDNF Val66Met polymorphism and the hippocampal volumes in healthy humans: a joint meta-analysis of published and new data. Neurosci Biobehav Rev 42:267–278

    Article  CAS  Google Scholar 

  • Harrisberger F, Smieskova R, Schmidt A, Lenz C, Walter A, Wittfeld K, Grabe HJ, Lang UE, Fusar-Poli P, Borgwardt S (2015) BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: a systematic review and meta-analysis. Neurosci Biobehav Rev 55:107–118

    Article  CAS  Google Scholar 

  • Hashimoto T, Fukui K, Takeuchi H, Yokota S, Kikuchi Y, Tomita H, Taki Y, Kawashima R (2016) Effects of the BDNF Val66Met polymorphism on gray matter volume in typically developing children and adolescents. Cereb Cortex 26:1795–1803

    Article  Google Scholar 

  • Kambeitz JP, Bhattacharyya S, Kambeitz-Ilankovic LM, Valli I, Collier DA, McGuire P (2012) Effect of BDNF val(66)met polymorphism on declarative memory and its neural substrate: a meta-analysis. Neurosci Biobehav Rev 36:2165–2177

    Article  CAS  Google Scholar 

  • Knickmeyer RC, Wang J, Zhu H, Geng X, Woolson S, Hamer RM, Konneker T, Lin W, Styner M, Gilmore JH (2014) Common variants in psychiatric risk genes predict brain structure at birth. Cereb Cortex 24:1230–1246

    Article  Google Scholar 

  • Lima Giacobbo B, Doorduin J, Klein HC, Dierckx R, Bromberg E, de Vries EFJ (2019) Brain-derived neurotrophic factor in brain disorders: focus on neuroinflammation. Mol Neurobiol 56:3295–3312

    Article  CAS  Google Scholar 

  • Molendijk ML, Bus BA, Spinhoven P, Kaimatzoglou A, Oude Voshaar RC, Penninx BW, Van IMH, Elzinga BM (2012) A systematic review and meta-analysis on the association between BDNF val(66)met and hippocampal volume–a genuine effect or a winners curse? Am J Med Genet B Neuropsychiatr Genet 159b:731–740

    Article  Google Scholar 

  • Montag C, Weber B, Fliessbach K, Elger C, Reuter M (2009) The BDNF Val66Met polymorphism impacts parahippocampal and amygdala volume in healthy humans: incremental support for a genetic risk factor for depression. Psychol Med 39:1831–1839

    Article  CAS  Google Scholar 

  • Otsuka Y, Chang L, Kawasaki Y, Wu D, Ceritoglu C, Oishi K, Ernst T, Miller M, Mori S, Oishi K (2019) A multi-atlas label fusion tool for neonatal brain MRI parcellation and quantification. J Neuroimaging 29:431–439

    PubMed  PubMed Central  Google Scholar 

  • Park H, Poo MM (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14:7–23

    Article  CAS  Google Scholar 

  • Petryshen TL, Sabeti PC, Aldinger KA, Fry B, Fan JB, Schaffner SF, Waggoner SG, Tahl AR, Sklar P (2010) Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry 15:810–815

    Article  CAS  Google Scholar 

  • Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, Egan MF, Meyer-Lindenberg A, Weinberger DR (2004) The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 24:10099–10102

    Article  CAS  Google Scholar 

  • Pivac N, Kim B, Nedic G, Joo YH, Kozaric-Kovacic D, Hong JP, Muck-Seler D (2009) Ethnic differences in brain-derived neurotrophic factor Val66Met polymorphism in Croatian and Korean healthy participants. Croat Med J 50:43–48

    Article  CAS  Google Scholar 

  • Shimizu E, Hashimoto K, Iyo M (2004) Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: the possibility to explain ethnic mental traits. Am J Med Genet B Neuropsychiatr Genet 126B:122–123

