In vivo31P NMR spectroscopy shows an increase in glycerophosphorylcholine concentration without alterations in mitochondrial function in the prefrontal cortex of medicated schizophrenic patients at rest

The 31P NMR localised method was used to study the metabolism of phospholipid and high energy phosphate in the prefrontal cortex. The spectra were taken from patients with schizophrenia (11 males) receiving neuroleptic medication, and were compared to normal controls (15 males). Their spectral intensities were analysed using a non‐linear least‐squares method with a prior knowledge of the fixed chemical shifts and linewidths, leading to further resolution into resonances of glycerophosphorylethanolamine (GPE), glycerophosphorylcholine (GPC), phosphorylethanolamine (PE) and phosphorylcholine (PC). The metabolite concentrations were calculated referring to the spectral intensities of phosphate phantoms with known concentrations. T1 values of phantom and cerebrum were estimated from a series of localised inversion recovery spectra to correct for the signal saturation effects. The schizophrenic patients showed an increased concentration of GPC but not GPE, PE or PC. Furthermore, no difference was observed regarding the concentration of high‐energy phosphates such as phosphocreatine, inorganic phosphate and ATP. The patients did not show any differences in mitochondrial function such as phosphorylation potential and the ratio of the rate of ATP synthesis. Thus, an increase in GPC concentration in the prefrontal cortex could be characteristic of the pathophysiology of schizophrenia with mild negative symptoms.

[1]  J. Rotrosen,et al.  Elevated PLA2 activity in schizophrenics and other psychiatric patients , 1993, Biological Psychiatry.

[2]  S. Bluml,et al.  Proton‐Decoupled 31P Magnetic Resonance Spectroscopy Reveals Osmotic and Metabolic Disturbances in Human Hepatic Encephalopathy , 1998, Journal of neurochemistry.

[3]  T. Inubushi,et al.  Correlations of phosphomonoesters measured by phosphorus-31 magnetic resonance spectroscopy in the frontal lobes and negative symptoms in schizophrenia , 1994, Psychiatry Research: Neuroimaging.

[4]  D. Ingvar,et al.  Distribution of cerebral activity in chronic schizophrenia. , 1974, Lancet.

[5]  G B Matson,et al.  P-31 MR spectroscopy of normal human brain and brain tumors. , 1990, Radiology.

[6]  P. Williamson,et al.  Correlation of Negative Symptoms in Schizophrenia with Frontal Lobe Parameters on Magnetic Resonance Imaging , 1991, British Journal of Psychiatry.

[7]  Thomas E. Nichols,et al.  Anterior cingulate gyrus dysfunction and selective attention deficits in schizophrenia: [15O]H2O PET study during single-trial Stroop task performance. , 1997, The American journal of psychiatry.

[8]  D. Weinberger Implications of normal brain development for the pathogenesis of schizophrenia. , 1987, Archives of general psychiatry.

[9]  W. Gattaz,et al.  Increased platelet phospholipase A2 activity in schizophrenia , 1995, Schizophrenia Research.

[10]  Robert G. Shulman,et al.  Cerebral metabolism in hyper‐ and hypocarbia , 1985, Neurology.

[11]  R. Khis [Pathogenesis of schizophrenia]. , 1969, Vestnik Akademii meditsinskikh nauk SSSR.

[12]  T. Brown,et al.  Investigation of broad resonances in 31P NMR spectra of the human brain in vivo , 1994, NMR in biomedicine.

[13]  T. Brown,et al.  Free magnesium levels in normal human brain and brain tumors: 31P chemical-shift imaging measurements at 1.5 T. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[14]  P. Kinnunen,et al.  Increased serum phospholipase A2 activity in schizophrenia: a replication study. , 1990, Biological psychiatry.

[15]  P. Williamson,et al.  An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy. , 1995, Archives of general psychiatry.

