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Neurodevelopment Alterations, Neurodegeneration, and Immunoinflammatory Patterns in the Pathophysiology of Schizophrenia

  • Bernardo Dell’Osso
  • Gregorio Spagnolin
  • Neva E. Suardi
  • A. Carlo Altamura
Chapter

Abstract

Schizophrenia is a highly disabling syndrome, with frequent onset in the first half of adult life. As for other major psychoses, the etiology of schizophrenia is supposed to involve a gene–environment interaction. In terms of pathophysiology, however, immune alterations have been repeatedly reported in schizophrenic patients, involving both the unspecific and specific pathways of the immune system and suggesting that infectious/autoimmune processes play an important role in the development of the disorder. In such perspective, it seems that schizophrenia may be associated with an imbalance in inflammatory cytokines. Alterations in the inflammatory and immune systems, moreover, seem to be already present in the early stages of schizophrenia, likely connected to specific neurodevelopmental abnormalities, which identify the roots of the disorder during brain development with consequences that do not manifest themselves until adolescence or early adulthood. At the same time, neuropathological studies and longitudinal observation in schizophrenia, showing progressive losses of gray matter in the frontal and temporal lobes of the brain, also support a neurodegenerative hypothesis, and, more recently, a novel mixed hypothesis, integrating the aforementioned models, has been put forward.

