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Neurodevelopmental and Neurodegenerative Alterations in the Pathophysiology of Schizophrenia: Focus on Neuro-Immuno-Inflammation

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Abstract

Schizophrenia is a severely impairing psychiatric disorder with a precocious onset, accounting for a conspicuous burden of disability worldwide. With respect to the etiology of schizophrenia, as for other major psychoses, the gene–environment interaction seems to be the most accredited model. In particular, alterations in the immune system have been repeatedly reported, involving both the unspecific and specific pathways of the immune system and suggesting that inflammatory/autoimmune processes might play an important role in the development of the disorder. Relating to this hypothesis, an imbalance in the inflammatory cytokines has been associated with schizophrenia and, more broadly, alterations in the inflammatory and immune systems seem to be already present in the early stages of the disorder. Such phenomenon could be responsible of specific neurodevelopmental abnormalities, which identify the roots of the disorder during brain development, with consequences that do not become clinically evident until adolescence or early adulthood. On the other hand, longitudinal cohort studies on schizophrenic patients demonstrated a progressive loss of grey matter, more evident in the frontal and temporal lobes of the brain. These two perspectives, the neurodevelopmental and neurodegenerative one, are thought to coexist in the complex and still unravelled etiology of schizophrenia, with studies supporting both of them. This chapter aims at providing the state of the art in the field.

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References

  1. Jones PB, Buckley PF. Schizophrenia. Amsterdam: Elsevier; 2006.

    Google Scholar 

  2. Gillberg C, Steffenburg S. Outcome and prognostic factors in infantile autism and similar conditions: a population-based study of 46 cases followed through puberty. J Autism Dev Disord. 1987;17:273–87.

    Article  CAS  PubMed  Google Scholar 

  3. Thomsen PH. Schizophrenia with childhood and adolescent onset: a nationwide register-based study. Acta Psychiatr Scand. 1996;94:187–93.

    Article  CAS  PubMed  Google Scholar 

  4. Amminger GP, Harris MG, Conus P, et al. Treated incidence of first episode psychosis in the catchment area of EPPIC between 1997 and 2000. Acta Psychiatr Scand. 2006;114:337–45.

    Article  CAS  PubMed  Google Scholar 

  5. British Psychological Society. Psychosis and schizophrenia in children and young people: recognition and management. Leicester: British Psychological Society; 2013.

    Google Scholar 

  6. Hollis C. Adult outcomes of child and adolescent onset schizophrenia: diagnostic stability and predictive validity. Am J Psychiatry. 2000;157:1652–9.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Altamura AC, Pozzoli S, Fiorentini A, Dell’Osso B. Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;42:63–70.

    Article  CAS  Google Scholar 

  9. Walker E, Lewine RJ. Prediction of adult-onset schizophrenia from childhood home movies of the patients. Am J Psychiatry. 1990;147(8):1052–6.

    Article  CAS  PubMed  Google Scholar 

  10. Csernansky JG. Neurodegeneration in schizophrenia: evidence from in vivo neuroimaging studies. Sci World J. 2007;7:135–43.

    Article  Google Scholar 

  11. Rund BR. Is schizophrenia a neurodegenerative disorder? Nord J Psychiatry. 2009;63(3):196–201.

    Article  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  PubMed  Google Scholar 

  15. Gourion D, Gourevitch R, Leprovost JB, Olié H lôo JP, Krebs MO. Neurodevelopmental hypothesis in schizophrenia. L’Encéphale. 2004;30:109–18.

    Article  CAS  PubMed  Google Scholar 

  16. Rapoport JL, Addington AM, Frangou S, Psych MR. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry. 2005;10:434–49.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Buckley P. The clinical stigmata of aberrant neurodevelopment in schizophrenia. J Nerv Ment Dis. 1998;186(2):79–86.

