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Prefrontal membrane phospholipid metabolism of child and adolescent offspring at risk for schizophrenia or schizoaffective disorder: an in vivo 31P MRS study

Abstract

In vivo 31P magnetic resonance spectroscopy (31P MRS) studies have shown abnormal membrane phospholipid metabolism in the prefrontal cortex (PF) in the early course of schizophrenia. It is unclear, however, whether these alterations also represent premorbid risk indicators in schizophrenia. In this paper, we report in vivo 31P MRS data on children and adolescents at high risk (HR) for schizophrenia. In vivo 31P MRS studies of the PF were conducted on 16 nonpsychotic HR offspring of parents with schizophrenia or schizoaffective disorder, and 37 age-matched healthy comparison (HC) subjects. While 11 of the HR subjects had evidence of Axis I psychopathology (HR-P), five HR subjects had none (HR-NP). We quantified the freely mobile phosphomonoester (PME) and phosphodiester (PDE) levels reflecting membrane phospholipid precursors and breakdown products, respectively, and the relatively broad signal underlying PDE and PME peaks, comprised of less mobile molecules with PDE and PME moieties (eg, synaptic vesicles and phosphorylated proteins). Compared to HC subjects, HR subjects had reductions in freely mobile PME; the differences were accounted for mainly by the HR-P subjects. Additionally, HR-P subjects showed increases in the broad signal underlying the PME and PDE peaks in the PF. To conclude, these data demonstrate new evidence for decreased synthesis of membrane phospholipids and possibly altered content or the molecular environment of synaptic vesicles and/or phosphoproteins in the PF of young offspring at risk for schizophrenia. Follow-up studies are needed to examine the predictive value of these measures for future emergence of schizophrenia in at-risk individuals.

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References

  1. Waddington JL . Schizophrenia: developmental neuroscience and pathobiology. Lancet 1993; 341: 531–536.

    Article  CAS  Google Scholar 

  2. Weinberger DR . Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44: 660–669.

    Article  CAS  Google Scholar 

  3. Murray RM, Lewis SW . Is schizophrenia a neurodevelopmental disorder? [editorial]. Br Med J (Clin Res Ed) 1987; 295: 681–682.

    Article  CAS  Google Scholar 

  4. Weinberger DR . From neuropathology to neurodevelopment. Lancet 1995; 346: 552–557.

    Article  CAS  Google Scholar 

  5. Feinberg I . Schizophrenia and late maturational brain changes in man. Psychopharmacol Bull 1982; 18: 29–31.

    Google Scholar 

  6. Hoffman RE, McGlashan TH . Parallel distributed processing and the emergence of schizophrenic symptoms. Schizophr Bull 1993; 19: 119–140.

    Article  CAS  Google Scholar 

  7. Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan DB, Tretta MG et al. Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry 1991; 48: 563–568.

    Article  CAS  Google Scholar 

  8. Keshavan MS, Anderson S, Pettegrew JW . Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? J Psychiatr Res 1994; 28: 239–265.

    Article  CAS  Google Scholar 

  9. Stanley JA, Pettegrew JW, Keshavan MS . Magnetic resonance spectroscopy in schizophrenia: methodological issues and findings —part I. Biol Psychiatry 2000; 48: 357–368.

    Article  CAS  Google Scholar 

  10. Geddes JW, Pandey GN, Keller JN, Pettegrew JW . Elevated phosphocholine and phosphatidyl choline following rat entorhinal cortex lesions. Neurobiol Aging 1997; 18: 305–308.

    Article  CAS  Google Scholar 

  11. Stanley JA, Pettegrew JW . Postprocessing method to segregate and quantify the broad components underlying the phosphodiester spectral region of in vivo (31)P brain spectra. Magn Reson Med 2001; 45: 390–396.

    Article  CAS  Google Scholar 

  12. Pettegrew JW, Panchalingam K, Klunk WE, McClure RJ, Muenz LR . Alterations of cerebral metabolism in probable Alzheimer's disease: a preliminary study. Neurobiol Aging 1994; 15: 117–132.

