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BDNF Val66Met polymorphism and brain volumes in multiple sclerosis

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Abstract

Brain derived neurotrophic factor (BDNF) regulates several CNS physiological and pathological processes. To investigate in multiple sclerosis (MS) patients, the relationship between the Val66Met polymorphism of BDNF and clinical markers of disease activity and MRI markers of focal and diffuse brain pathologies. 45 MS patients and 34 healthy controls (HCs) were genotyped and subjected to clinical-MRI examination. Global white matter fraction (gWM-f), gray matter-f (GM-f), cerebrospinal fluid-f (CSF-f), and abnormal WM-f were measured. We studied 26 Val/Val and 19 Val/Met patients and 23 Val/Val and 11 Val/Met HCs. We found that Val/Val patients had lower GM-f and higher CSF-f than Val/Val HCs; such differences were not statistically significant comparing Val/Met patients to HCs. The regression analysis showed that both Val/Met genotype and relapse number were associated with lower CSF-f. Our data suggest that Met allele might be a protective factor against MS as it is associated to a lower brain atrophy.

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References

  1. Trapp BD, Peterson JW, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285

    Article  CAS  PubMed  Google Scholar 

  2. Peterson JW, Bo L, Mork S, Chang A, Trapp BD (2001) Transected neuritis, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400

    Article  CAS  PubMed  Google Scholar 

  3. Kidd D, Barkof F, McConnell R, Algra PR, Allen IV, Revesz T (1999) Cortical lesions in multiple sclerosis. Brain 122:17–26

    Article  PubMed  Google Scholar 

  4. Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med 354(9):942–955

    Article  CAS  PubMed  Google Scholar 

  5. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M et al (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128(Pt 11):2705–2712

    Article  PubMed  Google Scholar 

  6. Bjartmar C, Kinkel RP, Kidd G, Rudick RA, Trapp BD (2001) Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 57(7):1248–1252

    CAS  PubMed  Google Scholar 

  7. Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T et al (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59(3):478–489

    Article  CAS  PubMed  Google Scholar 

  8. Lucchinetti CF, Bruck W, Lassmann H (2004) Evidence for pathogenic heterogeneity in multiple sclerosis. Ann Neurol 56(2):308

    Article  PubMed  Google Scholar 

  9. Tedeschi G, Lavorgna L, Russo P, Prinster A, Dinacci D, Savettieri G et al (2005) Brain atrophy and lesion load in a large population of patients with multiple sclerosis. Neurology 65(2):280–285

    Article  CAS  PubMed  Google Scholar 

  10. De Stefano N, Iannucci G, Sormani MP, Guidi L, Bartolozzi ML, Comi G et al (2002) MR correlates of cerebral atrophy in patients with multiple sclerosis. J Neurol 249(8):1072–1077

    Article  PubMed  Google Scholar 

  11. De Stefano N, Matthews PM, Filippi M, Agosta F, De Luca M, Bartolozzi ML et al (2003) Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology 60(7):1157–1162

    PubMed  Google Scholar 

  12. Pittock SJ, Lucchinetti CF (2007) The pathology of MS: new insights and potential clinical applications. Neurologist 13(2):45–56 (Review)

    Article  PubMed  Google Scholar 

  13. Ge Y, Grossman RI, Udupa JK, Babb JS, Nyul LG, Kolson DL (2001) Brain atrophy in relapsing–remitting multiple sclerosis: fractional volumetric analysis of gray matter and white matter. Radiology 220(3):606–610

    Article  CAS  PubMed  Google Scholar 

  14. Bermel RA, Bakshi R (2006) The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol 5(2):158–170 (Review)

    Article  PubMed  Google Scholar 

  15. Tedeschi G, Dinacci D, Comerci M, Lavorgna L, Savettieri G, Quattrone A et al (2008) Brain atrophy evolution and lesion load accrual in multiple sclerosis: a 2-year follow-up study. Mult Scler 79(11):1236–1244

    Google Scholar 

  16. Ramagopalan SV, Ebers GC (2008) Genes for multiple sclerosis. Lancet 371(9609):283–285

    Article  PubMed  Google Scholar 

  17. Ebers GC (2008) Environmental factors and multiple sclerosis. Lancet Neurol 7(3):268–277

    Article  PubMed  Google Scholar 

  18. Martínez A, Alvarez-Lafuente R, Mas A, Bartolomé M, García-Montojo M, de Las Heras V et al (2007) Environment-gene interaction in multiple sclerosis: human herpesvirus 6 and MHC2TA. Hum Immunol 68(8):685–689