Keywords

Cytokines Neurodegeneration Neurodevelopmental model Schizophrenia 

References

  1. 1.
    Jones PB, Buckley PF. Schizophrenia. Philadelphia: Elsevier; 2006.Google Scholar
  2. 2.
    Fish B, Marcus J, Hans S, Auerbach JG, Perdue S. Infants at risk for schizophrenia: sequelae of a genetic neurointegrative defect. Arch Gen Psychiatry. 1992;49:221–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Altamura AC, Pozzoli S, Fiorentini A, Dell’Osso B. Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:63–70.PubMedCrossRefGoogle Scholar
  4. 4.
    Walker E, Lewine RJ. Prediction of adult-onset schizophrenia from childhood home movies of the patients. Am J Psychiatry. 1990;147(8):1052–6.PubMedGoogle Scholar
  5. 5.
    Csernansky JG. Neurodegeneration in schizophrenia: evidence from in vivo neuroimaging studies. ScientificWorldJournal. 2007;7:135–43.PubMedCrossRefGoogle Scholar
  6. 6.
    Rund BR. Is schizophrenia a neurodegenerative disorder? Nord J Psychiatry. 2009;63(3):196–201.PubMedCrossRefGoogle Scholar
  7. 7.
    Boin F, Zanardini R, Pioli R, Altamura CA, Maes M, Gennarelli M. Association between −G308A tumor necrosis factor alpha gene polymorphism and schizophrenia. Mol Psychiatry. 2001;6(1):79–82.PubMedCrossRefGoogle Scholar
  8. 8.
    Lin A, Kenis G, Bignotti S, Tura GJ, De Jong R, Bosmans E, et al. The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr Res. 1998;32(1):9–15.PubMedCrossRefGoogle Scholar
  9. 9.
    Maes M, Bocchio Chiavetto L, Bignotti S, Battisa Tura GJ, et al. Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr Res. 2002;54(3):281–91.PubMedCrossRefGoogle Scholar
  10. 10.
    Gourion D, Gourevitch R, Leprovost JB, Olié H lôo JP, Krebs MO. Neurodevelopmental hypothesis in schizophrenia. Encéphale. 2004;30:109–18.PubMedCrossRefGoogle Scholar
  11. 11.
    Rapoport JL, Addington AM, Frangou S, Psych MR. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry. 2005;10:434–49.PubMedCrossRefGoogle Scholar
  12. 12.
    Singh SM, McDonald P, Murphy B, O’Reilly R. Incidental neurodevelopmental episodes in the etiology of schizophrenia: an expanded model involving epigenetics and development. Clin Genet. 2004;65:435–40.PubMedCrossRefGoogle Scholar
  13. 13.
    Buckley P. The clinical stigmata of aberrant neurodevelopment in schizophrenia. J Nerv Ment Dis. 1998;186(2):79–86.PubMedCrossRefGoogle Scholar
  14. 14.
    Keshavan MS, Murray RM. Neurodevelopment and adult psychopathology. Cambridge: Cambridge University Press; 1997.Google Scholar
  15. 15.
    Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44:660–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Fatemi SH, Folsom TD. The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull. 2009;35(3):528–48.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci. 2002;25:409–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Lloyd T, Dazzan P, Dean K, Park SB, Fearon P, Doody GA, et al. Minor physical anomalies in patients with first-episode psychosis: their frequency and diagnostic specificity. Psychol Med. 2008;38:71–7.PubMedGoogle Scholar
  19. 19.
    Meltzer HY, Fatemi SH. Schizophrenia and other psychotic disorders. In: Ebert MH, Loosen PT, Nurcombe B, editors. Current diagnosis and treatment in psychiatry. Norwalk: Appleton and Lange; 2000. p. 260–77.Google Scholar
  20. 20.
    Fatemi SH, Folsom TD. The neurodevelopmental hypothesis of schizophrenia. Revisited. Schizophr Bull. 2009;35(3):528–54.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Barkus E, Stirling J, Hopkins R, Lewis S. The presence of neurological soft signs along the psychosis proneness continuum. Schizophr Bull. 2006;32:573–7.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Niemi LT, Suvisaari JM, Tuulio-Henriksson A, Lonnqvist JK. Childhood developmental abnormalities in schizophrenia: evidence from high-risk studies. Schizophr Res. 2003;60:239–58.PubMedCrossRefGoogle Scholar
  23. 23.
    Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet. 2003;73:34–48.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Sullivan PF, Eaves LJ, Kendler KS, Neale MC. Genetic case–control association studies in neuropsychiatry. Arch Gen Psychiatry. 2001;58:1015–24.PubMedCrossRefGoogle Scholar
  25. 25.
    Cannon TD, van Erp TG, Rosso IM, Huttunen M, Lönnqvist J, Pirkola T, et al. Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry. 2002;59:35–41.PubMedCrossRefGoogle Scholar
  26. 26.
    Boog G. Obstetrical complications and subsequent schizophrenia in adolescent and young adult offsprings: is there a relationship? Eur J Obstet Gynecol Reprod Biol. 2004;114:130–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Schmidt-Kastner R, van Os J, W M Steinbusch H, Schmitz C. Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. Schizophr Res. 2006;84:253–71.PubMedCrossRefGoogle Scholar
  28. 28.
    Karlsson H, Bachmann S, Schroder J, McArthur J, Torrey EF, Yolken RH. Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia. Proc Natl Acad Sci U S A. 2001;98:4634–9.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Lewis DA. Retroviruses and the pathogenesis of schizophrenia. Proc Natl Acad Sci U S A. 2001;94:4293–4.CrossRefGoogle Scholar
  30. 30.
    Jones P, Cannon M. The new epidemiology of schizophrenia. Psychiatr Clin North Am. 1998;21(1):1–25.PubMedCrossRefGoogle Scholar