    Article  CAS  PubMed  Google Scholar 

  19. Keshavan MS, Murray RM. Neurodevelopment and adult psychopathology. Cambridge: Cambridge University Press; 1997.

    Google Scholar 

  20. Aas M, Dazzan P, Mondelli V, Melle I, Murray RM, Pariante CM. A systematic review of cognitive function in first-episode psychosis, including a discussion on childhood trauma, stress, and inflammation. Front Psych. 2014;4:182.

    Google Scholar 

  21. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44:660–9.

    Article  CAS  PubMed  Google Scholar 

  22. Fatemi SH, Folsom TD. The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull. 2009;35(3):528–48.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci. 2002;25:409–32.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. Meltzer HY, Fatemi SH. Schizophrenia and other psychotic disorders. In: Ebert MH, Loosen PT, Nurcombe B, editors. Current diagnosis and treatment in psychiatry. Norwalk, CT: Appleton and Lange; 2000. p. 260–77.

    Google Scholar 

  26. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 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.

    Article  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sullivan PF, Eaves LJ, Kendler KS, Neale MC. Genetic case–control association studies in neuropsychiatry. Arch Gen Psychiatry. 2001;58:1015–24.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  PubMed  Google Scholar 

  31. 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.

    Article  PubMed  Google Scholar 

  32. Schmidt-Kastner R, van Os J, Steinbusch H WM, Schmitz C. Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. Schizophr Res. 2006;84:253–71.

    Article  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lewis DA. Retroviruses and the pathogenesis of schizophrenia. Proc Natl Acad Sci U S A. 2001;94:4293–4.

    Article  Google Scholar 

  35. Jones P, Cannon M. The new epidemiology of schizophrenia. Psychiatr Clin North Am. 1998;21(1):1–25.

    Article  CAS  PubMed  Google Scholar 

  36. Mednick SA, Machon RA, Huttunen MO, Bonett D. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry. 1988;45:189–92.

    Article  CAS  PubMed  Google Scholar 

  37. Torrey EF, Rawlings R, Waldman IN. Schizophrenic births and viral diseases in two states. Schizophr Res. 1988;1:73–7.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    CAS  PubMed  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. 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.

    Article  PubMed  Google Scholar 

  42. 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.

    Article  CAS  PubMed  Google Scholar 

  43. Brown AS. Prenatal infection as a risk factor for schizophrenia. Schizophr Bull. 2006;32:200–2.

    Article  PubMed  PubMed Central  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. Jablensky A. Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Psychiatry Clin Neurosci. 2000;250(6):274–85.

    Article  CAS  PubMed  Google Scholar 

  46. 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.

    Article  PubMed  Google Scholar 

  47. Altamura AC, Pozzoli S, Fiorentini A, Dell'Osso B. Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;5(42):63–70.

    Article  Google Scholar 

  48. Garver DL, Tamas RL, Holcomb JA. Elevated interleukin-6 in the cerebrospinal fluid of a previously delineated schizophrenia subtype. Neuropsychopharmacology. 2003;28:1515–20.

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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.

    Article  CAS  PubMed  Google Scholar 

  51. 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.

    Article  PubMed  Google Scholar 

  52. 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.

    Article  CAS  PubMed  Google Scholar 

  53. 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.

    CAS  Google Scholar 

  54. 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.

    Article  PubMed  Google Scholar 

  55. Gulden J, Reiter JF. Neur-ons and neur-offs: regulators of neural induction in vertebrate embryos and embryonic cells. Hum Mol Genet. 2008;17:R60–6.

    Article  Google Scholar 

  56. Pinto L, Gotz M. Radial glial cell heterogeneity—the source of diverse progeny in the CNS. Prog Neurobiol. 2007;7:797–805.

    Google Scholar 

  57. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Deverman BE, Patterson P. Cytokines and CNS development. Neuron. 2009;64:61–77.

    Article  CAS  PubMed  Google Scholar 

  59. Chklovskii DB. Exact solution for the optimal neuronal layout problem. Neural Comput. 2004;16(10):2067–78.

    Article  PubMed  Google Scholar 

  60. Braun AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010;167:261–80.

    Article  Google Scholar 

  61. Patterson PH. Immune involvement in schizophrenia and autism. Etiology, pathology and animal models. Behav Brain Res. 2009;204:313–21.

