title: Prefrontal neuronal integrity predicts symptoms and cognition in schizophrenia and is sensitive to genetic heterogeneity.
abstract: Schizophrenia is a genetically complex syndrome with substantial inter-subject variability in multiple domains. Person-specific measures to resolve its heterogeneity could focus on the variability in prefrontal integrity, which this study indexed as relative rostralization within the anterior cingulate cortex (ACC). Twenty-two schizophrenia cases and 11 controls underwent rigorous diagnostic procedures, symptom assessments (PANSS, Deficit Syndrome Scale) and intelligence testing. All underwent multivoxel MRSI at 3T to measure concentrations of the neuronal-specific biomarker N-acetylaspartate (NAA) in all of the voxels of the ACC. The concentrations of NAA were separately calculated and then compared across the rostral and caudal subregions to generate a rostralization ratio, which was examined with respect to the study measures and to which cases carried a missense coding polymorphism in PTPRG, SCL39A13, TGM5, NTRK1 or ARMS/KIDINS220. Rostralization significantly differed between cases and controls (χ(2)=18.40, p<.0001). In cases, it predicted verbal intelligence (r=.469, p=.043) and trait negative symptoms (diminished emotional range (r=-.624, p=.010); curbed interests, r=-.558, p=.025). Rostralization was similar to controls for missense coding variants in TGM5 and was significantly greater than controls for the PTPRG variant carrier. This is the first study examining the utility of MRS metrics in describing pathological features at both group and person-specific levels. Rostralization predicted core illness features and differed based on which signaling genes were disrupted. While future studies in larger populations are needed, ACC rostralization appears to be a promising measure to reduce the heterogeneity of schizophrenia for genetic research and selecting cases for treatment studies.
authors.affiliation: Institute for Social and Psychiatric Initiatives (InSPIRES), Department of Psychiatry, New York University School of Medicine, NY, NY, USA. Electronic address: dolores.malaspina@nyumc.org.
authors.forename: Dolores
authors.initials: D
authors.lastname: Malaspina
authors.affiliation: Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University, New York, NY 10016, USA.
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Kranz
authors.affiliation: Genome Technology Center, New York University School of Medicine, NY, NY, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.affiliation: Department of Psychiatry, New York University School of Medicine, NY, NY, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Harroch
authors.affiliation: Institute for Social and Psychiatric Initiatives (InSPIRES), Department of Psychiatry, New York University School of Medicine, NY, NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Mazgaj
authors.affiliation: Institute for Social and Psychiatric Initiatives (InSPIRES), Department of Psychiatry, New York University School of Medicine, NY, NY, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Rothman
authors.affiliation: Institute for Social and Psychiatric Initiatives (InSPIRES), Department of Psychiatry, New York University School of Medicine, NY, NY, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Berns
authors.affiliation: Institute for Social and Psychiatric Initiatives (InSPIRES), Department of Psychiatry, New York University School of Medicine, NY, NY, USA.
authors.forename: Sumya
authors.initials: S
authors.lastname: Hasan
authors.affiliation: University at Buffalo, Department of Psychiatry, Buffalo, NY, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Antonius
authors.affiliation: New York State Psychiatric Institute, Division of Clinical Phenomenology, 1051 Riverside Drive, NY, NY, USA; Columbia University, Department of Psychiatry, NY, NY, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Goetz
authors.affiliation: Center for Advanced Imaging Innovation and Research (CAI2R), Department of Radiology, New York University School of Medicine, NY, NY, USA; Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, NY, NY, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Lazar
authors.affiliation: Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University, New York, NY 10016, USA.
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.affiliation: Center for Advanced Imaging Innovation and Research (CAI2R), Department of Radiology, New York University School of Medicine, NY, NY, USA; Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, NY, NY, USA.
authors.forename: Oded
authors.initials: O
authors.lastname: Gonen
mesh_terms: D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D003071:Cognition / Q000502:physiology*; D005260:Female; D006801:Humans; D007361:Intelligence Tests; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics; D011110:Polymorphism, Genetic; D017397:Prefrontal Cortex / Q000378:metabolism*; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*; D012565:Schizophrenic Psychology
chemical_list: C482591:KIDINS220 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D001224:Aspartic Acid; C000179:N-acetylaspartate; C516850:PTPRG protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5
keywords: Anterior cingulate cortex; Genotype; Magnetic resonance spectroscopy imaging; N-acetylaspartate; Rostralization; Schizophrenia