    Article  CAS  Google Scholar 

  13. McNamara R, Arias-Mendoza F, Brown TR . Investigation of broad resonances in 31P NMR spectra of the human brain in vivo. NMR Biomed 1994; 7: 237–242.

    Article  CAS  Google Scholar 

  14. Murphy EJ, Rajagopalan B, Brindle KM, Radda GK . Phospholipid bilayer contribution to 31P NMR spectra in vivo. Magn Reson Med 1989; 12: 282–289.

    Article  CAS  Google Scholar 

  15. Kilby PM, Allis JL, Radda GK . Spin–spin relaxation of the phosphodiester resonance in the 31P NMR spectrum of human brain. The determination of the concentrations of phosphodiester components. FEBS Lett 1990; 272: 163–165.

    Article  CAS  Google Scholar 

  16. Kilby PM, Bolas NM, Radda GK . 31P-NMR study of brain phospholipid structures in vivo. Biochim Biophys Acta 1991; 1085: 257–264.

    Article  CAS  Google Scholar 

  17. Burri R, Lazeyras F, Aue WP, Straehl P, Bigler P, Althaus U et al. Correlation between 31P NMR phosphomonoester and biochemically determined phosphorylethanolamine and phosphatidylethanolamine during development of the rat brain. Dev Neurosci 1988; 10: 213–221.

    Article  CAS  Google Scholar 

  18. Pettegrew JW, Panchalingam K, Withers G, McKeag D, Strychor S . Changes in brain energy and phospholipid metabolism during development and aging in the Fischer 344 rat. J Neuropathol Exp Neurol 1990; 49: 237–249.

    Article  CAS  Google Scholar 

  19. Buchli R, Martin E, Boesiger P, Rumpel H . Developmental changes of phosphorus metabolite concentrations in the human brain: a 31P magnetic resonance spectroscopy study in vivo. Pediatr Res 1994; 35: 431–435.

    Article  CAS  Google Scholar 

  20. Hanaoka S, Takashima S, Morooka K . Study of the maturation of the child's brain using 31P-MRS. Pediatr Neurol 1998; 18: 305–310.

    Article  CAS  Google Scholar 

  21. Bluml S, Seymour KJ, Ross BD . Developmental changes in choline- and ethanolamine-containing compounds measured with proton-decoupled (31)P MRS in in vivo human brain. Magn Reson Med 1999; 42: 643–654.

    Article  CAS  Google Scholar 

  22. Stanley JA, Minshew NJ, Keshavan MS, Panchalingam K, McClure RJ, Pettegrew JW . Assessing the age-dependent profile in the frontal and centrum semiovale regions of healthy normal controls using in vivo 31P MRS [Abstract]. Proceedings of the Eighth Annual Meeting of the International Society of Magnetic Resonance in Medicine. ISMRM: Berkeley, CA, 2000, p 1130.

    Google Scholar 

  23. Williamson P, Drost D, Stanley J, Carr T, Morrison S, Merskey H . Localized phosphorus 31 magnetic resonance spectroscopy in chronic schizophrenia patients and normal controls. Arch Gen Psychiatry 1991; 48: 578.

    Article  CAS  Google Scholar 

  24. Stanley JA, Williamson PC, Drost DJ, Carr TJ, Rylett RJ, Morrison-Stewart S et al. Membrane phospholipid metabolism and schizophrenia: an in vivo 31P-MR spectroscopy study. Schizophr Res 1994; 13: 209–215.

    Article  CAS  Google Scholar 

  25. Stanley JA, Williamson PC, Drost DJ, Carr TJ, Rylett RJ, Malla A et al. An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy. Arch Gen Psychiatry 1995; 52: 399–406.

    Article  CAS  Google Scholar 

  26. Fukuzako H, Fukuzako T, Hashiguchi T, Kodama S, Takigawa M, Fujimoto T . Changes in levels of phosphorous metabolites in temporal lobes of drug-naive schizophrenic patients. Am J Psychiatry 1999: 156: 1205–1208.

