NeuroMolecular Medicine

, Volume 13, Issue 4, pp 217–222

Brain-Derived Neurotrophic Factor and Alzheimer’s Disease: Physiopathology and Beyond

Review Paper

Abstract

Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system where it plays several pivotal roles in synaptic plasticity and neuronal survival. As a consequence, BDNF became a key target in the physiopathology of several neurological and psychiatric diseases. Recent studies have reported altered levels of BDNF in the circulation, i.e. serum or plasma, of patients with Alzheimer’s disease (AD), and low BDNF levels in the CSF as predictor of future cognitive decline in healthy older subjects. Altered BDNF circulating levels have also been reported in other neurodegenerative and psychiatric disorders, hampering its use as a specific biomarker for AD. Therefore, BDNF seems to be an unspecific biomarker of neuropsychiatric disorders marked by neurodegenerative changes.

Keywords

BDNF Alzheimer’s disease Mild cognitive impairment Biomarker Physiopathology 

References

  1. Akatsu, H., Yamagata, H. D., Kawamata, J., Kamino, K., Takeda, M., Yamamoto, T., et al. (2006). Variations in the BDNF gene in autopsy-confirmed Alzheimer’s disease and dementia with Lewy bodies in Japan. Dementia and Geriatric Cognitive Disorders, 22(3), 216–222.PubMedCrossRefGoogle Scholar
  2. Albert, M. S., Dekosky, S. T., Dickson, D., Dubois, B., Feldman, H. H., Fox, N. C., et al. (2011). The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers and Dementia, 7(3), 270–279.CrossRefGoogle Scholar
  3. Aliaga, E., Silhol, M., Bonneau, N., Maurice, T., Arancibia, S., & Tapia-Arancibia, L. (2010). Dual response of BDNF to sublethal concentrations of beta-amyloid peptides in cultured cortical neurons”. Neurobiology of Disease, 37, 208–217.PubMedCrossRefGoogle Scholar
  4. Angelucci, F., Spalletta, G., di Lulio, F., Ciaramella, A., Salani, F., Colantoni, L., et al. (2010). Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients are characterized by increased BDNF serum levels. Current Alzheimer Research, 7(1), 15–20.PubMedCrossRefGoogle Scholar
  5. Arancibia, S., Silhol, M., Moulivre, F., Meffre, J., Höllinger, I., Maurice, T., et al. (2008). Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats. Neurobiology of Disease, 31, 316–326.PubMedCrossRefGoogle Scholar
  6. Bodner, S. M., Berrettini, W., van Deerlin, V., Bennett, D. A., Wilson, R. S., Trojanowski, J. Q., et al. (2005). Genetic variation in the brain derived neurotrophic factor gene in Alzheimer’s disease. American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, 134B(1), 1–5.CrossRefGoogle Scholar
  7. Bramham, C. R., Worley, P. F., Moore, M. J., & Guzowski, J. F. (2008). The immediate early gene arc/arg3.1: Regulation, mechanisms, and function. Journal of Neuroscience, 28, 11760–11767.PubMedCrossRefGoogle Scholar
  8. Burbach, G. J., Hellweg, R., Haas, C. A., Del Turco, D., Deicke, U., Abramowski, D., et al. (2004). Induction of brain-derived neurotrophic factor in plaque-associated glial cells of aged APP23 transgenic mice. Journal of Neuroscience, 24, 2421–2430.PubMedCrossRefGoogle Scholar
  9. Chao, M. V. (2003). Neurotrophins and their receptors: A converge point for many signaling pathways. Nature Reviews Neuroscience, 4(4), 199–209.CrossRefGoogle Scholar
  10. Chen, Q., Nakajima, A., Choi, S. H., Xiong, X., Sisodia, S. S., & Tang, Y. P. (2008). Adult neurogenesis is functionally associated with AD-like neurodegeneration. Neurobiology of Disease, 29(2), 316–326.PubMedCrossRefGoogle Scholar
  11. Chen, T. J., Wang, D. C., & Chen, S. S. (2009). Amyloid-beta interrupts the PI3 K-Akt-mTOR signaling pathway that could be involved in brain-derived neurotrophic factor-induced Arc expression in rat cortical neurons. Journal of Neuroscience Research, 87, 2297–2307.PubMedCrossRefGoogle Scholar
  12. Cunha, A. B., Frey, B. N., Andreazza, A. C., et al. (2006). Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neuroscience Letters, 398(3), 215–219.PubMedCrossRefGoogle Scholar
