Serum kynurenic acid is reduced in affective psychosis.
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ABSTRACT:
SUBMITTER: Wurfel BE
PROVIDER: S-EPMC5534956 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The incidence of depression is approximately 2-fold greater in women than men but the biological mechanisms underlying this phenomenon remain unclear. One potential mechanism that has been understudied is immune function, which is modulated by sex hormones and differs considerably between males and females. The immune-regulating kynurenine pathway previously has been implicated in the pathogenesis of mood disorders. In particular, a decreased ratio of neuroprotective (kynurenic acid; KynA) to neurotoxic (3-hydroxykynurenine; 3HK and quinolinic acid; QA) kynurenine pathway metabolites has been reported in several mood disorder subtypes. Yet there is a paucity of research investigating sex differences in the kynurenine pathway in the context of depression. Similarly, oral contraceptive (OC) use has been shown to be a risk factor for depression but to our knowledge this epidemiological relationship has not been considered within the framework of immune dysfunction. Here, we compared the concentrations of c-reactive protein (CRP) and kynurenine pathway metabolites in a combined sample of subjects with major depressive disorder (MDD), bipolar disorder (BD), and healthy controls (HC) comprising 130 men and 350 women. CRP was measured in a CLIA-certified hospital laboratory. Kynurenine metabolites were quantified using high performance liquid chromatography with tandem mass spectrometry. Estradiol and progesterone were quantified with the Mesoscale Discovery (MSD) platform. After controlling for diagnosis, age, sex, BMI, analysis batch, and self-reported childhood trauma we found that women had significantly lower KynA/3HK and KynA/QA ratios than men, and that these results were driven by a decrease in KynA. There was no significant difference between males and females in the concentration of CRP. Further, women taking OC showed significantly higher levels of CRP and lower ratios of KynA/3HK and KynA/QA compared with women on no form of contraception. Moreover, among women using OC, progesterone concentrations were positively correlated with KynA, KynA/3HK, and KynA/QA. Although preliminary, our results indicate that on average, healthy women show the same pattern of kynurenine pathway metabolism as that observed in subjects with depression. This finding raises the possibility that a reduction in KynA concentrations in women may constitute a vulnerability factor that partly explains the higher incidence of depression in females. Further, the significant association between OC use and reduced KynA as well as increased CRP, could conceivably partially account for the epidemiological association between OC use and depression. Nonetheless, because of the cross-sectional nature of this study, these hypotheses need to be more rigorously tested with longitudinal designs and/or large epidemiological studies.
| S-EPMC5696064 | biostudies-other
Project description:OBJECTIVE:To examine the nature of the association between affective disorders and psychosis in Parkinson's disease (PD). BACKGROUND:In PD, psychosis and affective disorders are common and independently impact quality of life and mortality. Both depression and psychosis are correlated with the occurrence of cognitive dysfunction, suggesting that they may share neurobiological substrates. Anxiety has not been examined as a correlate of psychosis. METHODS:144 PD subjects were evaluated with the Schedule for Assessment of Positive Symptoms to assess psychotic features, while depression and anxiety were examined by the Structured Clinical Interview for DSM-IV-TR (SCID) and self-assessment scales Beck Depression Inventory II (BDI-II) and Beck Anxiety Inventory (BAI). Correlational analyses assessed associations between hallucinations and delusions with depression and anxiety. RESULTS:A diagnosis of anxiety (SCID) was significantly (p=.015) associated with hallucinations (OR=4.81, CI=1.36-16.99). Severity of anxiety (BAI) significantly predicted (p=.03) the presence of hallucinations (OR=1.08, CI=1.01-1.15) and delusions (OR=1.09, CR=1.01-1.17). Current depression (SCID) was significantly (p=.001) associated with the presence of hallucinations (OR=6.12, CI=2.04-18.39) and delusions (OR=7.14, CI=2.23-22.93). Multiple linear regressions revealed that severity of anxiety remained an independent predictor (p<.05) of both the number of types of hallucinations (t=3.06, p=.003) and delusions (t=2.87, p=.005). Severity of depression was a significant predictor of the total number of delusions (t=2.28, p=.024). CONCLUSIONS:This study demonstrates an association between depression and psychosis and, for the first time, an association between anxiety and psychosis. These associations may have implications on pathophysiology and treatment of psychosis in PD.