    CAS  PubMed  Google Scholar 

  27. Deicken RF, Merrin EL, Floyd TC, Weiner MW . Correlation between left frontal phospholipids and Wisconsin Card Sort Test performance in schizophrenia. Schizophr Res 1995; 14: 177–181.

    Article  CAS  Google Scholar 

  28. Shioiri T, Someya T, Murashita J, Kato T, Hamakawa H, Fujii K et al. Multiple regression analysis of relationship between frontal lobe phosphorus metabolism and clinical symptoms in patients with schizophrenia. Psychiatry Res 1997; 76: 113–122.

    Article  CAS  Google Scholar 

  29. Keshavan MS, Stanley JA, Pettegrew JW . Magnetic resonance spectroscopy in schizophrenia: methodogical issues and findings—Part II. Biol Psychiatry 2000; 48: 369–380.

    Article  CAS  Google Scholar 

  30. McGlashan TH . Duration of untreated psychosis in first-episode schizophrenia: marker or determinant of course? [see comments]. Biol Psychiatry 1999; 46: 899–907.

    Article  CAS  Google Scholar 

  31. Klemm S, Rzanny R, Riehemann S, Volz HP, Schmidt B, Gerhard UJ et al. Cerebral phosphate metabolism in first-degree relatives of patients with schizophrenia. Am J Psychiatry 2001; 158: 958–960.

    Article  CAS  Google Scholar 

  32. Amminger GP, Pape S, Rock D, Roberts SA, Squires-Wheeler E, Kestenbaum C et al. The New York high-risk project: comorbidity for axis I disorders is preceded by childhood behavioral disturbance. J Nerv Ment Dis 2000; 188: 751–756.

    Article  CAS  Google Scholar 

  33. Cornblatt B, Obuchowski M, Roberts S, Pollack S, Erlenmeyer-Kimling L . Cognitive and behavioral precursors of schizophrenia. Dev Psychopathol 1999; 11: 487–508.

    Article  CAS  Google Scholar 

  34. First MD, Spitzer RL, Gibbon M, Williams JBW . Structured Clinical Interview for DSM-IV Axis I Disorders—patient edition. Biometrics Research Department, NYSPI: New York, 1995.

    Google Scholar 

  35. Ambrosini PJ, Metz C, Prabucki K . Videotape reliability of the third revised edition of the K-SADS. J Am Acad Child Adolesc Psychiatry 1989; 28: 723–728.

    Article  CAS  Google Scholar 

  36. Isaac G, Schnall MD, Lenkinski RE, Vogele K . A design for a double-tuned birdcage coil for use in an integrated MRI/MRS examination. J Magn Reson 1990; 89: 41–50.

    Google Scholar 

  37. Lim KO, Pauly J, Webb P, Hurd R, Macovski A . Short TE phosphorus spectroscopy using a spin-echo pulse. Magn Reson Med 1994; 32: 98–103.

    Article  CAS  Google Scholar 

  38. Marquardt DW . An algorithm for least-squares estimation of non-linear parameters. Soc. Ind. Appl. Math. J 1963; 11: 431–441.

    Article  Google Scholar 

  39. Zeger SL, Liang KY . Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986; 42: 121–130.

    Article  CAS  Google Scholar 

  40. Kato T, Shioiri T, Murashita J, Hamakawa H, Inubushi T, Takahashi S . Lateralized abnormality of high-energy phosphate and bilateral reduction of phosphomonoester measured by phosphorus-31 magnetic resonance spectroscopy of the frontal lobes in schizophrenia. Psychiatry Res 1995; 61: 151–160.

    Article  CAS  Google Scholar 

  41. Potwarka JJ, Drost DJ, Williamson PC, Carr T, Canaran G, Rylett WJ et al. A 1H-decoupled 31P chemical shift imaging study of medicated schizophrenic patients and healthy controls. Biol Psychiatry 1999; 45: 687–693.