[16]  J. Growdon,et al.  Evidence for a membrane defect in Alzheimer disease brain. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Heinrich Sauer,et al.  31Phosphorus magnetic resonance spectroscopy of the dorsolateral prefrontal region in schizophrenics—a study including 50 patients and 36 controls , 1998, Biological Psychiatry.

[18]  P. Williamson,et al.  Membrane phospholipid metabolism and schizophrenia: an in vivo 31P-MR spectroscopy study , 1994, Schizophrenia Research.

[19]  W. Gattaz,et al.  Increased platelet membrane lysophosphatidylcholine in schizophrenia , 1991, Biological Psychiatry.

[20]  G. Fein,et al.  31Phosphorus magnetic resonance spectroscopy of the frontal and parietal lobes in chronic schizophrenia , 1994, Biological Psychiatry.

[21]  S. Bluml,et al.  Quantitative proton-decoupled 31P MRS of the schizophrenic brain in vivo. , 1999, Journal of computer assisted tomography.

[22]  H A Krebs,et al.  Cytosolic phosphorylation potential. , 1979, The Journal of biological chemistry.

[23]  T. Goldberg,et al.  Further evidence for dementia of the prefrontal type in schizophrenia? A controlled study of teaching the Wisconsin Card Sorting Test. , 1987, Archives of general psychiatry.

[24]  C. Boesch,et al.  Determination of saturation factors in 31P NMR spectra of the developing human brain , 1993, Magnetic resonance in medicine.

[25]  Peter Boesiger,et al.  Assessment of absolute metabolite concentrations in human tissue by 31P MRS in vivo. Part I: Cerebrum, cerebellum, cerebral gray and white matter , 1994, Magnetic resonance in medicine.

[26]  Daniel R. Weinberger,et al.  Schizophrenia and the frontal lobe , 1988, Trends in Neurosciences.

[27]  T. Inubushi,et al.  Lateralized abnormality of high-energy phosphate and bilateral reduction of phosphomonoester measured by phosphorus-31 magnetic resonance spectroscopy of the frontal lobes in schizophrenia , 1995, Psychiatry Research: Neuroimaging.

[28]  J. John Mann,et al.  In vivo neurochemistry of the brain in schizophrenia as revealed by magnetic resonance spectroscopy , 1998, Biological Psychiatry.

[29]  S. Rauch,et al.  Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance , 2000, Biological Psychiatry.

[30]  S Nioka,et al.  Multiple controls of oxidative metabolism in living tissues as studied by phosphorus magnetic resonance. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Matcheri S Keshavan,et al.  Magnetic resonance spectroscopy in schizophrenia: methodological issues and findings–part I , 2000, Biological Psychiatry.

[32]  R. Shulman,et al.  31P magnetization transfer studies of creatine kinase kinetics in living rabbit brain , 1987, Magnetic resonance in medicine.

[33]  M. Egan,et al.  Selective relationship between prefrontal N-acetylaspartate measures and negative symptoms in schizophrenia. , 2000, The American journal of psychiatry.

[34]  S Nioka,et al.  Relationship between intracellular pH and energy metabolism in dog brain as measured by 31P-NMR. , 1987, Journal of applied physiology.

[35]  M. Bárány,et al.  INCREASED GLYCEROL-3-PHOSPHORYLCHOUNE IN POST-MORTEM ALZHEIMER'S BRAIN , 1985, The Lancet.

[36]  L. Nowak,et al.  Electrophysiological studies of NMDA receptors , 1987, Trends in Neurosciences.

[37]  Karl J. Friston,et al.  Patterns of Cerebral Blood Flow in Schizophrenia , 1992, British Journal of Psychiatry.

[38]  P. Williamson,et al.  Localized phosphorus 31 magnetic resonance spectroscopy in chronic schizophrenic patients and normal controls. , 1991, Archives of general psychiatry.

[39]  S. Whatley,et al.  Mitochondrial involvement in schizophrenia and other functional psychoses , 1996, Neurochemical Research.