  13. Diniz, B. S., Pinto, J. A., Gonzaga, M. L., Guimarães, F. M., Gattaz, W. F., & Forlenza, O. V. (2009). To treat or not to treat? A meta-analysis of the use of cholinesterase inhibitors in mild cognitive impairment for delaying progression to Alzheimer’s disease. European Archives of Psychiatry and Clinical Neuroscience, 259(4), 248–256.PubMedCrossRefGoogle Scholar
  14. Diniz, B. S., Pinto Junior, J. A., & Forlenza, O. V. (2008). Do CSF total tau, phosphorylated tau, and beta-amyloid 42 help to predict progression of mild cognitive impairment to Alzheimer’s disease? A systematic review and meta-analysis of the literature. World Journal of Biological Psychiatry, 9(3), 172–182.PubMedCrossRefGoogle Scholar
  15. Diniz, B. S., Teixeira, A. L., Ojopi, E. B., Talib, L. L., Mendonça, V. A., Gattaz, W. F., et al. (2010a). Higher serum stnfr1 level predicts conversion from mild cognitive impairment to Alzheimer’s disease. Journal Alzheimers Disease, 22(4), 1305–1311.Google Scholar
  16. Diniz, B. S., Teixeira, A. L., Talib, L. L., Mendonça, V. A., Gattaz, W. F., & Forlenza, O. V. (2010b). Serum brain-derived neurotrophic factor level is reduced in antidepressant-free patients with late-life depression. World Journal of Biological Psychiatry, 11(3), 550–555.PubMedCrossRefGoogle Scholar
  17. Dubois, B., Feldman, H. H., Jacova, C., Dekosky, S. T., Barberger-Gateau, P., Cummings, J., et al. (2007). Research criteria for the diagnosis of Alzheimer’s disease: Revising the NINCDS-ADRDA criteria. Lancet Neurology, 6, 734–746.PubMedCrossRefGoogle Scholar
  18. Echeverria, V., Berman, D. E., & Arancio, O. (2007). Oligomers of beta-amyloid peptide inhibit BDNF-induced arc expression in cultured cortical Neurons. Current Alzheimer Research, 4(5), 518–521.PubMedCrossRefGoogle Scholar
  19. Forlenza, O. V., Diniz, B. S., & Gattaz, W. F. (2010a). Diagnosis and biomarkers of predementia in Alzheimer’s disease. BMC Medicine, 8, 89. doi:10.1186/1741-7015-8-89.PubMedCrossRefGoogle Scholar
  20. Forlenza, O. V., Diniz, B. S., Radanovic, M., Santos, F. S., Talib, L. L., & Gattaz, W. F. (2011a). Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: Randomised controlled trial. British Journal of Psychiatry, 198(5), 351–356.PubMedCrossRefGoogle Scholar
  21. Forlenza, O. V., Diniz, B. S., Talib, L. L., Mendonça, V. A., Ojopi, E. B., Gattaz, W. F., et al. (2009). Increased serum IL-1beta level in Alzheimer’s disease and mild cognitive impairment. Dementia and Geriatric Cognitive Disorder, 28(6), 507–512.CrossRefGoogle Scholar
  22. Forlenza, O. V., Diniz, B. S., Talib, L. L., Radanovic, M., Yassuda, M. S., Ojopi, E. B., et al. (2010b). Clinical and biological predictors of Alzheimer’s disease in patients with amnestic mild cognitive impairment. Revista Brasileira de Psiquiatria, 32(3), 216–222.PubMedCrossRefGoogle Scholar
  23. Forlenza, O. V., Diniz, B. S., Teixeira, A. L., Ojopi, E. B., Talib, L. L., Mendonça, V. A., et al. (2010c). Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment. World Journal of Biological Psychiatry, 11(6), 774–780.PubMedCrossRefGoogle Scholar
  24. Forlenza, O. V., Torres, C. A., Talib, L. L., de Paula, V. J., Joaquim, H. P., Diniz, B. S., et al. (2011b). Increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer’s disease. Journal of Psychiatric Research, 45(2), 220–224.PubMedCrossRefGoogle Scholar
  25. Fu, W., Lu, C., & Mattson, M. P. (2002). Telomerase mediates the cell survival-promoting actions of brain-derived neurotrophic factor and secreted amyloid precursor protein in developing hippocampal neurons. Journal of Neuroscience, 22(24), 10710–10719.PubMedGoogle Scholar
  26. Fujimura, H., Altar, C. A., Chen, R., Nakamura, T., Nakahashi, T., Kambayashi, J., et al. (2002). Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thrombosis and Haemostasis, 87(4), 728–734.PubMedGoogle Scholar