    Article  CAS  Google Scholar 

  42. Stanley JA, Keshavan MS, Panchalingam K, McClure RJ, Pettegrew JW . Membrane phospholipid metabolite alterations in prefrontal and basal ganglia regions in schizophrenia: an in vivo 31P and 1H MRSI study. Proceedings of the 9th Annual meeting of the International Society of Magnetic Resonance in Medicine. ISMRM: Berkeley, CA, 2001.

    Google Scholar 

  43. Zipursky RB, Lambe EK, Kapur S, Mikulis DJ . Cerebral gray matter volume deficits in first episode psychosis. Arch Gen Psychiatry 1998; 55: 540–546.

    Article  CAS  Google Scholar 

  44. Goldstein JM, Goodman JM, Seidman LJ, Kennedy DN, Makris N, Lee H et al. Cortical abnormalities in schizophrenia identified by structural magnetic resonance imaging. Arch Gen Psychiatry 1999; 56: 537–447.

    Article  CAS  Google Scholar 

  45. Sanfilipo M, Lafargue T, Rusinek H, Arena L, Loneragan C, Lautin A et al. Volumetric measure of the frontal and temporal lobe regions in schizophrenia: relationship to negative symptoms. Arch Gen Psychiatry 2000; 57: 471–480.

    Article  CAS  Google Scholar 

  46. Rajkowska G, Selemon LD, Goldman-Rakic PS . Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry 1998; 55: 215–224.

    Article  CAS  Google Scholar 

  47. Pierri JN, Chaudry AS, Woo TU, Lewis DA . Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. Am J Psychiatry 1999; 156: 1709–1719.

    CAS  PubMed  Google Scholar 

  48. Selemon LD, Goldman-Rakic PS . The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 1999; 45: 17–25.

    Article  CAS  Google Scholar 

  49. Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P . Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 2000; 28: 53–67.

    Article  CAS  Google Scholar 

  50. Stevens JR . Abnormal reinnervation as a basis for schizophrenia: a hypothesis. Arch Gen Psychiatry 1992; 49: 238–243.

    Article  CAS  Google Scholar 

  51. Glantz LA, Lewis DA . Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia: regional and diagnostic specificity. Arch Gen Psychiatry 1997; 54: 943–952.

    Article  CAS  Google Scholar 

  52. Gabriel SM, Haroutunian V, Powchik P, Honer WG, Davidson M, Davies P et al. Increased concentrations of presynaptic proteins in the cingulate cortex of subjects with schizophrenia. Arch Gen Psychiatry 1997; 54: 559–566.

    Article  CAS  Google Scholar 

  53. Ong WY, Garey LJ . Ultrastructural features of biopsied temporopolar cortex (area 38) in a case of schizophrenia. Schizophr Res 1993; 10: 15–27.

    Article  CAS  Google Scholar 

  54. Yao JK, van Kammen DP . Red blood cell membrane dynamics in schizophrenia. I. Membrane fluidity. Schizophr Res 1994; 11: 209–216.

    Article  CAS  Google Scholar 

  55. Azorin JM, Samuelian-Massat C, Jeanningros R, Widmer J, Tissot R . Erythrocyte membrane transports of monoamine precursor amino acids in schizophrenia. Encephale 1991; 17: 83–86.

    CAS  PubMed  Google Scholar 

  56. Erlenmeyer-Kimling L, Squires-Wheeler E, Hilldoff-Adamo UH, Bassett AS, Cornblatt BA, Kestenbaum CJ et al. The New York High-Risk Project. Psychoses and cluster A personality disorders in offspring of schizophrenic parents at 23 years of follow-up. Arch Gen Psychiatry 1995; 52: 857–865.

    Article  CAS  Google Scholar 

  57. Parnas J, Cannon TD, Jacobsen B, Schulsinger H, Schulsinger F, Mednick SA . Lifetime DSM-III-R diagnostic outcomes in the offspring of schizophrenic mothers. Results from the Copenhagen High-Risk Study. Arch Gen Psychiatry 1993; 50: 707–714.