    Article  Google Scholar 

  • Tang X, Oishi K, Faria AV, Hillis AE, Albert MS, Mori S, Miller MI (2013) Bayesian parameter estimation and segmentation in the multi-atlas random orbit model. PLoS ONE 8:e65591

    Article  CAS  Google Scholar 

  • Wierenga L, Langen M, Ambrosino S, van Dijk S, Oranje B, Durston S (2014) Typical development of basal ganglia, hippocampus, amygdala and cerebellum from age 7 to 24. Neuroimage 96:67–72

    Article  Google Scholar 

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Acknowledgements

This publication was made possible by grants R01HD065955, 2K24DA16170, U54NS056883, and P41EB015909 from the National Institutes of Health. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official view of NIH. The authors are grateful to the families of our research participants, the referring pediatricians/neonatologists (Dr. Lillian Fujimoto, Dr. Lois Chiu, and Dr. Joseph Hudak), and our research staff (Steve Buchthal, Sara Hayama, Heather Johansen), who assisted with the data collection and data transfer. We also thank our board-certified Neuroradiologist, Dr. Doris Lin, for the radiological image reading.

Funding

This publication was made possible by National Institutes of Health (Grants R01HD065955, 2K24DA16170, U54NS056883, and P41EB015909).

Author information

Authors and Affiliations

  1. Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Yukako Kawasaki, Kenichi Oishi & Dan Wu

  2. Division of Neonatology, Maternal and Perinatal Center, Toyama University Hospital, Toyama, Japan

    Yukako Kawasaki

  3. Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA

    Antonette Hernandez, Thomas Ernst & Linda Chang

  4. Departments of Diagnostic Radiology and Nuclear Medicine, and Neurology, University of Maryland School of Medicine, Baltimore, MD, USA

    Thomas Ernst & Linda Chang

  5. Department of Neurology, Johns Hopkins University of School of Medicine, Baltimore, MD, USA

    Thomas Ernst & Linda Chang

  6. Key Laboratory for Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China

    Dan Wu

  7. Department of Neurology, Kobe University Graduate School of Medicine, Kobe, Japan

    Yoshihisa Otsuka

  8. Center for Imaging Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Can Ceritoglu

Authors
  1. Yukako Kawasaki
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  2. Kenichi Oishi
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  3. Antonette Hernandez
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  4. Thomas Ernst
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  5. Dan Wu
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  6. Yoshihisa Otsuka
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  7. Can Ceritoglu
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  8. Linda Chang
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Contributions

All authors on this manuscript have: (1) made a significant contribution to the conception and design or the analysis and interpretation of the data, (2) participated in the drafting of the article or reviewing and/or revising it for intellectual content; (3) approved the final version of the manuscript. All authors will also take full responsibility for the work.

Corresponding author

Correspondence to Linda Chang.

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Conflict of interest

Nothing to report.

Ethical approval

This study was approved by the Cooperative Institutional Review Board of the Queen's Medical Center, the University of Hawaii and the Johns Hopkins University.

Consent to participate

All parents of the infants signed the IRB-approved informed consent forms before the study procedures.

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Supplementary Information

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Supplementary file1 (DOCX 16 KB)

429_2020_2207_MOESM2_ESM.jpg

Supplementary Figure. Scatterplots similar to those in Fig. 2 comparing the two subject groups (Met-: open circles, dotted lines; Met + : black circles, solid lines), are shown for the volumes in each brain regions assessed, except these were the actual measurements without normalization to ICV. All brain volumes, globally or regionally, showed the expected age-dependent increase across the PMA studied (JPG 150 KB)

Supplementary file3 (DOCX 27 KB)

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Kawasaki, Y., Oishi, K., Hernandez, A. et al. Brain-derived neurotrophic factor Val66Met variant on brain volumes in infants. Brain Struct Funct 226, 919–925 (2021). https://doi.org/10.1007/s00429-020-02207-2

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  • DOI: https://doi.org/10.1007/s00429-020-02207-2

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