| S-EPMC5608273 | biostudies-other
Project description:The aim of this work was to investigate serum and milk levels of tryptophan (TRP), kynurenine (KYN), and kynurenic acid (KYNA), as well as the activity of indoleamine 2,3-dioxygenase (IDO) in cows with mastitis due to Prototheca algae. The study was prompted by previous research showing a link between the KYN pathway of TRP metabolism and bovine mastitis of bacterial etiology. The study was carried out over a 2-year period (2018-2019) and included quarter milk and serum samples collected from six dairy herds in Poland. The samples were obtained from healthy cows and cows with Prototheca mastitis of either clinical and subclinical manifestation, as determined upon direct measurement of the somatic cell count or indirectly by performing a California Mastitis Test on suspected quarters. Both TRP and KYN concentrations were significantly lower in milk of mastitic cows compared to healthy animals (0.8 vs. 8.72 µM, p = 0.001; 0.07 vs. 0.32 µM, p = 0.001, respectively). The difference in TRP and KYN concentrations in the sera of the two animal groups was much less pronounced (25.55 vs. 27.57 µM, 3.03 vs. 3.56 nM, respectively). The concentration of KYNA was almost at the same level in milk (1.73 vs. 1.70 nM) and in serum (80.47 vs. 75.48 nM) of both mastitic and healthy cows. The data showed that the level of TRP and its metabolites in serum was conspicuously higher compared to milk in all cows under the study. The activity of IDO was significantly higher in milk of cows with Prototheca mastitis compared to healthy animals (71.4 vs. 40.86, p < 0.05), while in serum it was pretty much the same (135.94 vs. 124.98, p > 0.05). The IDO activity differed significantly between serum and milk both for mastitic (135.94 vs. 71.4, p < 0.05) and healthy cows (124.98 vs. 40.86, p < 0.001). In conclusion, low values of TRP and KYN concentrations or elevated IDO activity in milk samples might be used as markers of mastitis due to infectious causes, including Prototheca spp.
| S-EPMC8698139 | biostudies-literature
Project description:Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.
| S-EPMC4965332 | biostudies-literature
Project description:Increased innate immune activation and inflammation are common findings in psychotic and affective (mood) disorders such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD), including increased numbers and activation of monocytes and macrophages. These findings often differ depending on the disorder, for example, we previously found increases in circulating inflammatory cytokines associated with monocytes and macrophages in SCZ, while BD had increases in anti-inflammatory cytokines. Despite these differences, few studies have specifically compared immune dysfunction in affective versus non-affective psychotic disorders and none have compared functional monocyte responses across these disorders. To address this, we recruited 25 first episode psychosis (FEP) patients and 23 healthy controls (HC). FEP patients were further grouped based on the presence (AFF) or absence (NON) of mood disorder. We isolated peripheral blood mononuclear cells and cultured them for 1 week with M-CSF to obtain monocyte-derived macrophages. These cells were then stimulated for 24 h to skew them to inflammatory and alternative phenotypes, in order to identify differences in these responses. Following stimulation with LPS and LPS plus IFNγ, we found that macrophages from the NON-group had diminished inflammatory responses compared to both HC and AFF groups. Interestingly, when skewing macrophages to an alternative phenotype using LPS plus IL-4, the AFF macrophages increased production of inflammatory cytokines. Receiver operating curve analysis showed predictive power of inflammatory cytokine concentrations after LPS stimulation in the AFF group versus NON-group. Our results suggest dysfunctional monocyte responses in both affective and non-affective psychotic disorder, with varying types of immune dysfunction depending on the presence or absence of a mood component.
| S-EPMC7943877 | biostudies-literature
Project description:BackgroundComputational linguistic methodology allows quantification of speech abnormalities in non-affective psychosis. For this patient group, incoherent speech has long been described as a symptom of formal thought disorder. Our study is an interdisciplinary attempt at developing a model of incoherence in non-affective psychosis, informed by computational linguistic methodology as well as psychiatric research, which both conceptualize incoherence as associative loosening. The primary aim of this pilot study was methodological: to validate the model against clinical data and reduce bias in automated coherence analysis.MethodsSpeech samples were obtained from patients with a diagnosis of schizophrenia or schizoaffective disorder, who were divided into two groups of n = 20 subjects each, based on different clinical ratings of positive formal thought disorder, and n = 20 healthy control subjects.ResultsCoherence metrics that were automatically derived from interview transcripts significantly predicted clinical ratings of thought disorder. Significant results from multinomial regression analysis revealed that group membership (controls vs. patients with vs. without formal thought disorder) could be predicted based on automated coherence analysis when bias was considered. Further improvement of the regression model was reached by including variables that psychiatric research has shown to inform clinical diagnostics of positive formal thought disorder.ConclusionsAutomated coherence analysis may capture different features of incoherent speech than clinical ratings of formal thought disorder. Models of incoherence in non-affective psychosis should include automatically derived coherence metrics as well as lexical and syntactic features that influence the comprehensibility of speech.
| S-EPMC7466436 | biostudies-literature
Project description:Tryptophan-kynurenine metabolism plays an important role in the pathogenesis of several psychiatric diseases but its physiological function in peripheral tissues remains unclear. Physical exercise training activates a biochemical pathway in skeletal muscle that protects from neuroinflammation and, as a byproduct, leads to kynurenic acid accumulation in the periphery. We therefore investigated the effects of kynurenic acid in murine white adipose tissue. We used microarrays to detail global programme of gene expression underlying Kynurenic acid mediated effects on inguinal primary adipocytes.
