title: Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder.
abstract: Inflammation-related changes in the concentrations of kynurenine-pathway metabolites occur in depression secondary to medical conditions but have not been well characterized in primary bipolar disorder (BD), with contradictory results potentially attributable to the presence or absence of psychosis and/or medication effects. In contrast, reductions in hippocampal and amygdalar volume that theoretically reflect dendritic atrophy occurring in the context of a neurotoxic process are commonly reported in unmedicated BD patients. Here we tested whether the concentrations of putatively neuroprotective (kynurenic acid, KynA) and neurotoxic (3-hydroxy-kynurenine, 3HK and quinolinic acid, QA) kynurenine-pathway metabolites were altered in primary BD and whether these metabolites were associated with hippocampal and amygdalar volume. Twenty-five moderately-to-severely depressed unmedicated subjects and 38 moderately-to-severely depressed medicated subjects who met DSM-IV-TR criteria for BD, as well as 48 healthy controls (HCs) completed a structural MRI scan and provided a blood sample for kynurenine metabolite analysis, performed using high performance liquid chromatography with tandem mass spectrometry. Gray matter volumes were measured with the automated segmentation software, FreeSurfer. A putative neuroprotective index, KynA/QA, was significantly lower in the BD subjects relative to the HCs, a finding that was unrelated to current treatment with medication or a prior history of psychosis. Further, another putative neuroprotective index, KynA/3HK was positively associated with hippocampal volume in the BD group after controlling for age, sex, body mass index (BMI), and intracranial volume (ICV). Kyn/3HK was significantly associated with total amygdalar volume in the BD group, but after controlling for age, sex, BMI, but not ICV, this association was reduced to a trend. In addition, Kyn/3HK was positively associated with amygdalar volume in the HCs although the association was no longer significant after accounting for the effects of age, sex, and BMI. The results raise the possibility that BD-associated abnormalities in kynurenine metabolism may impact the structure of the hippocampus and amygdala, highlighting a pathway through which inflammation may exert neuropathological effects in the context of depression.
authors.affiliation: Laureate Institute for Brain Research, Tulsa, OK, USA; Faculty of Community Medicine, University of Tulsa, Tulsa, OK, USA. Electronic address: jsavitz@laureateinstitute.org.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Savitz
authors.affiliation: Division of Internal Medicine, Department of Symptom Research, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Dantzer
authors.affiliation: Laureate Institute for Brain Research, Tulsa, OK, USA.
authors.forename: Brent E
authors.initials: BE
authors.lastname: Wurfel
authors.affiliation: Laureate Institute for Brain Research, Tulsa, OK, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Victor
authors.affiliation: Laureate Institute for Brain Research, Tulsa, OK, USA.
authors.forename: Bart N
authors.initials: BN
authors.lastname: Ford
authors.affiliation: Laureate Institute for Brain Research, Tulsa, OK, USA; College of Engineering, University of Oklahoma, Tulsa, OK, USA.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Bodurka
authors.affiliation: Laureate Institute for Brain Research, Tulsa, OK, USA; Faculty of Community Medicine, University of Tulsa, Tulsa, OK, USA.
authors.forename: P S F
authors.initials: PS
authors.lastname: Bellgowan
authors.affiliation: Departments of Surgery and Psychiatry, University of Oklahoma College of Medicine, Tulsa, OK, USA; Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, Tulsa, OK, USA; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA.
authors.forename: T Kent
authors.initials: TK
authors.lastname: Teague
authors.affiliation: Janssen Pharmaceuticals of Johnson & Johnson, Inc., Titusville, NJ, USA.
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Drevets
mesh_terms: D000328:Adult; D000679:Amygdala / Q000473:pathology*; D001714:Bipolar Disorder / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007736:Kynurenic Acid / Q000097:blood*; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017378:Quinolinic Acid / Q000097:blood*
chemical_list: C005045:3-hydroxykynurenine; D007737:Kynurenine; D017378:Quinolinic Acid; D007736:Kynurenic Acid
keywords: Bipolar disorder; Hippocampus; Inflammation; Kynurenine; Magnetic resonance imaging; Quinolinic acid