title: White matter abnormalities in 22q11.2 deletion syndrome: preliminary associations with the Nogo-66 receptor gene and symptoms of psychosis.
abstract: BACKGROUND
  This study utilized diffusion tensor imaging (DTI) to analyze white matter tractography in the anterior limb of the internal capsule (ALIC), fornix, and uncinate fasciculus (UF) of individuals with 22q11.2 deletion syndrome and controls. Aberrations in these tracts have been previously associated with schizophrenia. With up to 25% of individuals with 22q11.2DS developing schizophrenia in adulthood, we hypothesized reduction in structural integrity of these tracts, including an association with prodromal symptoms of psychosis. We further predicted an association between allelic variation in a functional polymorphism of the Nogo-66 receptor gene and 22q11.2DS white matter integrity.
  
  
  METHODS
  Tractography was conducted using fiber assignment by streamline tracking algorithm in DTI Studio. Subjects were genotyped for the rs701428 SNP of the Nogo-66 receptor gene, and assessed for presence of prodromal symptoms.
  
  
  RESULTS
  We found significant group differences between 22q11.2DS and controls in DTI metrics for all three tracts. DTI metrics of ALIC and UF were associated with prodromal symptoms in 22q11.2DS. Further, ALIC DTI metrics were associated with allelic variation of the rs701428 SNP of the Nogo-66 receptor gene in 22q11.2DS.
  
  
  CONCLUSIONS
  Alterations in DTI metrics suggest white matter microstructural anomalies of the ALIC, fornix, and UF in 22q11.2DS. Structural differences in ALIC appear to be associated with the Nogo-66 receptor gene, which has been linked to myelin-mediated axonal growth inhibition. Moreover, the association between psychosis symptoms and ALIC and UF metrics suggests that the Nogo-66 receptor gene may represent a susceptibility gene for psychosis through its disruption of white matter microstructure and myelin-associated axonal growth.
authors: Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse, NY, United States.
authors: Matthew D
authors: MD
authors: Perlstein
authors: Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse, NY, United States.
authors: Moeed R
authors: MR
authors: Chohan
authors: Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse, NY, United States.
authors: Ioana L
authors: IL
authors: Coman
authors: Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse, NY, United States; Department of Psychology, Syracuse University, Syracuse, NY, United States.
authors: Kevin M
authors: KM
authors: Antshel
authors: Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse, NY, United States.
authors: Wanda P
authors: WP
authors: Fremont
authors: Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse, NY, United States.
authors: Matthew H
authors: MH
authors: Gnirke
authors: Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
authors: Zora
authors: Z
authors: Kikinis
authors: Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse, NY, United States; Department of Neuroscience and Physiology, State University of New York at Upstate Medical University, Syracuse, NY, United States.
authors: Frank A
authors: FA
authors: Middleton
authors: Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse, NY, United States.
authors: Petya D
authors: PD
authors: Radoeva
authors: Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; Clinical Neuroscience Division, Laboratory of Neuroscience, Department of Psychiatry, VA Boston Healthcare System, Harvard Medical School, Boston, MA, United States.
authors: Martha E
authors: ME
authors: Shenton
authors: Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse, NY, United States. Electronic address: katesw@upstate.edu.
authors: Wendy R
authors: WR
authors: Kates
mesh_terms: D000293:Adolescent; D002540:Cerebral Cortex / Q000473:pathology; D004062:DiGeorge Syndrome / Q000150:complications / Q000235:genetics*; D056324:Diffusion Tensor Imaging; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D005787:Gene Frequency; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D056784:Leukoencephalopathies / Q000209:etiology / Q000235:genetics*; D008297:Male; D015999:Multivariate Analysis; D009185:Myelin Proteins / Q000235:genetics*; D009483:Neuropsychological Tests; D000070816:Nogo Receptor 1; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; C486580:RTN4R protein, human; D011956:Receptors, Cell Surface
keywords: Anterior limb of internal capsule; Diffusion tensor imaging (DTI); RTN4R gene; Uncinate fasciculus; Velo-cardio-facial syndrome; rs701428