[40]  R. Roth,et al.  Phencyclidine Model of Frontal Cortical Dysfunction in Nonhuman Primates , 2000 .

[41]  P R Luyten,et al.  Experimental approaches to image localized human 31P NMR spectroscopy , 1989, Magnetic resonance in medicine.

[42]  G. Duncan,et al.  An integrated view of pathophysiological models of schizophrenia , 1999, Brain Research Reviews.

[43]  Jeffrey C. Erlich,et al.  Increased phospholipid breakdown in schizophrenia. Evidence for the involvement of a calcium-independent phospholipase A2. , 1997, Archives of general psychiatry.

[44]  B. Toone,et al.  Changes in regional cerebral blood flow due to cognitive activation among patients with schizophrenia. , 2000, The British journal of psychiatry : the journal of mental science.

[45]  M. Keshavan,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. , 1991, Archives of general psychiatry.

[46]  T. Sigmundsson,et al.  Frontal lobe N-acetylaspartate correlates with psychopathology in schizophrenia: a proton magnetic resonance spectroscopy study , 2003, Schizophrenia Research.

[47]  Ravi S. Menon,et al.  Region-specific changes in phospholipid metabolism in chronic, medicated schizophrenia , 2002, British Journal of Psychiatry.

[48]  N C Andreasen,et al.  Negative symptoms in schizophrenia , 1982 .

[49]  T. Asakura,et al.  Study of chronic schizophrenics using 31P magnetic resonance chemical shift imaging , 1992, Acta psychiatrica Scandinavica.

[50]  C. Hardy,et al.  AIDS dementia complex: brain high-energy phosphate metabolite deficits. , 1990, Radiology.

[51]  G. Matson,et al.  Quantitation of in vivo phosphorus metabolites in human brain with magnetic resonance spectroscopic imaging (MRSI). , 1993, Magnetic resonance imaging.

[52]  L. Cavelier,et al.  Decreased cytochrome-c oxidase activity and lack of age-related accumulation of mitochondrial DNA deletions in the brains of schizophrenics. , 1995, Genomics.

[53]  P. Williamson,et al.  A 1H-decoupled 31P chemical shift imaging study of medicated schizophrenic patients and healthy controls , 1999, Biological Psychiatry.

[54]  L. Horrocks,et al.  Phospholipase A2 and Its Role in Brain Tissue , 1997, Journal of neurochemistry.

[55]  O. Shirakawa,et al.  Opposite changes in phosphoinositide-specific phospholipase C immunoreactivity in the left prefrontal and superior temporal cortex of patients with chronic schizophrenia , 1999, Biological Psychiatry.

[56]  H. Fukuzako,et al.  Haloperidol Improves Membrane Phospholipid Abnormalities in Temporal Lobes of Schizophrenic Patients , 1999, Neuropsychopharmacology.

[57]  T. Inubushi,et al.  Multiple regression analysis of relationship between frontal lobe phosphorus metabolism and clinical symptoms in patients with schizophrenia , 1997, Psychiatry Research: Neuroimaging.

[58]  Mathias Schreckenberger,et al.  Correlation of positive symptoms exclusively to hyperperfusion or hypoperfusion of cerebral cortex in never-treated schizophrenics , 1997, The Lancet.

[59]  T. Mosher,et al.  Simultaneous determination of intracellular magnesium and pH from the three 31P NMR Chemical shifts of ATP. , 1993, Analytical biochemistry.

[60]  S. Kish,et al.  Differential alteration of phospholipase A2 activities in brain of patients with schizophrenia , 1999, Brain Research.

[61]  P. Renshaw,et al.  Functional magnetic resonance imaging of schizophrenic patients and comparison subjects during word production. , 1996, The American journal of psychiatry.

[62]  M. Weiner,et al.  Noninvasive quantitation of phosphorus metabolites in human tissue by NMR spectroscopy , 1989 .