  27. Fukumoto, N., Fujii, T., Combarros, O., Kamboh, M. I., Tsai, S. J., Matsushita, S., et al. (2010). Sexually dimorphic effect of the Val66Met polymorphism of BDNF on susceptibility to Alzheimer’s disease: New data and meta-analysis. American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, 153B(1), 224–235.Google Scholar
  28. Gunstad, J., Benitez, A., Smith, J., Glickman, E., Spitznagel, M. B., Alexander, T., et al. (2008). Serum brain-derived neurotrophic factor is associated with cognitive function in healthy older adults. Journal of Geriatric Psychiatry and Neurology, 21(3), 166–170.PubMedCrossRefGoogle Scholar
  29. Hooper, C., Killick, R., & Lovestone, S. (2008). The GSK3 hypothesis of Alzheimer’s disease. Journal of Neurochemistry, 104, 1433–1439.PubMedCrossRefGoogle Scholar
  30. Hu, Y., & Russek, S. J. (2008). BDNF and the diseased nervous system: A delicate balance between adaptive and pathological processes of gene regulation. Journal of Neurochemistry, 105, 1–17.PubMedCrossRefGoogle Scholar
  31. Hwang, J. P., Tsai, S. J., Hong, C. J., Yang, C. H., Lirng, J. F., & Yang, Y. M. (2006). The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiology of Aging, 27(12), 1834–1837.PubMedCrossRefGoogle Scholar
  32. Jack, C. R., Knopman, D. S., Jagust, W. J., Shaw, L. M., Aisen, P. S., Weiner, M. W., et al. (2009). Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurology, 9(1), 119–128.CrossRefGoogle Scholar
  33. Karege, F., Bondolfi, G., Gervasoni, N., Schwald, M., Aubry, J. M., & Bertschy, G. (2005). Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biological Psychiatry, 57(9), 1068–1072.PubMedCrossRefGoogle Scholar
  34. Kimura, N., Takahashi, M., Tashiro, T., & Terao, K. (2006). Amyloid-beta up-regulates brain-derived neurotrophic factor production from astrocytes: Rescue from amyloid beta-related neuritic degeneration. Journal of Neuroscience Research, 84, 782–789.PubMedCrossRefGoogle Scholar
  35. Kunugi, H., Ueki, A., Otsuka, M., Isse, K., Hirasawa, H., Kato, N., et al. (2001). A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer’s disease. Molecular Psychiatry, 6(1), 83–86.PubMedCrossRefGoogle Scholar
  36. Laske, C., Stransky, E., Leyhe, T., Eschweiler, G. W., Maetzler, W., Wittorf, A., et al. (2007). BDNF serum and CSF concentrations in Alzheimer’s disease, normal pressure hydrocephalus and healthy controls. Journal of Psychiatric Research, 41(5), 387–394.PubMedCrossRefGoogle Scholar
  37. Laske, C., Stransky, E., Leyhe, T., Eschweiler, G. W., Wittorf, A., Richartz, E., et al. (2006). Stage-dependent BDNF serum concentrations in Alzheimer’s disease. Journal of Neural Transmission, 113, 1217–1224.PubMedCrossRefGoogle Scholar
  38. Lee, J. G., Shin, B. S., You, Y. S., Kim, J. E., Yoon, S. W., Jeon, D. W., et al. (2009). Decreased serum brain-derived neurotrophic factor levels in elderly Korean with dementia. Psychiatry Investigation, 6(4), 299–305.PubMedCrossRefGoogle Scholar
  39. Leyhe, T., Eschweiler, G. W., Stransky, E., Gasser, T., Annas, P., Basun, H., et al. (2009). Increase of BDNF serum concentration in lithium treated patients with early Alzheimer’s disease. Journal of Alzheimers Disease, 16, 649–656.Google Scholar
  40. Leyhe, T., Stransky, E., Eschweiler, G. W., Buchkremer, G., & Laske, C. (2008). Increase of BDNF serum concentration during donepezil treatment of patients with early Alzheimer’s disease. European Archives of Psychiatry and Clinical Neuroscience, 258(2), 124–128.PubMedCrossRefGoogle Scholar
  41. Li, G., Peskind, E. R., Millard, S. P., Chi, P., Sokal, I., Yu, C. E., et al. (2009). Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PloS One, 4(5), e5424. doi:10.1371/journal.pone.0005424.
  42. Longo, F. M., Yang, T., Knowles, J. K., Xie, Y., Moore, L. A., & Massa, S. M. (2007). Small molecule neurotrophin receptor ligands: Novel strategies for targeting Alzheimer’s disease mechanisms. Current Alzheimer Research, 4(5), 503–506.PubMedCrossRefGoogle Scholar