    Article  CAS  PubMed  Google Scholar 

  62. 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.

    Article  CAS  PubMed  Google Scholar 

  63. Kim YK, Kim L, Lee MS. Relationships between interleukins, neurotransmitters and psychopathology in drug-free male schizophrenics. Schizophr Res. 2000;44:165–75.

    Article  CAS  PubMed  Google Scholar 

  64. Muller N, Schwarz M. Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res. 2006;10(2):131–48.

    Article  CAS  PubMed  Google Scholar 

  65. 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.

    Article  CAS  PubMed  Google Scholar 

  66. Waddington JL. Neurodynamics of abnormalities in cerebral metabolism and structure in schizophrenia. Schizophr Bull. 1993;19:55–69.

    Article  CAS  PubMed  Google Scholar 

  67. Keshavan MS, Berger G, Zipursky RB, Wood SJ, Pantelis C. Neurobiology of early psychosis. Br J Psychiatry Suppl. 2005;48:s8–18.

    Article  PubMed  Google Scholar 

  68. Suddath RL, Casanova MF, Goldberg TE, et al. Temporal lobe pathology in schizophrenia: a quantitative MRI study. Am J Psychiatry. 1989;146:464–72.

    Article  CAS  PubMed  Google Scholar 

  69. 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.

    Article  CAS  PubMed  Google Scholar 

  70. 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.

    Article  CAS  PubMed  Google Scholar 

  71. Falkai P, Bogerts B. Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci. 1986;236:154–61.

    Article  CAS  PubMed  Google Scholar 

  72. Jakob H, Beckmann H. Prenatal developmental disturbances in the limbic allocortex in schizophrenics. J Neural Transm. 1986;65:303–26.

    Article  CAS  PubMed  Google Scholar 

  73. 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.

    Article  CAS  PubMed  Google Scholar 

  74. Luchins DJ, Weinberger DR, Wyatt RJ. Schizophrenia and cerebral asymmetry detected by computed tomography. Am J Psychiatry. 1982;139:753–7.

    Article  CAS  PubMed  Google Scholar 

  75. 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.

    Article  CAS  PubMed  Google Scholar 

  76. 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.

    Article  CAS  Google Scholar 

  77. 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.

    Article  CAS  PubMed  Google Scholar 

  78. 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.

    Article  CAS  PubMed  Google Scholar 

  79. 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.

    Article  Google Scholar 

  80. 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.

    Article  CAS  PubMed  Google Scholar 

  81. 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(1–3):259–264. pii: S0920-9964(13)00523-9 [Epub ahead of print]. https://doi.org/10.1016/j.schres.2013.09.024.

    Article  PubMed  Google Scholar 

  82. Olney JW, Newcomer JW, Farber NB. NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res. 1999;33:523–33.

    Article  CAS  PubMed  Google Scholar 

  83. 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.

    Article  CAS  PubMed  Google Scholar 

  84. Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF. Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr Res. 2006;81:47–63.

    Article  PubMed  Google Scholar 

  85. De Zio D, Giunta L, Corvaro M, Ferraro E, Cecconi F. Expanding roles of programmed cell death in mammalian neurodevelopment. Sem cell developmental. Biol. 2005;16:281–94.

    Google Scholar 

  86. Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000;57:925–35.

    Article  CAS  PubMed  Google Scholar 

  87. 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.

    Article  CAS  PubMed  Google Scholar 

  88. 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.

    Article  CAS  PubMed  Google Scholar 

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Dell’Osso, B., Carlotta Palazzo, M., Carlo Altamura, A. (2018). Neurodevelopmental and Neurodegenerative Alterations in the Pathophysiology of Schizophrenia: Focus on Neuro-Immuno-Inflammation. In: Galimberti, D., Scarpini, E. (eds) Neurodegenerative Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-72938-1_16

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