title: In vivo evidence for cerebral bioenergetic abnormalities in schizophrenia measured using 31P magnetization transfer spectroscopy.
abstract: OBJECTIVE
  Abnormalities in neural activity and cerebral bioenergetics have been observed in schizophrenia (SZ). Further defining energy metabolism anomalies would provide crucial information about molecular mechanisms underlying SZ and may be valuable for developing novel treatment strategies.
  
  
  OBJECTIVE
  To investigate cerebral bioenergetics in SZ via measurement of creatine kinase activity using in vivo 31P magnetization transfer spectroscopy.
  
  
  METHODS
  Cross-sectional case-control study in the setting of clinical services and a brain imaging center of an academic psychiatric hospital. Twenty-six participants with chronic SZ (including a subgroup diagnosed as having schizoaffective disorder) and 26 age-matched and sex-matched healthy control subjects (25 usable magnetic resonance spectroscopy data sets from the latter).
  
  
  METHODS
  31P magnetization transfer spectroscopy.
  
  
  METHODS
  The primary outcome measure was the forward rate constant (k(f)) of the creatine kinase enzyme in the frontal lobe. We also collected independent measures of brain intracellular pH and steady-state metabolite ratios of high-energy phosphate-containing compounds (phosphocreatine and adenosine triphosphate [ATP]), inorganic phosphate, and the 2 membrane phospholipids phosphodiester and phosphomonoester.
  
  
  RESULTS
  A substantial (22%) and statistically significant (P = .003) reduction in creatine kinase kf was observed in SZ. In addition, intracellular pH was significantly reduced (7.00 in the SZ group vs 7.03 in the control group, P = .007) in this condition. The phosphocreatine to ATP ratio, inorganic phosphate to ATP ratio, and phosphomonoester to ATP ratio were not substantially altered in SZ, but a significant (P = .02) reduction was found in the phosphodiester to ATP ratio. The abnormalities were similar between SZ and schizoaffective disorder.
  
  
  CONCLUSIONS
  Using a novel 31P magnetization transfer magnetic resonance spectroscopy approach, we provide direct and compelling evidence for a specific bioenergetic abnormality in SZ. Reduced kf of the creatine kinase enzyme is consistent with an abnormality in storage and use of brain energy. The intracellular pH reduction suggests a relative increase in the contribution of glycolysis to ATP synthesis, providing convergent evidence for bioenergetic abnormalities in SZ. The similar phosphocreatine to ATP ratios in SZ and healthy controls suggest that the underlying bioenergetics abnormality is not associated with change in this metabolite ratio.
authors.affiliation: Psychotic Disorders Division, McLean Hospital, Belmont, Massachusetts2Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
authors.forename: Fei
authors.initials: F
authors.lastname: Du
authors.affiliation: Psychotic Disorders Division, McLean Hospital, Belmont, Massachusetts.
authors.forename: Alissa J
authors.initials: AJ
authors.lastname: Cooper
authors.affiliation: Psychotic Disorders Division, McLean Hospital, Belmont, Massachusetts.
authors.forename: Thida
authors.initials: T
authors.lastname: Thida
authors.affiliation: Psychotic Disorders Division, McLean Hospital, Belmont, Massachusetts.
authors.forename: Selma
authors.initials: S
authors.lastname: Sehovic
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts3McLean Imaging Center, McLean Hospital, Belmont, Massachusetts.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Lukas
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts4Shervert Frazier Research Institute, McLean Hospital, Belmont, Massachusetts.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Cohen
authors.affiliation: Department of Radiology, University of California, San Francisco.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Psychotic Disorders Division, McLean Hospital, Belmont, Massachusetts2Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
authors.forename: Dost
authors.initials: D
authors.lastname: Ongür
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000328:Adult; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry; D016022:Case-Control Studies; D003402:Creatine Kinase / Q000378:metabolism; D003430:Cross-Sectional Studies; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D010725:Phosphocreatine / Q000032:analysis; D010759:Phosphorus Isotopes / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D010759:Phosphorus Isotopes; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D003402:Creatine Kinase