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Insulin-Like Growth Factors

Neurobiological Regulators of Brain Growth in Autism?

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Book cover Autism

Part of the book series: Current Clinical Neurology ((CCNEU))

Abstract

In autism, disruption of normal neurobiological mechanisms is found, but it is not known which specific developmentally important molecules might be involved in this disorder. Increased cerebral volume or brain weight is found across studies in autism. Pathological brain growth and premature developmental arrest are suggested to be restricted to the first years of life. We found a correlation between insulin-like growth factor-1 (IGF-1) concentrations and head growth in children with autism but not in the controls. At an early stage of infantile autism, the cerebrospinal fluid (CSF) concentration of IGF-1 was lower than in the comparison group, but not in older children. This suggests a disruption of normal neurobiological mechanisms at an early age. Furthermore, we also found normal CSF nerve growth factor (NGF) in autism, but low NGF and normal IGF-1 in Rett syndrome (RS). There is evidence that IGF-1 is important for cerebellar development, and low CSF IGF-1 concentrations may lead to cerebellar abnormalities. In autism, almost all neuropathological studies have reported decreased numbers of Purkinje cells in the cerebellum. NGF is important for cholinergic neurons of the forebrain, and the cholinergic system is affected in RS. Therefore, autism and RS could be distinguished by their different levels of the two growth factors. This is in agreement with the different morphological and neurochemical findings in the two syndromes. In autism, there seems to be a disruption of normal neurobiological mechanisms due to “premature growth without guidance.” The data suggest that the IGF system may play an important role in the pathophysiology of autism. Autism is a behaviorally defined condition in which social interaction and reciprocal communication are disturbed. Aberrant behavioral expression in children with autism is usually noticed by the parents, typically between 12 and 24 months of age. The diagnosis is based on clinical criteria. The etiopathogenesis is unknown. Disruption of normal neurobiological mechanisms has been found, but it is not known what specific developmentally important molecules might be involved in this disorder. Nelson et al. 2001 [1] have suggested that in autism there is a relationship between abnormal concentrations of growth factors and abnormal patterns of brain growth. Knowledge of the important roles of neurotrophic factors in relation to the development of the brain is growing.

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References

  1. Nelson K, Grether J, Groen L, Dambrosia J, Dickens B, Jelliffe L, Hansen R, Phillips T. Neuropeptides and neurotrophins in neonatal blood of children with autism and mental retardation. Ann Neurol 2001; 49: 597–606.

    Article  PubMed  CAS  Google Scholar 

  2. Leventhal P, Russel J, Feldman E. IGFs and the nervous system. In: Rosenfeld R, Roberts C eds: The IGF System: Molecular Biology, Physiology, and Clinical Application. Totawa, NJ: Humana Press, 1999: 425–455.

    Google Scholar 

  3. Mozell R, McMorris F. Insulin-like growth factor I stimulates oligodendrocyte development and myelination in rat brain aggregate culture. J Neurosci 1999; 30: 382–390.

    Google Scholar 

  4. Laudiero L, Aloe L, Levi-Montalcini R, Buttnelli C, Schiffre D, Offesen S, Otten U. Multiple sclerosis patients express increased levels of beta-nerve growth factor in the cerebrospinal fluid. Neurosci Lett 1992; 147; 9–12.

    Article  PubMed  CAS  Google Scholar 

  5. Xie K, Wang T, Olafsson P, Mizuno K, Lu B. Activity-dependent expression of NT-3 muscle cells in culture: Implications in the development of neuromuscular junctions. J Neurosci 1997; 17; 2947–2958.

    PubMed  CAS  Google Scholar 

  6. Torres-Aleman I, Villaba M, Nieto-Bona M. Insulin-like growth factor-1 modulation of cerebellar cell populations is developmentally stage-dependent and mediated by specific intracellular pathways. Neuroscience 1998; 83: 321–334.

    Article  PubMed  CAS  Google Scholar 

  7. Yuen E, Mobley W. Therapeutic potential of neurotrophic factors for neurological disorders. Ann Neurol 1996; 40: 346–354.

    Article  PubMed  CAS  Google Scholar 

  8. Dore S, Kar S, Quirion R. Rediscovering an old friend, IGF-1: Potential use in the treatment of neurodegenerative diseases. Trends Neurosci 1997; 20; 326–331.