    Article  CAS  Google Scholar 

  58. Gottesman II . Schizophrenia Genesis: The Origins of Madness. WH Freeman and Company: New York, 1991.

    Google Scholar 

  59. Tsuang MT, Stone WS, Faraone SV . Toward reformulating the diagnosis of schizophrenia. Am J Psychiatry 2000; 157: 1041–1050.

    Article  CAS  Google Scholar 

  60. Lewine RR, Watt NF, Prentky RA, Fryer JH . Childhood behaviour in schizophrenia, personality disorder, depression, and neurosis. Br J Psychiatry 1978; 133: 347–357.

    Article  CAS  Google Scholar 

  61. Baum KM, Walker EF . Childhood behavioral precursors of adult symptom dimensions in schizophrenia. Schizophr Res 1995; 16: 111–120.

    Article  CAS  Google Scholar 

  62. Parnas J, Schulsinger F, Teasdale W, Schulsinger H, Feldman PM, Mednick SA . Perinatal complications and clinical outcome. Br J Psychiatry 1982; 140: 416–420.

    Article  CAS  Google Scholar 

  63. Amminger GP, Pape S, Rock D, Roberts SA, Ott SL, Squires-Wheeler E et al. Relationship between childhood behavioral disturbance and later schizophrenia in the New York High-Risk Project. Am J Psychiatry 1999; 156: 525–530.

    CAS  PubMed  Google Scholar 

  64. Erlenmeyer-Kimling L, Rock D, Roberts SA, Janal M, Kestenbaum C, Cornblatt B et al. Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychoses: the New York High-Risk Project [in process citation]. Am J Psychiatry 2000; 157: 1416–1422.

    Article  CAS  Google Scholar 

  65. Cornblatt B, Obuchowski M, Schnur D, O'Brien JD . Hillside study of risk and early detection in schizophrenia. Br J Psychiatry Suppl 1998; 172: 26–32.

    Article  CAS  Google Scholar 

  66. Frank Y, Pavlakis SG . Brain imaging in neurobehavioral disorders. Pediatr Neurol 2001; 25: 278–287.

    Article  CAS  Google Scholar 

  67. Stanley JA . In vivo magnetic resonance spectroscopy and its application to neuropsychiatric disorders. Can J Psychiatry 2002; 47: 315–326.

    Article  Google Scholar 

  68. Keshavan MS, Dick E, Mankowski I, Harenski K, Montrose DM, Diwadkar V et al. Decreased left amygdala and hippocampal volumes in young offspring at risk for schizophrenia. Schizophr Res 2002; 58: 173–183.

    Article  Google Scholar 

  69. Jensen JE, Al-Semaan YM, Williamson PC, Neufeld RW, Menon RW, Schaeffer B et al. Region-specific changes in phospholipid metabolism in chronic, medicated schizophrenia: (31)P-MRS study at 4.0 Tesla. Br J Psychiatry 2002; 180: 39–44.

    Article  Google Scholar 

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Acknowledgements

This work was supported in part by NIMH Grants MH45203, MH45156, MH01180, MH01433 and a NARSAD Established Investigator Award (MSK); NS #33355 (NJM) and MH #46614 (JWP). We gratefully acknowledge the help of Melissa Zeigler and Mandayam Sujata in clinical assessments, and Germaine Miller and Dennis McKeag in postprocessing of data. We are also grateful for the time-domain fitting software package, which was provided by Dr Drost's laboratory, University of Western Ontario, London, Ontario, Canada.

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Keshavan, M., Stanley, J., Montrose, D. et al. Prefrontal membrane phospholipid metabolism of child and adolescent offspring at risk for schizophrenia or schizoaffective disorder: an in vivo 31P MRS study. Mol Psychiatry 8, 316–323 (2003). https://doi.org/10.1038/sj.mp.4001325

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