title: Cerebral volumetric abnormalities in Neurofibromatosis type 1: associations with parent ratings of social and attention problems, executive dysfunction, and autistic mannerisms.
abstract: BACKGROUND
  Neurofibromatosis type 1 (NF1) is a single-gene neurodevelopmental disorder, in which social and cognitive problems are highly prevalent. Several commonly observed central nervous system (CNS) abnormalities in NF1 might underlie these social and cognitive problems. Cerebral volumetric abnormalities are among the most consistently observed CNS abnormalities in NF1. This study investigated whether differences were present between NF1 patients and healthy controls (HC) in volumetric measures of cortical and subcortical brain regions and whether differential associations existed for NF1 patients and HC between the volumetric measures and parent ratings of social skills, attention problems, social problems, autistic mannerisms, and executive dysfunction.
  
  
  METHODS
  Fifteen NF1 patients (mean age 12.9 years, SD 2.6) and 18 healthy controls (HC, mean age 13.8 years, SD 3.6) underwent 3 T MRI scanning. Segmentation of cortical gray and white matter, as well as volumetry of subcortical nuclei, was carried out. Voxel-based morphometry was performed to assess cortical gray matter density. Correlations were calculated, for NF1-patients and HC separately, between MRI parameters and scores on selected dimensions of the following behavior rating scales: the Social Skills Rating System, the Child Behavior Checklist, the Social Responsiveness Scale, the Behavior Rating Inventory of Executive Functioning, and the Dysexecutive Questionnaire.
  
  
  RESULTS
  After correction for age, sex, and intracranial volume, larger volumes of all subcortical regions were found in NF1 patients compared to controls. Patients further showed decreased gray matter density in midline regions of the frontal and parietal lobes and larger total white matter volume. Significantly more social and attention problems, more autistic mannerisms, and poorer executive functioning were reported for NF1 patients compared to HC. In NF1 patients, larger left putamen volume and larger total white matter volume were associated with more social problems and poorer executive functioning, larger right amygdala volume with poorer executive functioning and autistic mannerisms, and smaller precentral gyrus gray matter density was associated with more social problems. In controls, only significant negative correlations were observed: larger volumes (and greater gray matter density) were associated with better outcomes.
  
  
  CONCLUSIONS
  Widespread volumetric differences between patients and controls were found in cortical and subcortical brain regions. In NF1 patients but not HC, larger volumes were associated with poorer behavior ratings.
authors.affiliation: Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands.|Department of Clinical Child and Adolescent Studies, Leiden University, Leiden, The Netherlands.|Department of Clinical Child and Adolescent Studies-Neurodevelopmental Disorders, Faculty of Social Sciences, Leiden University, P.O. Box 9555, 2300 RB Leiden, The Netherlands.
authors.forename: Stephan Cj
authors.initials: SC
authors.lastname: Huijbregts
authors.affiliation: Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands.|Department of Clinical Child and Adolescent Studies, Leiden University, Leiden, The Netherlands.|Department of Neurology, Medical University of Graz, Graz, Austria.
authors.forename: Marisa
authors.initials: M
authors.lastname: Loitfelder
authors.affiliation: Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands.|Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.|Institute of Psychology, Leiden University, Leiden, The Netherlands.
authors.forename: Serge A
authors.initials: SA
authors.lastname: Rombouts
authors.affiliation: Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands.|Department of Clinical Child and Adolescent Studies, Leiden University, Leiden, The Netherlands.
authors.forename: Hanna
authors.initials: H
authors.lastname: Swaab
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.|Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Berit M
authors.initials: BM
authors.lastname: Verbist
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Enrico B
authors.initials: EB
authors.lastname: Arkink
authors.affiliation: Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands.|Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Van Buchem
authors.affiliation: Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands.|Department of Psychiatry and Psychotherapy, Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ilya M
authors.initials: IM
authors.lastname: Veer
keywords: Executive and social functioning; Gray matter; Magnetic resonance imaging; Neurofibromatosis type 1; Subcortical volume; Voxel-based morphometry