    Article  PubMed  Google Scholar 

  19. Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2(1):24–32

    Article  CAS  PubMed  Google Scholar 

  20. Ockel M, Lewin GR, Barde YA (1996) In vivo effects of neurotrophin-3 during sensory neurogenesis. Development 122(1):301–307

    CAS  PubMed  Google Scholar 

  21. Hofer M, Pagliusi SR, Hohn A, Leibrock J, Barde YA (1990) Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J 9(8):2459–2464

    CAS  PubMed  Google Scholar 

  22. Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9(5):224–237

    Article  PubMed  Google Scholar 

  23. Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T (2007) Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics 90(3):397–406

    Article  CAS  PubMed  Google Scholar 

  24. Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76(2):99–125

    Article  CAS  PubMed  Google Scholar 

  25. Zhou XF, Song XY, Zhong JH, Barati S, Zhou FH, Johnson SM (2004) Distribution and localization of probrain-derived neurotrophic factor-like immunoreactivity in the peripheral and central nervous system of the adult rat. J Neurochem 91(3):704–715

    Article  CAS  PubMed  Google Scholar 

  26. Kojima M, Takei N, Numakawa T, Ishikawa Y, Suzuki S, Matsumoto T et al (2001) Biological characterization and optical imaging of brain-derived neurotrophic factor-green fluorescent protein suggest an activity-dependent local release of brain-derived neurotrophic factor in neurites of cultured hippocampal neurons. J Neurosci Res 64(1):1–10

    Article  CAS  PubMed  Google Scholar 

  27. Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE et al (1999) Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med 189(5):865–870

    Article  CAS  PubMed  Google Scholar 

  28. Besser M, Wank R (1999) Cutting edge: clonally restricted production of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors. J Immunol 62(11):6303–6306

    Google Scholar 

  29. Braun A, Lommatzsch M, Mannsfeldt A, Neuhaus-Steinmetz U, Fischer A, Schnoy N et al (1999) Cellular sources of enhanced brain-derived neurotrophic factor production in a mouse model of allergic inflammation. Am J Respir Cell Mol Biol 21(4):537–546

    CAS  PubMed  Google Scholar 

  30. Stadelmann C, Kerschensteiner M, Misgeld T, Brück W, Hohlfeld R, Lassmann H (2002) BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 125(Pt 1):75–85

    Article  PubMed  Google Scholar 

  31. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS (2004) Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 24(18):4401–4411

    Article  CAS  PubMed  Google Scholar 

  32. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al (2003) The BDNF Val66Met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112(2):257–269

    Article  CAS  PubMed  Google Scholar 

  33. Stern AJ, Savostyanova AA, Goldman A, Barnett AS, van der Veen JW, Callicott JH et al (2008) Impact of the brain-derived neurotrophic factor Val66Met polymorphism on levels of hippocampal N-acetylaspartate assessed by magnetic resonance spectroscopic imaging at 3 Tesla. Biol Psychiatr 64(10):856–862

    Article  CAS  Google Scholar 

  34. Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE et al (2004) The brainderived neurotrophic factor Val66Met polymorphism and variation in human cortical morphology. J Neurosci 24(45):10099–10102

    Article  CAS  PubMed  Google Scholar 

  35. 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 Psychiatr 59(9):812–815

    Article  CAS  Google Scholar 

  36. Nemoto K, Ohnishi T, Mori T, Moriguchi Y, Hashimoto R, Asada T et al (2006) The Val66Met polymorphism of the brain-derived neurotrophic factor gene affects age-related brain morphology. Neurosci Lett 397(1–2):25–29

    Article  CAS  PubMed  Google Scholar 

  37. Takahashi T, Suzuki M, Tsunoda M, Kawamura Y, Takahashi N, Tsuneki H et al (2008) Association between the brain-derived neurotrophic factor Val66Met polymorphism and brain morphology in a Japanese sample of schizophrenia and healthy comparisons. Neurosci Lett 435(1):34–39

    Article  CAS  PubMed  Google Scholar 

  38. Sublette ME, Baca-Garcia E, Parsey RV, Oquendo MA, Rodrigues SM, Galfalvy H et al (2008) Effect of BDNF Val66Met polymorphism on age-related amygdala volume changes in healthy subjects. Prog Neuropsychopharmacol Biol Psychiatr 32(7):1652–1655