    Article  PubMed  CAS  Google Scholar 

  9. Russo V, Gluckman E, Feldman L, Werther G. The insulin-like growth factor system and its pleiotropic functions in brain. Endocr. Rev. 2005; 26: 916–943.

    Article  PubMed  CAS  Google Scholar 

  10. D`Mello S, Borodezt K, Soltoff S. Insulin-like growth factor and potassium depolarisation maintain neuronal survival by distinct pathways: Possible involvement of Pl 3-kinase in IGF-1 signalling. J Neurosci 1997; 17: 1548–1560.

    CAS  Google Scholar 

  11. Bondy C, Werner H, Roberts C, LeRoith D. Cellular patterns of type-1 insulin-like growth factor receptor gene expression during maturation of the rat brain: Comparison of the insulin-like growth factors I and II. Neuroscience 1992; 46: 909–923.

    Article  PubMed  CAS  Google Scholar 

  12. McKelvie P, Rosen K, Kinney H, Villa-Komaroff L. Insulin-like growth factor II expression in the developing brain. J Neuropathol Exp Neurol 1992; 51: 464–471.

    Article  PubMed  CAS  Google Scholar 

  13. Han V. Is the central nervous system a target for growth hormone and insulin-like growth factors? Acta Paediatr 1995; 411 (Suppl):3–8.

    Article  CAS  Google Scholar 

  14. Barres B, Hart I, Coles H. et al. Cell death and control of cell survival in oligodendrocyte lineage. Cell 1992; 70: 31–42.

    Article  PubMed  CAS  Google Scholar 

  15. Beck K, Powell-Braxton L, Widmer H, Valverd J, Hefti F. Igf1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons. Neuron 1995; 14: 717–730.

    Article  PubMed  CAS  Google Scholar 

  16. Schoenle E, Haselbacher G, Briner J, Janzer R, Gammeltoff S, Humbel R, Prader A. Elevated concentration of IGF II in brain tissue from an infant with macrocephaly. J Pediats 1986; 108: 737–740.

    Google Scholar 

  17. Rotwein P, Burges S, Milbrandt J, Krause J. Differential expression of insulin-like growth factor genes in rat central nervous system. Proc Natl Acad Sci USA 1988; 85: 265–269.

    Article  PubMed  CAS  Google Scholar 

  18. Torres-Aleman I, Barrios W, Liedo A, Bericiano J. The insulin-like growth factor I system in cerebellar degeneration. Ann Neurol 1996; 39: 335–342.

    Article  PubMed  CAS  Google Scholar 

  19. Werther G, Russo V, Baker N, Buler G. The role of insulin-like growth factor system in developing brain. Horm Res 1998; 49: 37–40.

    Article  PubMed  CAS  Google Scholar 

  20. Fukudome Y, Tabata T, Miyoshi T et al. Insulin-like growth factor-1 as a promoting factor for cerebellar Purkinje cell development. Eur J Neurosci 2003; 17: 2006–2016.

    Article  PubMed  Google Scholar 

  21. Riikonen R, Somer M, Turpeinen U. Low insulin-like growth factor (IGF-1) in cerebrospinal fluid of children with progressive encephalopathy, hypsarrhythmia, and optic atrophy (PEHO) syndrome and cerebellar degeneration. Epilepsia 1999; 40: 1642–1648.

    Article  PubMed  CAS  Google Scholar 

  22. Riikonen R, Vanhanen S-L, Tyynelä J, et al. CSF insulin-like growth factor-1 in infantile neuronal ceroid lipofuscinosis. Neurology 2000; 54: 1828–1832.

    PubMed  CAS  Google Scholar 

  23. Piven J, Saliba K, Bailey J, Arndt S. An MRI study of autism. The cerebellum revisted. Neurology 1997; 49: 546–551.

    PubMed  CAS  Google Scholar 

  24. Courchesne E, Karns C, Davis H, Ziccardi R, Carper R, Tigue Z, Chisum H, Moses P, Pierce K, Lord C, Lincoln A, Pizzo S, Schreibman L, Haas R, Akshoomoff N, Courchesne R. Unusual brain growth patterns in early life in patients with autistic disorder. An MRI Study. Neurology 2001; 57: 243–254.

