Abstract
Diffusion tensor imaging (DTI) studies consistently reported abnormalities in fractional anisotropy (FA) and radial diffusivity (RD), measures of the integrity of white matter (WM), in bipolar disorder (BD), that may reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD. We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA (and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE) and 19 age- and gender-matched healthy adults (CONT). There was a significant effect of group upon FA in these a priori WM tracts (BDE<CONT: F[1,41]=6.8; P=0.013) and RD (BDE>CONT: F[1,41]=10.3; P=0.003), and a significant between-group difference in LPH (BDE>CONT: t[40]=2.4; P=0.022), but not in 4-HNE. Multivariate multiple regression analyses revealed that LPH variance explained, respectively, 59 and 51% of the variance of FA and RD across all study participants. This is the first study to examine relationships between measures of WM integrity and peripheral measures of lipid peroxidation. Our findings suggest that serum LPH may be useful in the development of a clinically relevant, yet easily obtainable and inexpensive, peripheral biomarkers of BD.
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References
Phillips ML, Frank E . Redefining bipolar disorder: toward DSM-V. Am J Psychiatry 2006; 163: 1135–1136.
Kupfer DJ, Angst J, Berk M, Dickerson F, Frangou S, Frank E et al. Advances in bipolar disorder: selected sessions from the 2011 International Conference on Bipolar Disorder. Ann NY Acad Sci 2011; 1242: 1–25.
Frey BN, Andreazza AC, Houenou J, Jamain S, Goldstein B, Frye MA et al. Biomarkers in bipolar disorder: a positional paper from the International Society for Bipolar Disorders Biomarkers Committee. ANZJP 2012 submitted.
Hirschfeld RM, Vornik LA . Bipolar disorder-costs and comorbidity. Am J Manag Care 2005; 11 (3 Suppl): S85–S90.
WHO. The Global Burden of Disease: 2004 Update. WHO: Geneva, Switzerland, 2008.
Goodwin FK, Jamison KR . Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression 2nd edn. Oxford University Press: New York, NY, 2007; 1: 355–378.
Hirschfeld RM, Lewis L, Vornik LA . Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry 2003; 64: 161–174.
Vederine F-E, Wessa M, Leboyer M, Houenou J . A meta-analysis of whole-brain diffusion tensor imaging studies in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 1820–1826.
Brambilla P, Bellani M, Yeh P-H, Soares JC, Tansella M . White matter connectivity in bipolar disorder. Int Rev Psychiatry 2009; 21: 380–386.
Sexton CE, Mackay CE, Ebmeier KP . A systematic review of diffusion tensor imaging studies in affective disorders. Biol Psychiatry 2009; 66: 814–823.
Womer FY, Kalmar JH, Wang F, Blumberg HP . A ventral prefrontal-amygdala neural system in bipolar disorder: a view from neuroimaging research. Acta Neuropsychiatr 2009; 21: 228–238.
Mahon K, Burdick KE, Szeszko PR . A role for white matter abnormalities in the pathophysiology of bipolar disorder. Neurosci Biobehav Rev 2010; 34: 533–554.
Heng S, Song AW, Sim K . White matter abnormalities in bipolar disorder: insights from diffusion tensor imaging studies. J Neural Transm 2010; 117: 639–654.
Yurgelun-Todd DA, Silveri MM, Gruber SA, Rohan ML, Pimentel PJ . White matter abnormalities observed in bipolar disorder: a diffusion tensor imaging study. Bipolar Disord 2007; 9: 504–512.
Chaddock CA, Barker GJ, Marshall N, Schulze K, Hall MH, Fern A et al. White matter microstructural impairments and genetic liability to familial bipolar I disorder. Br J Psychiatry 2009; 194: 527–534.
Benedetti F, Yeh P-H, Bellani M, Radaelli D, Nicoletti MA, Poletti S et al. Disruption of white matter integrity in bipolar depression as a possible structural marker of illness. Biol Psychiatry 2011; 69: 309–317.
Houenou J, Wessa M, Douaud G, Leboyer M, Chanraud S, Perrin M et al. Increased white matter connectivity in euthymic bipolar patients: diffusion tensor tractography between the subgenual cingulate and the amygdalo-hippocampal complex. Mol Psychiatry 2007; 12: 1001–1010.
Benedetti F, Absinta M, Rocca MA, Radaelli D, Poletti S, Bernasconi A et al. Tract-specific white matter structural disruption in patients with bipolar disorder. Bipolar Disord 2011; 13: 414–424.
Lin F, Weng S, Xie B, Wu G, Lei H . Abnormal frontal cortex white matter connections in bipolar disorder: a DTI tractography study. J Affect Disord 2011; 131: 299–306.
McIntosh AM, Maniega SM, Lymer GKS, McKirdy J, Hall J, Sussmann JE et al. White matter tractography in bipolar disorder and schizophrenia. Biol Psychiatry 2008; 64: 1088–1092.
Sussmann JE, Lymer GKS, McKirdy J, Moorhead TWJ, Maniega SM, Job D et al. White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging. Bipolar Disord 2009; 11: 11–18.
Versace A, Almeida JRC, Hassel S, Walsh ND, Novelli M, Klein CR et al. Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics. Arch Gen Psychiatry 2008; 65: 1041–1052.
Wang F, Kalmar JH, He Y, Jackowski M, Chepenik LG, Edmiston EE et al. Functional and structural connectivity between the perigenual anterior cingulate and amygdala in bipolar disorder. Biol Psychiatry 2009; 66: 516–521.
Wakana S, Caprihan A, Panzenboeck MM, Fallon JH, Perry M, Gollub RL et al. Reproducibility of quantitative tractography methods applied to cerebral white matter. Neuroimage 2007; 36: 630–644.
Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH . Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 2003; 20: 1714–1722.
Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH . Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage 2002; 17: 1429–1436.
Sun S-W, Liang H-F, Cross AH, Song S-K . Evolving Wallerian degeneration after transient retinal ischemia in mice characterized by diffusion tensor imaging. Neuroimage 2008; 40: 1–10.
Xie M, Wang Q, Wu TH, Song SK, Sun SW . Delayed axonal degeneration in slow Wallerian degeneration mutant mice detected using diffusion tensor imaging. Neuroscience 2011; 197: 339–347.
Klawiter EC, Schmidt RE, Trinkaus K, Liang H-F, Budde MD, Naismith RT et al. Radial diffusivity predicts demyelination in ex vivo multiple sclerosis spinal cords. Neuroimage 2011; 55: 1454–1460.
Halliwell B, Gutteridge JM . Lipid peroxidation, oxygen radicals, cell damage, and antioxidant therapy. Lancet 1984; 1: 1396–1397.
Halliwell B, Gutteridge JMC . Free Radicals in Biology and Medicine 4th edn Oxford University Press: Oxford, New York, 2007 xxxvi, 851 p, 858 p. of plates pp.
Ng F, Berk M, Dean O, Bush AI . Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 2008; 11: 851–876.
Andreazza AC . Combining redox-proteomics and epigenomics to explain the involvement of oxidative stress in psychiatric disorders. Mol Biosyst 2012; 8: 2503–2512.
Young LT . Is bipolar disorder a mitochondrial disease? J Psychiatry Neurosci 2007; 32: 160–161.
First MB, Spitzer RL, Gibbon ML, Williams JBW . Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. vol. (SCID-I/P). Biometrics Research, New York State Psychiatric Institute: New York, 2002.
Hamilton M . A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62.
Young RC, Biggs JT, Ziegler VE, Meyer DA . A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133: 429–435.
Annett M . A classification of hand preference by association analysis. Br J Psychol 1970; 61: 303–321.
Yendiki A, Panneck P, Srinivasan P, Stevens A, Zollei L, Augustinack J et al. Automated probabilistic reconstruction of white-matter pathways in health and disease using an atlas of the underlying anatomy. Front Neuroinform 2011; 5: 23.
Jbabdi S, Woolrich MW, Andersson JLR, Behrens TEJ . A Bayesian framework for global tractography. Neuroimage 2007; 37: 116–129.
Fischl B . FreeSurfer. Neuroimage 2012; 62: 774–781.
Shi R, Rickett T, Sun W . Acrolein-mediated injury in nervous system trauma and diseases. Mol Nutr Food Res 2011; 55: 1320–1331.
Shi Y, Sun W, McBride JJ, Cheng JX, Shi R . Acrolein induces myelin damage in mammalian spinal cord. J Neurochem 2011; 117: 554–564.
Konat GW, Wiggins RC . Effect of reactive oxygen species on myelin membrane proteins. J Neurochem 1985; 45: 1113–1118.
Almeida JRC, Phillips ML . Distinguishing between unipolar depression and bipolar depression: current and future clinical neuroimaging perspectives. Biol Psychiatry 2013; 73: 111–118.
Berman SB, Hastings TG . Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson's disease. J Neurochem 1999; 73: 1127–1137.
Phillips M, Ladouceur C, Drevets W . A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder. Mol Psychiatry 2008; 13: 833–857.
Andreazza AC, Kauer-Sant'Anna M, Frey BN, Bond DJ, Kapczinski F, Young LT et al. Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord 2008; 111: 135–144.
Adibhatla RM, Hatcher JF . Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 2010; 12: 125–169.
Andreazza AC, Kapczinski F, Kauer-Sant'Anna M, Walz JC, Bond DJ, Goncalves CA et al. 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. J Psychiatry Neurosci 2009; 34: 263–271.
Gawryluk JW, Wang J-F, Andreazza AC, Shao L, Yatham LN, Young LT . Prefrontal cortex glutathione S-transferase levels in patients with bipolar disorder, major depression and schizophrenia. Int J Neuropsychopharmacol 2011; 14: 1069–1074.
Altshuler L, Suppes T, Black D, Nolen WA, Keck PE, Frye MA et al. Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up. Am J Psychiatry 2003; 160: 1252–1262.
Zanetti MV, Jackowski MP, Versace A, Almeida JR, Hassel S, Duran FL et al. State-dependent microstructural white matter changes in bipolar I depression. Eur Arch Psychiatry Clin Neurosci 2009; 259: 316–328.
Smit LA, Katan MB, Wanders AJ, Basu S, Brouwer IA . A high intake of trans fatty acids has little effect on markers of inflammation and oxidative stress in humans. J Nutr 2011; 141: 1673–1678.
Acknowledgements
We acknowledge the technical assistance of Dr Leemans in the preprocessing of the DTI images. This study was supported in part by R01 MH076971–01 (Dr Phillips) and MH63480 (Dr Nimgaonkar) from National Institutes of Health, by a NARSAD (National Alliance for Research on Schizophrenia and Depression) Young Investigator Award (Dr Versace) and by Canadian Institute of Health Research (CIHR; Dr Young, Dr Andreazza).
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Versace, A., Andreazza, A., Young, L. et al. Elevated serum measures of lipid peroxidation and abnormal prefrontal white matter in euthymic bipolar adults: toward peripheral biomarkers of bipolar disorder. Mol Psychiatry 19, 200–208 (2014). https://doi.org/10.1038/mp.2012.188
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DOI: https://doi.org/10.1038/mp.2012.188
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