Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder |
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| Affiliation: | 1. Laureate Institute for Brain Research, Tulsa, OK, USA;2. Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA;3. Janssen Pharmaceuticals of Johnson & Johnson, Inc., Titusville, NJ, USA;4. College of Engineering, University of Oklahoma, Tulsa, OK, USA;5. Department of Surgery, University of Oklahoma College of Medicine, Tulsa, OK, USA;6. Department of Psychiatry, University of Oklahoma College of Medicine, Tulsa, OK, USA;7. Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, Tulsa, OK, USA;8. Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA;9. Division of Internal Medicine, Department of Symptom Research, MD Anderson Cancer Center, Houston, TX, USA;10. Faculty of Community Medicine, University of Tulsa, Tulsa, OK, USA;1. Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;2. Center of Research on Psychology in Somatic Diseases, Tilburg University, The Netherlands;3. Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands;4. Department of Laboratory Medicine, University Medical Center, University of Groningen, Groningen, The Netherlands;1. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USA;2. Institute of Ophthalmology, University College London, London, UK;3. Neurexpert Ltd., London, UK;1. Laureate Institute for Brain Research, Tulsa, OK, USA;2. Faculty of Community Medicine, University of Tulsa, Tulsa, OK, USA;3. Division of Internal Medicine, Department of Symptom Research, MD Anderson Cancer Center, Houston, TX, USA;4. College of Engineering, University of Oklahoma, Tulsa, OK, USA;5. Departments of Surgery and Psychiatry, University of Oklahoma College of Medicine, Tulsa, OK, USA;6. Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, Tulsa, OK, USA;7. Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA;8. Janssen Pharmaceuticals of Johnson & Johnson, Inc., Titusville, NJ, USA;1. Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, TX, USA;2. Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil;3. Graduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, RS, Brazil;4. Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil;5. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA;1. Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway;2. Institute of Clinical Science, University of Bergen, Norway;3. Department of Global Public Health and Primary Care, University of Bergen, Norway;4. Division of Mental and Physical Health, Norwegian Institute of Public Health, Bergen, Norway;5. Department of Heart Disease, Haukeland University Hospital, Bergen, Norway;6. BevitalA/S, Bergen, Norway;7. Department of Clinical Medicine, University of Bergen, Norway;8. Department of Old Age Psychiatry, King’s College University, London, UK;9. Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway;10. Department of Pharmacology, University of Oxford, UK |
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| Abstract: | Reductions in gray matter volume of the medial prefrontal cortex (mPFC), especially the rostral and subgenual anterior cingulate cortex (rACC, sgACC) are a widely reported finding in major depressive disorder (MDD). Inflammatory mediators, which are elevated in a subgroup of patients with MDD, activate the kynurenine metabolic pathway and increase production of neuroactive metabolites such as kynurenic acid (KynA), 3-hydroxykynurenine (3HK) and quinolinic acid (QA) which influence neuroplasticity. It is not known whether the alterations in brain structure and function observed in major depressive disorders are due to the direct effect of inflammatory mediators or the effects of neurotoxic kynurenine metabolites. Here, using partial posterior predictive distribution mediation analysis, we tested whether the serum concentrations of kynurenine pathway metabolites mediated reductions in cortical thickness in mPFC regions in MDD. Further, we tested whether any association between C-reactive protein (CRP) and cortical thickness would be mediated by kynurenine pathway metabolites. Seventy-three unmedicated subjects who met DSM-IV-TR criteria for MDD and 91 healthy controls (HC) completed MRI scanning using a pulse sequence optimized for tissue contrast resolution. Automated cortical parcellation was performed using the PALS-B12 Brodmann area atlas as implemented in FreeSurfer in order to compare the cortical thickness and cortical area of six PFC regions: Brodmann areas (BA) 9, 10, 11, 24, 25, and 32. Serum concentrations of kynurenine pathway metabolites were determined by high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) detection, while high-sensitivity CRP concentration was measured immunoturbidimetrically. Compared with HCs, the MDD group showed a reduction in cortical thickness of the right BA24 (p < 0.01) and BA32 (p < 0.05) regions and MDD patients with a greater number of depressive episodes displayed thinner cortex in BA32 (p < 0.05). Consistent with our previous findings in an overlapping sample, the KynA/3HK ratio and the log KynA/QA were reduced in the MDD group relative to the HC group (p’s < 0.05) and symptoms of anhedonia were negatively correlated with log KynA/QA in the MDD group (p < 0.05). Both KynA/3HK and log KynA/QA at least partially mediated the relationship between diagnosis and cortical thickness of right BA32 (p’s < 0.05). CRP was inversely associated with BA32 thickness (p < 0.01) and KynA/3HK partially mediated the relationship between CRP and the thickness of right BA32 (p < 0.05). The results raise the possibility that the relative imbalance between KynA and neurotoxic kynurenine metabolites may partially explain the reductions in mPFC thickness observed in MDD, and further that these changes are more strongly linked to the putative effects of neuroactive kynurenine metabolites than those of inflammatory mediators. |
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| Keywords: | Major depressive disorder Magnetic resonance imaging Medial prefrontal cortex Quinolinic acid Inflammation Kynurenine |
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