    Google Scholar 

  25. Sparks B, Friedman S, Shaw D, Aylward E, Echelard D, Artru A, Maravilla K, Giedd J, Munson J, Dawson G, Dager S. Brain structural abnormalities in young children with autism spectrum disorder. Neurology 2002; 59: 184–192.

    PubMed  CAS  Google Scholar 

  26. Herbert M, Ziegler A, Makris N, Filipek P, Filipek P, Kemper T, Normandin J, Sanders H, Kennedy D, Caviness V. Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol 2004; 55: 530–540.

    Article  PubMed  Google Scholar 

  27. Davincovitch M, Patterson B, Gartside P. Head circumference measurements in children with autism. J Child Neurol 1996; 11: 389–393.

    Article  Google Scholar 

  28. Redcay E, Courchesene E. When is the brain enlarged in autism? A meta-analysis of all brain size reports. Biol Psychaitry 2005; 58: 1–9.

    Article  Google Scholar 

  29. Rodier P, Ingram J, Tisdale B et al. Embryological origin for autism; developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol 1996; 370: 247–261.

    Article  PubMed  CAS  Google Scholar 

  30. Bauman M, Kemper T. Histoanatomic observations of the brain in early infantile autism. Neurology 1985; 35: 866–874.

    PubMed  CAS  Google Scholar 

  31. Rapin I, Katzman R. Neurobiology of autism. Ann Neurol 1998; 43: 7–14.

    Article  PubMed  CAS  Google Scholar 

  32. Casanova M, Buxhoeveden D, Switala A, Roy E. Minicolumnar pathology in autism. Neurology 2002; 58: 428–432.

    PubMed  Google Scholar 

  33. Courchesne E, Pierce K. Brain overgrowth in autism during a critical time in development: Implications for frontal pyramidal neuron and interneuron development and connectivity. Int J Dev Neurosci 2005; 23: 153–170.

    Article  PubMed  Google Scholar 

  34. Vargas D, Nascimbene C, Krishnan C, Zimmerman A, Pardo C. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005; 57: 67–81.

    Article  PubMed  CAS  Google Scholar 

  35. Riikonen R, Makkonen I, Turpeinen U, Kuikka J, Kokki H. Cerebrospinal fluid insulin-like growth factors IGF-1 and IGF-2 in infantile autism. Dev Med Child Neurol 2006; 48: 751–755.

    Article  PubMed  Google Scholar 

  36. Townsend J, Courchesne E, Covington J, Westerfield M, Harris N, Lyden P, Lowren T, Press G. Spatial attention deficits in patients with acquired or developmental cerebellar abnormality. J Neurosci 1999; 19: 5632–5563.

    PubMed  CAS  Google Scholar 

  37. Allen G, Muller R, Courchesne E. Cerebellar function in autism: functional magnetic resonance image activation during a simple motor task. Biol Psychiatry 2004; 56: 269–278.

    Article  PubMed  Google Scholar 

  38. Chugani D, Muzik O, Behen M, Rothermel R, Janisse J, Lee J, Chugani H. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 1999; 45: 287–295.

    Article  PubMed  CAS  Google Scholar 

  39. Makkonen I, Riikonen R, Kokki H, Airaksinen M, Kuikka J. Serotonin and dopamine transporter binding in children and adolescents with autism. Dev Med Child Neurol 2008 August, in press.

    Google Scholar 

  40. Castren E. Neurotrophic effects of antidepressant drugs. Curr Opin Pharmacol 2004; 4: 58–64.

    Google Scholar 

  41. Lambert H, Weiss E, Lauder J. Activation of 5-HT receptors that stimulate the adenylyl cyclase pathway positively regulates IGF-1 in cultured craniofacial mesenchymal cells. Dev Neurosci 2001; 23: 70–77.

    Article  PubMed  CAS  Google Scholar 

  42. DeLong G, Rich C, Burch S. Fluoxetine response in children with autistic spectrum disorders: Correlation with familial major affective disorder and intellectual achievement. Dev Med Child Neurol 2002; 44: 652–659.

    Article  PubMed  Google Scholar 

  43. Hollander E, Phillips A, Chaplin W, Zagursky K, Novotny S, Wasserman S, Iyengar R. A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism. Neuropsychopharmacology 2005; 30; 582–589.