    Article  CAS  Google Scholar 

  39. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR (2003) Brainderived neurotrophic factor Val66Met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23(17):6690–6694

    CAS  PubMed  Google Scholar 

  40. Miyajima F, Ollier W, Mayes A, Jackson A, Thacker N, Rabbitt P, Pendleton N, Horan M, Payton A (2008) Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav 7(4):411–417 (Epub 2007 Oct)

    Article  CAS  PubMed  Google Scholar 

  41. Frodl T, Schüle C, Schmitt G, Born C, Baghai T, Zill P, Bottlender R, Rupprecht R, Bondy B, Reiser M, Möller HJ, Meisenzahl EM (2007) Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatr 64(4):410–416

    Article  CAS  PubMed  Google Scholar 

  42. Mirakhur A, Moorhead TW, Stanfield AC, McKirdy J, Sussmann JE, Hall J, Lawrie SM, Johnstone EC, McIntosh AM (2009) Changes in gyrification over 4 years in bipolar disorder and their association with the brain-derived neurotrophic factor valine(66) methionine variant. Biol Psychiatr 66:293–297

    Article  CAS  Google Scholar 

  43. Ho BC, Milev P, O’Leary DS, Librant A, Andreasen NC, Wassink TH (2006) Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatr 63(7):731–740

    Article  CAS  PubMed  Google Scholar 

  44. Ho BC, Andreasen NC, Dawson JD, Wassink TH (2007) Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. Am J Psychiatr 164(12):1890–1899

    Article  PubMed  Google Scholar 

  45. Weinstock-Guttman B, Zivadinov R, Tamaño-Blanco M, Abdelrahman N, Badgett D, Durfee J, Hussein S et al (2007) Immune cell BDNF secretion is associated with white matter volume in multiple sclerosis. J Neuroimmunol 188(1–2):167–174 (Epub 2007 Jun 28)

    Article  CAS  PubMed  Google Scholar 

  46. Liguori M, Fera F, Patitucci A, Manna I, Condino F, Valentino P et al (2008) A longitudinal observation of brain-derived neurotrophic factor mRNA levels in patients with relapsing–remitting multiple sclerosis. Brain Res 1256:123–128

    Article  PubMed  Google Scholar 

  47. Zivadinov R, Weinstock-Guttman B, Benedict R, Tamaño-Blanco M, Hussein S, Abdelrahman N et al (2007) Preservation of gray matter volume in multiple sclerosis patients with the Met allele of the rs6265 (Val66Met) SNP of brain-derived neurotrophic factor. Hum Mol Genet 16(22):2659–2668 (Epub 2007 Jul 26)

    Article  CAS  PubMed  Google Scholar 

  48. Liguori M, Fera F, Gioia MC, Valentino P, Manna I, Condino F et al (2007) Investigating the role of brain derived neurotrophic factor in relapsing–remitting multiple sclerosis. Genes Brain Behav 6(2):177–183

    Article  CAS  PubMed  Google Scholar 

  49. Blanco Y, Gómez-Choco M, Arostegui JL, Casanova B, Martínez-Rodríguez JE, Boscá I, Munteis E, Yagüe J, Graus F, Saiz A (2006) No association of the Val66Met polymorphism of brain-derived neurotrophic factor BDNF) to multiple sclerosis. Neurosci Lett 396(3):217–219 (Epub 2005 Dec 13)

    Article  CAS  PubMed  Google Scholar 

  50. Lindquist S, Schott BH, Ban M, Compston DA, Sawcer S, Sailer M (2005) The BDNF-Val66Met polymorphism: implications for susceptibility to multiple sclerosis and severity of disease. J Neuroimmunol 167(1–2):183–185

    Article  CAS  PubMed  Google Scholar 

  51. Alfano B, Brunetti A, Larobina M, Quarantelli M, Tedeschi E, Ciarmiello A et al (2000) Automated segmentation and measurement of global white matter lesion volume in patients with multiple sclerosis. J Magn Reson Imaging 12:799–807

    Article  CAS  PubMed  Google Scholar 

  52. Lanzillo R, Prinster A, Scarano V, Liuzzi R, Coppola G, Florio C et al (2006) Neuropsychological assessment, quantitative MRI and ApoE gene polymorphisms in a series of MS patients treated with IFN β-1b. J Neurol Sci 245(1–2):141–145 (Epub 2006 Apr 19)