2017-12-16 | GSE108158 | GEO
Project description:Psychosis disorders share overlapping symptoms and are characterized by a wide-spread breakdown in functional brain integration. Although neuroimaging studies have identified numerous connectivity abnormalities in affective and non-affective psychoses, whether they have specific or unique connectivity abnormalities, especially within the early stage is still poorly understood. The early phase of psychosis is a critical period with fewer chronic confounds and when treatment intervention may be most effective. In this work, we examined whole-brain functional network connectivity (FNC) from both static and dynamic perspectives in patients with affective psychosis (PAP) or with non-affective psychosis (PnAP) and healthy controls (HCs). A fully automated independent component analysis (ICA) pipeline called "Neuromark" was applied to high-quality functional magnetic resonance imaging (fMRI) data with 113 early-phase psychosis patients (32 PAP and 81 PnAP) and 52 HCs. Relative to the HCs, both psychosis groups showed common abnormalities in static FNC (sFNC) between the thalamus and sensorimotor domain, and between subcortical regions and the cerebellum. PAP had specifically decreased sFNC between the superior temporal gyrus and the paracentral lobule, and between the cerebellum and the middle temporal gyrus/inferior parietal lobule. On the other hand, PnAP showed increased sFNC between the fusiform gyrus and the superior medial frontal gyrus. Dynamic FNC (dFNC) was investigated using a combination of a sliding window approach, clustering analysis, and graph analysis. Three reoccurring brain states were identified, among which both psychosis groups had fewer occurrences in one antagonism state (state 2) and showed decreased network efficiency within an intermediate state (state 1). Compared with HCs and PnAP, PAP also showed a significantly increased number of state transitions, indicating more unstable brain connections in affective psychosis. We further found that the identified connectivity features were associated with the overall positive and negative syndrome scale, an assessment instrument for general psychopathology and positive symptoms. Our findings support the view that subcortical-cortical information processing is disrupted within five years of the initial onset of psychosis and provide new evidence that abnormalities in both static and dynamic connectivity consist of shared and unique features for the early affective and non-affective psychoses.
| S-EPMC8250435 | biostudies-literature
Project description:The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA receptor (NMDAR) and as a negative allosteric modulator at the ?7 nicotinic acetylcholine receptor. Levels of KYNA are elevated in CSF and the postmortem brain of schizophrenia patients, and these elevated levels of KYNA could contribute to NMDAR hypofunction and the cognitive deficits and negative symptoms associated with this disease. However, the impact of endogenously produced KYNA on brain function and behavior is less well understood due to a paucity of pharmacological tools. To address this issue, we identified PF-04859989, a brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II), the enzyme responsible for most brain KYNA synthesis. In rats, systemic administration of PF-04859989 dose-dependently reduced brain KYNA to as little as 28% of basal levels, and prevented amphetamine- and ketamine-induced disruption of auditory gating and improved performance in a sustained attention task. It also prevented ketamine-induced disruption of performance in a working memory task and a spatial memory task in rodents and nonhuman primates, respectively. Together, these findings support the hypotheses that endogenous KYNA impacts cognitive function and that inhibition of KAT II, and consequent lowering of endogenous brain KYNA levels, improves cognitive performance under conditions considered relevant for schizophrenia.
| S-EPMC6802596 | biostudies-literature
Project description:Hypofunction of glutamatergic signaling is causally linked to neurodevelopmental disorders, including psychotic disorders like schizophrenia and bipolar disorder. Kynurenic acid (KYNA) has been found to be elevated in postmortem brain tissue and cerebrospinal fluid of patients with psychotic illnesses and may be involved in the hypoglutamatergia and cognitive dysfunction experienced by these patients. As insults during the prenatal period are hypothesized to be linked to the pathophysiology of psychotic disorders, we presently utilized the embryonic kynurenine (EKyn) paradigm to induce a prenatal hit. Pregnant Wistar dams were fed chow laced with kynurenine to stimulate fetal brain KYNA elevation from embryonic day 15 to embryonic day 22. Control dams (ECon) were fed unlaced chow. Plasma and hippocampal tissue from young adult (postnatal day 56) ECon and EKyn male and female offspring were collected at the beginning of the light (Zeitgeber time, ZT 0) and dark (ZT 12) phases to assess kynurenine pathway metabolites. Hippocampal tissue was also collected at ZT 6 and ZT 18. In separate animals, in vivo microdialysis was conducted in the dorsal hippocampus to assess extracellular KYNA, glutamate, and γ-aminobutyric acid (GABA). Biochemical analyses revealed no changes in peripheral metabolites, yet hippocampal tissue KYNA levels were significantly impacted by EKyn treatment, and increased in male EKyn offspring at ZT 6. Interestingly, extracellular hippocampal KYNA levels were only elevated in male EKyn offspring during the light phase. Decreases in extracellular glutamate levels were found in the dorsal hippocampus of EKyn male and female offspring, while decreased GABA levels were present only in males during the dark phase. The current findings suggest that the EKyn paradigm may be a useful tool for investigation of sex- and time-dependent changes in hippocampal neuromodulation elicited by prenatal KYNA elevation, which may influence behavioral phenotypes and have translational relevance to psychotic disorders.
| S-EPMC8484637 | biostudies-literature