title: Widespread reductions of white matter integrity in patients with long-term remission of Cushing's disease.
abstract: BACKGROUND
  Hypercortisolism leads to various physical, psychological and cognitive symptoms, which may partly persist after the treatment of Cushing's disease. The aim of the present study was to investigate abnormalities in white matter integrity in patients with long-term remission of Cushing's disease, and their relation with psychological symptoms, cognitive impairment and clinical characteristics.
  
  
  METHODS
  In patients with long-term remission of Cushing's disease (n = 22) and matched healthy controls (n = 22) we examined fractional anisotropy (FA) values of white matter in a region-of-interest (ROI; bilateral cingulate cingulum, bilateral hippocampal cingulum, bilateral uncinate fasciculus and corpus callosum) and the whole brain, using 3 T diffusion tensor imaging (DTI) and a tract-based spatial statistics (TBSS) approach. Psychological and cognitive functioning were assessed with validated questionnaires and clinical severity was assessed using the Cushing's syndrome Severity Index.
  
  
  RESULTS
  The ROI analysis showed FA reductions in all of the hypothesized regions, with the exception of the bilateral hippocampal cingulum, in patients when compared to controls. The exploratory whole brain analysis showed multiple regions with lower FA values throughout the brain. Patients reported more apathy (p = .003) and more depressive symptoms (p < .001), whereas depression symptom severity in the patient group was negatively associated with FA in the left uncinate fasciculus (p < 0.05). Post-hoc analyses showed increased radial and mean diffusivity in the patient group.
  
  
  CONCLUSIONS
  Patients with a history of endogenous hypercortisolism in present remission show widespread changes of white matter integrity in the brain, with abnormalities in the integrity of the uncinate fasciculus being related to the severity of depressive symptoms, suggesting persistent structural effects of hypercortisolism.
authors.affiliation: Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands ; Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
authors.forename: Steven J A
authors.initials: SJ
authors.lastname: van der Werff
authors.affiliation: Leiden Institute for Brain and Cognition, Leiden, The Netherlands ; Department of Endocrinology and Metabolic Diseases and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cornelie D
authors.initials: CD
authors.lastname: Andela
authors.affiliation: Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands ; Leiden Institute for Brain and Cognition, Leiden, The Netherlands ; Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
authors.forename: J
authors.initials: J
authors.lastname: Nienke Pannekoek
authors.affiliation: Leiden Institute for Brain and Cognition, Leiden, The Netherlands ; Department of Endocrinology and Metabolic Diseases and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Onno C
authors.initials: OC
authors.lastname: Meijer
authors.affiliation: Leiden Institute for Brain and Cognition, 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, Leiden, The Netherlands ; Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands ; Institute of Psychology, Leiden University, The Netherlands.
authors.forename: Serge A R B
authors.initials: SA
authors.lastname: Rombouts
authors.affiliation: Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Roos C
authors.initials: RC
authors.lastname: van der Mast
authors.affiliation: Leiden Institute for Brain and Cognition, Leiden, The Netherlands ; Department of Endocrinology and Metabolic Diseases and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nienke R
authors.initials: NR
authors.lastname: Biermasz
authors.affiliation: Leiden Institute for Brain and Cognition, Leiden, The Netherlands ; Department of Endocrinology and Metabolic Diseases and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Pereira
authors.affiliation: Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands ; Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
authors.forename: Nic J A
authors.initials: NJ
authors.lastname: van der Wee
mesh_terms: D000293:Adolescent; D000328:Adult; D016880:Anisotropy; D003072:Cognition Disorders / Q000209:etiology; D003480:Cushing Syndrome / Q000150:complications / Q000473:pathology*; D056324:Diffusion Tensor Imaging; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders / Q000209:etiology; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D011594:Psychometrics; D012008:Recurrence; D012720:Severity of Illness Index; D013223:Statistics as Topic; D066127:White Matter / Q000473:pathology*; D055815:Young Adult
keywords: Cingulum; Corpus callosum; Cortisol; Cushing's disease; Diffusion tensor imaging; Hypercortisolism; Uncinate fasciculus