  43. Machado-Vieira, R., Dietrich, M. O., Leke, R., Cereser, V. H., Zanatto, V., Kapczinski, F., et al. (2007). Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode. Biological Psychiatry, 61(2), 142–144.PubMedCrossRefGoogle Scholar
  44. Massa, S. M., Yang, T., Xie, Y., Shi, J., Bilgen, M., Joyce, J. N., et al. (2010). Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. Journal of Clinical Investigation, 120(5), 1774–1785. doi:10.1172/JCI41356.PubMedCrossRefGoogle Scholar
  45. Mattson, M. P. (2004). Pathways towards and away from Alzheimer’s disease. Nature, 430(7000), 631–639.PubMedCrossRefGoogle Scholar
  46. Mrak, R. E. (2009). Neuropathology and the neuroinflammation idea”. Journal Alzheimers Disease, 18(3), 473–481.Google Scholar
  47. Nagahara, A. H., Merrill, D. A., Coppola, G., Tsukada, S., Schroeder, B. E., Shaked, G. M., et al. (2009). Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nature Medicine, 15, 331–337.PubMedCrossRefGoogle Scholar
  48. Nakahashi, T., Fujimura, H., Altar, C. A., Li, J., Kambayashi, J., Tandon, N. N., et al. (2000). Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Letters, 470(2), 113–117.PubMedCrossRefGoogle Scholar
  49. Nishimura, A. L., Oliveira, J. R., Mitne-Neto, M., Guindalini, C., Nitrini, R., Bahia, V. S., et al. (2004). Lack of association between the brain-derived neurotrophin factor (C-270T) polymorphism and late-onset Alzheimer’s disease (LOAD) in Brazilian patients. Journal of Molecular Neuroscience, 22(3), 257–260.PubMedCrossRefGoogle Scholar
  50. Nishitomi, K., Sakaguchi, G., Horikoshi, Y., Gray, A. J., Maeda, M., Hirata-Fukae, C., et al. (2006). BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. Journal of Neurochemistry, 99(6), 1555–1563.PubMedCrossRefGoogle Scholar
  51. Olin, D., MacMurray, J., & Comings, D. E. (2005). Risk of late-onset Alzheimer’s disease associated with BDNF C270T polymorphism. Neuroscience Letters, 381(3), 275–278.PubMedCrossRefGoogle Scholar
  52. Peng, S., Garzon, D. J., Marchese, M., Klein, W., Ginsberg, S. D., Francis, B. M., et al. (2009). Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer’s disease. Journal of Neuroscience, 29, 9321–9329.PubMedCrossRefGoogle Scholar
  53. Poon, W. W., Blurton-Jones, M., Tu, C. H., Feinberg, L. M., Chabrier, M. A., Harris, J. W., et al. (2011). beta-Amyloid impairs axonal BDNF retrograde trafficking. Neurobiology of Aging, 32(5), 821–833.PubMedCrossRefGoogle Scholar
  54. Price, R. D., Milne, S. A., Sharkey, J., & Matsuoka, N. (2007). Advances in small molecules promoting neurotrophic function. Pharmacology and Therapeutics, 115(2), 292–306.PubMedCrossRefGoogle Scholar
  55. Reichardt, L. F. (2006). Neurotrophin-regulated signaling pathways. Philosophical Transactions of the Royal Society London, Part B, Biological Science, 361(1473), 1545–1564.CrossRefGoogle Scholar
  56. Ribeiro, L., Busnello, J. V., Cantor, R. M., Whelan, F., Whittaker, P., Deloukas, P., et al. (2007). The brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism and depression in Mexican-Americans. Neuroreport, 18(12), 1291–1293.PubMedCrossRefGoogle Scholar
  57. Rohe, M., Synowitz, M., Glass, R., Paul, S. M., Nykjaer, A., & Willnow, T. E. (2009). Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. Journal of Neuroscience, 29(49), 15472–154782009.PubMedCrossRefGoogle Scholar
  58. Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., et al. (1996). Secreted amyloid beta-protein similar to that in senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 APP mutations linked to familial Alzheimer’s disease. Nature Medicine, 2, 864–870.PubMedCrossRefGoogle Scholar
  59. Shruster, A., Melamed, E., & Offen, D. (2010). Neurogenesis in the aged and neurodegenerative brain. Apoptosis, 15(11), 1415–1421.PubMedCrossRefGoogle Scholar
