Kynurenine pathway and white matter microstructure in bipolar disorder.
Decreased availability of serotonin in the central nervous system has been suggested to be a central factor in the pathogenesis of depression. Activation of indoleamine 2-3 dioxygenase following a pro-inflammatory state could reduce the amount of tryptophan converted to serotonin and increase the production of tryptophan catabolites such as kynurenic acid, an antagonist of ionotropic excitatory aminoacid receptors, whose levels are reduced in bipolar disorder. Abnormalities in white matter (WM) integrity have been widely reported in BD. We then hypothesized that metabolites involved in serotoninergic turnover in BD could influence DTI measures of WM microstructure. Peripheral levels of tryptophan, kynurenine, kynurenic acid, 3-hydroxy-kynurenine, and 5-HIAA were analysed in 22 patients affected by BD and 15 healthy controls. WM microstructure was evaluated using diffusion tensor imaging and tract-based spatial statistics with threshold-free cluster enhancement only in bipolar patients. We observed that kynurenic acid and 5-HIAA were reduced in BD and associated with DTI measures of WM integrity in several association fibres: inferior and superior longitudinal fasciculus, cingulum bundle, corpus callosum, uncus, anterior thalamic radiation and corona radiata. Our results seem to suggest that higher levels of 5-HIAA, a measure of serotonin levels, and higher levels of kynurenic acid, which protects from glutamate excitotoxicity, could exert a protective effect on WM microstructure. Reduced levels of these metabolites in BD thus seem to confirm a crucial role of serotonin turnover in BD pathophysiology.
Department of Clinical Neurosciences, San Raffaele Turro, Istituto Scientifico Ospedale San Raffaele, University Vita-Salute San Raffaele, Via Stamira D'Ancona 20, Milan, Italy. poletti.sara@hsr.it.
Sara
http://orcid.org/0000-0001-9594-0246
S
Poletti
Psychiatry Department, Ludwig-Maximilian University, Munich, Germany.
Aye Mu
AM
Myint
Institute for Laboratory Medicine of Munich University, Ludwig-Maximilian University, Munich, Germany.
Gregor
G
Schüetze
Department of Clinical Neurosciences, San Raffaele Turro, Istituto Scientifico Ospedale San Raffaele, University Vita-Salute San Raffaele, Via Stamira D'Ancona 20, Milan, Italy.
Irene
I
Bollettini
Department of Clinical Neurosciences, San Raffaele Turro, Istituto Scientifico Ospedale San Raffaele, University Vita-Salute San Raffaele, Via Stamira D'Ancona 20, Milan, Italy.
Elena
E
Mazza
Clinical Chemistry, Ludwig-Maximilian University, Munich, Germany.
Doris
D
Grillitsch
Department of Clinical Neurosciences, San Raffaele Turro, Istituto Scientifico Ospedale San Raffaele, University Vita-Salute San Raffaele, Via Stamira D'Ancona 20, Milan, Italy.
Clara
C
Locatelli
Institute for Laboratory Medicine of Munich University, Ludwig-Maximilian University, Munich, Germany.
Markus
M
Schwarz
Department of Clinical Neurosciences, San Raffaele Turro, Istituto Scientifico Ospedale San Raffaele, University Vita-Salute San Raffaele, Via Stamira D'Ancona 20, Milan, Italy.
Cristina
C
Colombo
Department of Clinical Neurosciences, San Raffaele Turro, Istituto Scientifico Ospedale San Raffaele, University Vita-Salute San Raffaele, Via Stamira D'Ancona 20, Milan, Italy.
Francesco
F
Benedetti
D000328:Adult; D001714:Bipolar Disorder / Q000000981:diagnostic imaging* / Q000378:metabolism*; D056324:Diffusion Tensor Imaging; D005260:Female; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007736:Kynurenic Acid / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014364:Tryptophan / Q000378:metabolism; D066127:White Matter / Q000000981:diagnostic imaging* / Q000378:metabolism*; D055815:Young Adult
D012701:Serotonin; D007737:Kynurenine; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan; D007736:Kynurenic Acid
5-HIAA; Bipolar disorder; IDO; Kynurenic acid; TBSS; White matter