  31. 31.
    Mednick SA, Machon RA, Huttunen MO, Bonett D. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry. 1988;45:189–92.PubMedCrossRefGoogle Scholar
  32. 32.
    Torrey EF, Rawlings R, Waldman IN. Schizophrenic births and viral diseases in two states. Schizophr Res. 1988;1:73–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Suvisaari J, Haukka J, Tanskanen A, Hovi T, Lönnqvist J. Association between prenatal exposure to poliovirus infection and adult schizophrenia. Am J Psychiatry. 1999;156:1100–2.PubMedGoogle Scholar
  34. 34.
    Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry. 2001;58:1032–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Watson CG, Kucala T, Tilleskjor C, Jacobs L. Schizophrenic birth seasonality in relation to the incidence of infectious diseases and temperature extremes. Arch Gen Psychiatry. 1984;41:85–90.PubMedCrossRefGoogle Scholar
  36. 36.
    Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry. 2004;61:774–80.PubMedCrossRefGoogle Scholar
  37. 37.
    Brown AS, Schaefer CA, Wyatt RJ, Goetz R, Begg MD, Gorman JM, Susser ES. Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study. Schizophr Bull. 2000;26:287–95.PubMedCrossRefGoogle Scholar
  38. 38.
    Brown AS. Prenatal infection as a risk factor for schizophrenia. Schizophr Bull. 2006;32:200–2.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Altamura AC, Boin F, Maes M. HPA axis and cytokines dysregulation in schizophrenia: potential implications for the antipsychotics treatment. Eur Neuropsychopharmacol. 1999;10:1–4.PubMedCrossRefGoogle Scholar
  40. 40.
    Jablensky A. Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Psychiatry Clin Neurosci. 2000;250(6):274–85.PubMedCrossRefGoogle Scholar
  41. 41.
    Mundo E, Altamura AC, Vismara S, Zanardini R, Bignotti S, Randazzo R, et al. MCP-1 gene (SCYA2) and schizophrenia: a case–control association study. Am J Med Genet B Neuropsychiatr Genet. 2005;132B:1–4.PubMedCrossRefGoogle Scholar
  42. 42.
    Altamura AC, Pozzoli S, Fiorentini A, Dell’Osso B. Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology. Prog Neuropsychopharmacol Biol Psychiatry. 2013;5(42):63–70.CrossRefGoogle Scholar
  43. 43.
    Garver DL, Tamas RL, Holcomb JA. Elevated interleukin-6 in the cerebrospinal fluid of a previously delineated schizophrenia subtype. Neuropsychopharmacology. 2003;28:1515–20.PubMedCrossRefGoogle Scholar
  44. 44.
    Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70:663–71.PubMedCrossRefGoogle Scholar
  45. 45.
    Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokines alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63:801–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Nunes SO, Matsuo T, Kaminami MS, Watanabe MA, Reiche EM, Itano EN. An autoimmune or an inflammatory process in patients with schizophrenia, schizoaffective disorder, and their biological relatives. Schizophr Res. 2006;84:180–2.PubMedCrossRefGoogle Scholar
  47. 47.
    Ganguli R, Yang Z, Shurin G, Chengappa KN, Brar JS, Gubbi AV, Rabin BS. Serum interleukin-6 concentration in schizophrenia: elevation associated with duration of illness. Psychiatry Res. 1994;51:1–10.PubMedCrossRefGoogle Scholar
  48. 48.
    Naudin J, Mege JL, Azorin JM, Dassa D. Elevated circulating levels of IL-6 in schizophrenia: an overview. Eur Arch Psychiatry Clin Neurosci. 1996;20(3):269–73.Google Scholar
  49. 49.
    Müller N, Riedel M, Scheppach C, Brandstätter B, Sokullu S, Krampe K, et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry. 2002;159:1029–34.PubMedCrossRefGoogle Scholar
  50. 50.
    Gulden J, Reiter JF. Nuer-ons and neur-offs: regulators of neural induction in vertebrate embryos and embryonic cells. Hum Mol Genet. 2008;17:R60–6.CrossRefGoogle Scholar
  51. 51.
    Pinto L, Gotz M. Radial glial cell heterogeneity—the source of diverse progeny in the CNS. Prog Neurobiol. 2007;7:797–805.Google Scholar
  52. 52.
    Lee RH, Mills EA, Schwartz N, Bell MR, Deeg KE, Ruthazer ES, et al. Neurodevelopmental effects of chronic exposure to elevated levels of pro-inflammatory cytokines in a developing visual system. Neural Dev. 2010;5:2.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Deverman BE, Patterson P. Cytokines and CNS development. Neuron. 2009;64:61–77.PubMedCrossRefGoogle Scholar
  54. 54.
    Chklovskii DB. Exact solution for the optimal neuronal layout problem. Neural Comput. 2004;16(10):2067–78.PubMedCrossRefGoogle Scholar
  55. 55.
    Braun AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010;167:261–80.CrossRefGoogle Scholar
  56. 56.
    Patterson PH. Immune involvement in schizophrenia and autism. Etiology, pathology and animal models. Behav Brain Res. 2009;204:313–21.PubMedCrossRefGoogle Scholar
  57. 57.
    Bresee C, Rapaport MH. Persistently increased serum soluble interleukin-2 receptors in continuously ill patients with schizophrenia. Int J Neuropsychopharmacol. 2009;12(6):861–5.PubMedCrossRefGoogle Scholar
  58. 58.
    Kim YK, Kim L, Lee MS. Relationships between interleukins, neurotransmitters and psychopathology in drug-free male schizophrenics. Schizophr Res. 2000;44:165–75.PubMedCrossRefGoogle Scholar
  59. 59.
