title: Dentate gyrus-cornu ammonis (CA) 4 volume is decreased and associated with depressive episodes and lipid peroxidation in bipolar II disorder: Longitudinal and cross-sectional analyses.
abstract: Reduced dentate gyrus volume and increased oxidative stress have emerged as potential pathophysiological mechanisms in bipolar disorder. However, the relationship between dentate gyrus volume and peripheral oxidative stress markers remains unknown. Here, we examined dentate gyrus-cornu ammonis (CA) 4 volume longitudinally in patients with bipolar II disorder (BD-II) and healthy controls and investigated whether BD-II is associated with elevated peripheral levels of oxidative stress.
  
  
  
  We acquired high-resolution structural 3T-magnetic resonance imaging (MRI) images and quantified hippocampal subfield volumes using an automated segmentation algorithm in individuals with BD-II (n=29) and controls (n=33). The participants were scanned twice, at study inclusion and on average 2.4 years later. In addition, we measured peripheral levels of two lipid peroxidation markers (4-hydroxy-2-nonenal [4-HNE] and lipid hydroperoxides [LPH]).
  
  
  
  First, we demonstrated that the automated hippocampal subfield segmentation technique employed in this work reliably measured dentate gyrus-CA4 volume. Second, we found a decreased left dentate gyrus-CA4 volume in patients and that a larger number of depressive episodes between T1 and T2 predicted greater volume decline. Finally, we showed that 4-HNE was elevated in BD-II and that 4-HNE was negatively associated with left and right dentate gyrus-CA4 volumes in patients.
  
  
  
  These results are consistent with a role for the dentate gyrus in the pathophysiology of bipolar disorder and suggest that depressive episodes and elevated oxidative stress might contribute to hippocampal volume decreases. In addition, these findings provide further support for the hypothesis that peripheral lipid peroxidation markers may reflect brain alterations in bipolar disorders.
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway.|Norwegian Centre for Mental Disorders Research, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Torbjørn
authors.initials: T
authors.lastname: Elvsåshagen
authors.affiliation: Department of Psychiatry, Santa Maria's University Hospital, University of Lisbon, Lisbon, Portugal.|Department of Pharmacology and Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Pedro
authors.initials: P
authors.lastname: Zuzarte
authors.affiliation: Norwegian Centre for Mental Disorders Research, Oslo University Hospital, Oslo, Norway.|Department of Psychology, University of Oslo, Oslo, Norway.
authors.forename: Lars T
authors.initials: LT
authors.lastname: Westlye
authors.affiliation: Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway.
authors.forename: Erlend
authors.initials: E
authors.lastname: Bøen
authors.affiliation: Department of Oncology, Oslo University Hospital, Oslo, Norway.
authors.forename: Dag
authors.initials: D
authors.lastname: Josefsen
authors.affiliation: Section of Psychosocial Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.|Department of Behavioural Sciences in Medicine, University of Oslo, Oslo, Norway.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Boye
authors.affiliation: The Intervention Centre, Oslo University Hospital, Oslo, Norway.
authors.forename: Per K
authors.initials: PK
authors.lastname: Hol
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Research and Education, Oslo University Hospital, Oslo, Norway.
authors.forename: Ulrik F
authors.initials: UF
authors.lastname: Malt
authors.affiliation: Department of Pharmacology and Psychiatry, University of Toronto, Toronto, ON, Canada.|Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: L Trevor
authors.initials: LT
authors.lastname: Young
authors.affiliation: Department of Pharmacology and Psychiatry, University of Toronto, Toronto, ON, Canada.|Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Andreazza
mesh_terms: D000328:Adult; D000447:Aldehydes / Q000032:analysis; D015415:Biomarkers / Q000032:analysis; D001714:Bipolar Disorder / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D003430:Cross-Sectional Studies; D018891:Dentate Gyrus / Q000000981:diagnostic imaging / Q000473:pathology; D003863:Depression / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009929:Organ Size; D018384:Oxidative Stress / Q000502:physiology; D013223:Statistics as Topic
chemical_list: D000447:Aldehydes; D015415:Biomarkers; C027576:4-hydroxy-2-nonenal
keywords: atrophy; bipolar disorder; dentate gyrus; depression; depressive episode; hippocampus; lipid peroxidation; oxidative stress