    Article  CAS  PubMed  Google Scholar 

  53. Tedeschi G, Dinacci D, Lavorgna L, Prinster A, Savettieri G, Quattrone A et al (2007) Correlation between fatigue and brain atrophy and lesion load in multiple sclerosis patients independent of disability. J Neurol Sci 263(1–2):15–19

    Article  PubMed  Google Scholar 

  54. Quarantelli M, Ciarmiello A, Morra VB, Orefice G, Larobina M, Lanzillo R et al (2003) Brain tissue volume changes in relapsing-remitting multiple sclerosis: correlation with lesion load. Neuroimage 18(2):360–366

    Article  PubMed  Google Scholar 

  55. Alfano B, Brunetti A, Covelli EM, Quarantelli M, Panico MR, Ciarmiello A, Salvatore M (1997) Unsupervised, automated segmentation of the normal brain using a multispectral relaxometric magnetic resonance approach. Magn Reson Med 37(1):84–93

    Article  CAS  PubMed  Google Scholar 

  56. Alfano B, Brunetti A, Larobina M, Quarantelli M, Tedeschi E, Ciarmiello A et al (2000) Automated segmentation and measurement of global white matter lesion volume in patients with multiple sclerosis. J Magn Reson Imaging 12(6):799–807

    Article  CAS  PubMed  Google Scholar 

  57. Alfano B, Quarantelli M, Brunetti A, Larobina M, Covelli EM, Tedeschi E et al (1998) Reproducibility of intracranial volume measurement by unsupervised multispectral brain segmentation. Magn Reson Med 39(3):497–499

    Article  CAS  PubMed  Google Scholar 

  58. Alfano B, Brunetti A, Covelli EM, Quarantelli M, Panico MR, Ciarmiello A et al (1997) Unsupervised, automated segmentation of the normal brain using a multispectral relaxometric magnetic resonance approach. Magn Reson Med 37:84–93

    Article  CAS  PubMed  Google Scholar 

  59. Kurtzke JF (1983) Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452

    CAS  PubMed  Google Scholar 

  60. Pelletier D, Garrison K, Henry R (2004) Measurement of whole-brain atrophy in multiple sclerosis. J Neuroimaging 14(3 Suppl):11S–19S (Review)

    Article  PubMed  Google Scholar 

  61. Cheng CY, Hong CJ, Yu YW, Chen TJ, Wu HC, Tsai SJ (2005) Brain-derived neurotrophic factor (Val66Met) genetic polymorphism is associated with substance abuse in males. Brain Res Mol Brain Res 140(1–2):86–90 (Epub 2005 Aug 18)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We wish to thank “Fondazione Cesare Serono”, Italy for supporting the study by renting the MRI mobile machine. We wish to thank Stefano de Renzis M.D. for supporting the study with additional editing.

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Authors and Affiliations

  1. Department of Neurological Science, Second University of Naples, Piazza Miraglia 2, 80131, Naples, Italy

    D. Dinacci, A. Tessitore, A. Russo, L. Lavorgna, R. Sacco, S. Bonavita, A. Gallo, G. Servillo, L. Marcuccio & G. Tedeschi

  2. Oncology Reference Center of Basilicata, IRCCS-CROB, Rionero in Vulture (PZ), Italy

    M. L. De Bonis

  3. Opera CRO Scientific Advisor Board, Genoa, Italy

    O. Picconi

  4. Institute of Biostructure and Bioimaging, National Research Council, Naples, Italy

    M. Comerci & B. Alfano

  5. Department of Biochemistry and Biophysics “F.Cedrangolo”, Second University of Naples, Naples, Italy

    P. Galletti

  6. Institute Hermitage Capodimonte, Naples, Italy

    A. Tessitore, S. Bonavita & G. Tedeschi

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  1. D. Dinacci
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  2. A. Tessitore
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  4. M. L. De Bonis
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  13. P. Galletti
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  14. B. Alfano
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  15. G. Tedeschi
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Correspondence to D. Dinacci.

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D. Dinacci and A. Tessitore contributed equally to the work.

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Dinacci, D., Tessitore, A., Russo, A. et al. BDNF Val66Met polymorphism and brain volumes in multiple sclerosis. Neurol Sci 32, 117–123 (2011). https://doi.org/10.1007/s10072-010-0433-z

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