    Article  PubMed  CAS  Google Scholar 

  44. Johnston M, Jeon O, Pevsner J, Blue M, Naidu S. Neurobiology of Rett syndrome: A genetic disorder of synapse development. Brain Dev 2001; 23 (Suppl):1S206–213.

    Google Scholar 

  45. Lappalainen R, Lindholm D, Riikonen R. Low levels of nerve growth factor in cerebrospinal fluid of children with Rett syndrome. J Child Neurol 1996; 11: 296–300.

    Article  PubMed  CAS  Google Scholar 

  46. Riikonen R, Vanhala R. Levels of cerebrospinal fluid nerve-growth factor differ in infantile autism and Rett syndrome. Dev Med Child Neurol 1999; 41: 148–152.

    Google Scholar 

  47. Vanhala R, Turpeinen U, Riikonen R. Insulin-like growth factor-1 in cerebrospinal fluid and serum in Rett syndrome. J Child Neurol 2000; 15: 797–802.

    Article  PubMed  CAS  Google Scholar 

  48. Vanhala R, Turpeinen U, Riikonen R. Low levels of insulin-like growth factor-1 in cerebrospinal fluid in children with autism. Dev Med Child Neurol 2001; 43: 614–616.

    Article  PubMed  CAS  Google Scholar 

  49. Riikonen R. Neurotrophic factors in the pathogenesis of Rett syndrome. J Child Neurol 2003; 18: 693–697.

    Article  PubMed  Google Scholar 

  50. Mills L, Hediger M, Molloy C, Chrousos G, Manning-Courtney P, Yu K, Brasington M, England L. Elevated levels of growth-related hormones in autism and autism spectrum disorders. Clin Endocrinol 2007; 67: 230–237.

    Google Scholar 

  51. Armstrong D, Dunn J, Antalffy B, Trivedi R. Selective dendritic alterations in the cortex of Rett syndrome. J Neuropathol Exp Neurol 1995; 54; 195–201.

    Article  PubMed  CAS  Google Scholar 

  52. Armstrong D, Dunn J, Schultz R et al. Organ growth in Rett syndrome; a post-mortem examination and analysis. Paediatr Neurol 1999; 20: 125–129.

    Article  CAS  Google Scholar 

  53. Cook E, Courchesne R, Lord C et al. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997; 2: 247–250.

    Article  PubMed  Google Scholar 

  54. Lipani J, Battacharjee M, Corey D, Lee D. Reduced nerve growth factor in Rett syndrome D postmortem brain tissue. J Neuropathol Exp Neurol 2000; 59; 889–895.

    Google Scholar 

  55. Wenk G, Naidu S, Casanova M, Kitt C, Moser H. Altered neurochemical markers in Rett `s syndrome. Neurology 1991; 41: 1753–1756.

    PubMed  CAS  Google Scholar 

  56. Coleman P, Romano J, Lapham I, Simon W. Cell counts in cerebral cortex in autistic patient. J Autism Dev Disord 1985; 15: 245–255.

    Article  PubMed  CAS  Google Scholar 

  57. Anderson G, Freedman D, Cohen D et al. Whole blood serotonin in autistic and normal subjects. J Child Psychol Psychiatry 1987; 28: 885–900.

    Article  PubMed  CAS  Google Scholar 

  58. Lappalainen R, Liewenthal K, Sainio K, Riikonen R. Brain perfusion SPECT and EEG findings in Rett syndrome. Acta Paediatr Scand 1997; 95: 44–50.

    CAS  Google Scholar 

  59. Raymond G, Bauman M, Kemper T. Hippocampus in autism: A Golgi analysis. Acta Neuropathol (Berl) 1996; 91: 117–119.

    Article  CAS  Google Scholar 

  60. Uvebrandt P, Bjure J, Sixt R et al. Regional cerebral blood flow: SPECT as a tool for localization of brain dysfunction. In: Hagberg B, (ed.) Rett Syndrome – Clinical and Biological Aspects. London: Mac Keith Press, 1993; 80–85.

    Google Scholar 

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Riikonen, R. (2008). Insulin-Like Growth Factors. In: Autism. Current Clinical Neurology. Humana Press. https://doi.org/10.1007/978-1-60327-489-0_10

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  • DOI: https://doi.org/10.1007/978-1-60327-489-0_10

  • Publisher Name: Humana Press

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