    Muller N, Schwarz M. Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res. 2006;10(2):131–48.PubMedCrossRefGoogle Scholar
  60. 60.
    Akiyama K. Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration. Schizophr Res. 1999;37:97–106.PubMedCrossRefGoogle Scholar
  61. 61.
    Waddington JL. Neurodynamics of abnormalities in cerebral metabolism and structure in schizophrenia. Schizophr Bull. 1993;19:55–69.PubMedCrossRefGoogle Scholar
  62. 62.
    Keshavan MS, Berger G, Zipursky RB, Wood SJ, Pantelis C. Neurobiology of early psychosis. Br J Psychiatry Suppl. 2005;48:s8–18.PubMedCrossRefGoogle Scholar
  63. 63.
    Suddath RL, Casanova MF, Goldberg TE, et al. Temporal lobe pathology in schizophrenia: a quantitative MRI study. Am J Psychiatry. 1989;146:464–72.PubMedGoogle Scholar
  64. 64.
    Breier A, Buchanan RW, Elkashef A, Munson RC, Kirkpatrick B, Gellad F. Brain morphology and schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures. Arch Gen Psychiatry. 1992;49:921–6.PubMedCrossRefGoogle Scholar
  65. 65.
    McCarley RW, Shenton ME, O’Donnell BF, Faux SF, Kikinis R, Nestor PG, Jolesz FA. Auditory P300 abnormalities and left posterior superior temporal gyrus volume reduction in schizophrenia. Arch Gen Psychiatry. 1993;50:190–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Falkai P, Bogerts B. Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci. 1986;236:154–61.PubMedCrossRefGoogle Scholar
  67. 67.
    Jakob H, Beckmann H. Prenatal developmental disturbances in the limbic allocortex in schizophrenics. J Neural Transm. 1986;65:303–26.PubMedCrossRefGoogle Scholar
  68. 68.
    Kikinis R, Shenton ME, Gerig G, Hokama H, Haimson J, O’Donnell BF, et al. Temporal lobe sulco-gyral pattern anomalies in schizophrenia: an in vivo MR three-dimensional surface rendering study. Neurosci Lett. 1994;182:7–12.PubMedCrossRefGoogle Scholar
  69. 69.
    Luchins DJ, Weinberger DR, Wyatt RJ. Schizophrenia and cerebral asymmetry detected by computed tomography. Am J Psychiatry. 1982;139:753–7.PubMedGoogle Scholar
  70. 70.
    Johnstone EC, Crow TJ, Frith CD, Husband J, Kreel L. Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet. 1976;2(7992):924–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Heckers S, Heinsen H, Heinsen Y, Beckmann H. Morphometry of the parahippocampal gyrus in schizophrenics and controls. Some anatomical considerations. J Neural Transm. 1990;80:151–5.CrossRefGoogle Scholar
  72. 72.
    Davis KL, Buchsbaum MS, Shihabuddin L, Spiegel-Cohen J, Metzger M, Frecska E, et al. Ventricular enlargement in poor-outcome schizophrenia. Biol Psychiatry. 1998;43:783–93.PubMedCrossRefGoogle Scholar
  73. 73.
    Nair TR, Christensen JD, Kingsbury SJ, Kumar NG, Terry WM, Garver DL. Progression of cerebroventricular enlargement and the subtyping of schizophrenia. Psychiatry Res. 1997;74(3):141–50.PubMedCrossRefGoogle Scholar
  74. 74.
    Illowsky BP, Juliano DM, Bigelow LB, Weinberger DR. Stability of CT scan findings in schizophrenia: results of an 8 year follow-up study. J Neurol Neurosurg Psychiatry. 1998;51:209–13.CrossRefGoogle Scholar
  75. 75.
    Nasrallah HA, Olson SC, McCalley-Whitters M, Chapman S, Jacoby CG. Cerebral ventricular enlargement in schizophrenia: a preliminary follow-up study. Arch Gen Psychiatry. 1986;43:157–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Sprooten E, Papmeyer M, Smyth AM, Vincenz D, Honold S, Conlon GA, et al. Cortical thickness in first-episode schizophrenia patients and individuals at high familial risk: a cross-sectional comparison. Schizophr Res. 2013;151:259–64. doi: 10.1016/j.schres.2013.09.024. pii: S0920-9964(13)00523-9.PubMedCrossRefGoogle Scholar
  77. 77.
    Olney JW, Newcomer JW, Farber NB. NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res. 1999;33:523–33.PubMedCrossRefGoogle Scholar
  78. 78.
    Farber NB, Hanslick J, Kirby C, McWilliams L, Olney JW. Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity. Neuropsychopharmacology. 1998;18:57–62.PubMedCrossRefGoogle Scholar
  79. 79.
    Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF. Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr Res. 2006;81:47–63.PubMedCrossRefGoogle Scholar
  80. 80.
    De Zio D, Giunta L, Corvaro M, Ferraro E, Cecconi F. Expanding roles of programmed cell death in mammalian neurodevelopment. Semin Cell Dev Biol. 2005;16:281–94.PubMedCrossRefGoogle Scholar
  81. 81.
    Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000;57:925–35.PubMedCrossRefGoogle Scholar
  82. 82.
    Susser E, Hoek HW, Brown A. Neurodevelopmental disorders after prenatal famine: the story of the Dutch Famine Study. Am J Epidemiol. 1998;147:213–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Altamura AC. A multidimensional (pharmacokinetic and clinical–biological) approach to neuroleptic response in schizophrenia. With particular reference to drug resistance. Schizophr Res. 1993;8(3):187–98.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2014

Authors and Affiliations

  • Bernardo Dell’Osso
    • 1
  • Gregorio Spagnolin
    • 1
  • Neva E. Suardi
    • 1
  • A. Carlo Altamura
    • 1
  1. 1.Department of PsychiatryUniversity of Milan, Fondazione IRCCS Cà Granda, Ospedale Maggiore PoliclinicoMilanItaly

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