  60. Sousa, R. T., van de Bilt, M. T., Diniz, B. S., Ladeira, R. B., Portela, L. V., Souza, D. O., et al. (2011). Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: A preliminary 4-week study. Neuroscience Letters, 494(1), 54–56.PubMedCrossRefGoogle Scholar
  61. Swerdlow, R. H. (2007). Is aging part of Alzheimer’s disease, or is Alzheimer’s disease part of aging? Neurobiology of Aging, 28(10), 1465–1480.PubMedCrossRefGoogle Scholar
  62. Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2010). The Alzheimer’s disease mitochondrial cascade hypothesis. Journal Alzheimers Disease, 20(Suppl 2), S265–S279.Google Scholar
  63. Tapia-Arancibia, L., Aliaga, E., Silhol, M., & Arancibia, S. (2008). New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Research Reviews, 59(1), 201–220.PubMedCrossRefGoogle Scholar
  64. Taylor, W. D., Zuchner, S., McQuoid, D. R., Steffens, D. C., Speer, M. C., & Krishnan, K. R. (2007). Allelic differences in the brain-derived neurotrophic factor Val66Met polymorphism in late-life depression. American Journal of Geriatric Psychiatry, 15(10), 850–857.PubMedCrossRefGoogle Scholar
  65. Teixeira, A. L., Barbosa, I. G., Diniz, B. S., & Kummer, A. (2010). Circulating levels of brain-derived neurotrophic factor: Correlation with mood, cognition and motor function. Biomarkers in Medicine, 4(6), 871–887.PubMedCrossRefGoogle Scholar
  66. Thornton, E., Vink, R., Blumbergs, P. C., & Van Den Heuvel, C. (2006). Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats. Brain Research, 1094(1), 38–46.PubMedCrossRefGoogle Scholar
  67. Tsai, S. J., Hong, C. J., Liu, H. C., Liu, T. Y., Hsu, L. E., & Lin, C. H. (2004). Association analysis of brain-derived neurotrophic factor Val66Met polymorphisms with Alzheimer’s disease and age of onset. Neuropsychobiology, 49(1), 10–12.PubMedCrossRefGoogle Scholar
  68. Tsai, S. J., Hong, C. J., Liu, H. C., Liu, T. Y., & Liou, Y. J. (2006). The brain-derived neurotrophic factor gene as a possible susceptibility candidate for Alzheimer’s disease in a Chinese population. Dementia and Geriatric Cognitive Disorders, 21(3), 139–143.PubMedCrossRefGoogle Scholar
  69. Vepsäläinen, S., Castren, E., Helisalmi, S., Iivonen, S., Mannermaa, A., Lehtovirta, M., et al. (2005). Genetic analysis of BDNF and TrkB gene polymorphisms in Alzheimer’s disease. Journal of Neurology, 252(4), 423–428.PubMedCrossRefGoogle Scholar
  70. Wang, D. C., Chen, S. S., Lee, Y. C., & Chen, T. J. (2006). Amyloid-beta at sublethal level impairs BDNF-induced arc expression in cortical neurons. Neuroscience Letters, 398, 78–82.PubMedCrossRefGoogle Scholar
  71. Winblad, B., Palmer, K., Kivipelto, M., Jelic, V., Fratiglioni, L., Wahlund, L., et al. (2004). Mild cognitive impairment–beyond controversies, towards a consensus: Report of the international working group on mild cognitive impairment. Journal of Internal Medicine, 256, 240–246.PubMedCrossRefGoogle Scholar
  72. Yasutake, C., Kuroda, K., Yanagawa, T., Okamura, T., & Yoneda, H. (2006). Serum BDNF, TNF-alpha and IL-1beta levels in dementia patients: Comparison between Alzheimer’s disease and vascular dementia. European Archives of Psychiatry and Clinical Neuroscience, 256(7), 402–406.PubMedCrossRefGoogle Scholar
  73. Yu, H., Zhang, Z., Shi, Y., Bai, F., Xie, C., Qian, Y., et al. (2008). Association study of the decreased serum BDNF concentrations in amnestic mild cognitive impairment and the Val66Met polymorphism in Chinese Han. Journal of Clinical Psychiatry, 69, 1104–1111.PubMedCrossRefGoogle Scholar
  74. Zhang, J., Sokal, I., Peskind, E. R., Quinn, J. F., Jankovic, J., Kenney, C., et al. (2008). CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. American Journal of Clinical Pathololgy, 129(4), 526–529.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of MedicineUniversity of São PauloSão PauloBrazil
  2. 2.Group of Neuroimmunology, Laboratory of ImmunopharmachologyInstitute of Biological Sciences and School of Medicine, Federal University of Minas GeraisBelo HorizonteBrazil

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