Immunological protein profiling of first-episode psychosis patients identifies CSF and blood biomarkers correlating with disease severity.

BACKGROUND AND HYPOTHESIS: Immune activation is suggested to play an important role in psychosis. In this study, a large number of immune-related proteins were analyzed to obtain a more comprehensive picture of immune aberrations in schizophrenia. STUDY DESIGN: Ninety-two immune markers were analyzed by the Olink Protein Extension Assay (Inflammatory Panel) in plasma and cerebrospinal fluid (CSF) from 77 first-episode psychosis (FEP) patients (of which 43 later received the diagnosis of schizophrenia) and 56 healthy controls, all recruited from the Karolinska Schizophrenia Project (KaSP), Stockholm, Sweden. STUDY RESULTS: Differential analysis showed that 12 of 92 inflammatory proteins were significantly higher in the plasma of FEP patients (n = 77) than in controls, and several proteins were positively correlated with disease severity. Patients from the same cohort diagnosed with schizophrenia (n = 43), showed significantly higher levels of 15 plasma proteins compared to controls whereas those not receiving this diagnosis showed no significant differences. The presently used OLINK inflammatory panel allowed the detection of only 47 CSF proteins of which only CD5 differed between patients and controls. CONCLUSIONS: The levels of several peripheral immune markers, particularly those interfering with WNT/ß-catenin signaling, were significantly higher in patients with FEP than in healthy controls and associated with illness severity.

Dual administration of lipopolysaccharide induces behavioural changes in rats relevant to psychotic disorders.

OBJECTIVE: We previously reported that dual injections of lipopolysaccharide (LPS) in mice constitute a valuable tool for investigating the contribution of inflammation to psychotic disorders. The present study investigated how immune activation affects the kynurenine pathway and rat behaviour of relevance for psychotic disorders. METHODS: Male Sprague Dawley rats were treated with either dual injections of LPS (0.5 mg/kg + 0.5 mg/kg, i.p.) or dual injections of saline. Twenty-four hours after the second injection, behavioural tests were carried out, including locomotor activity test, fear conditioning test, spontaneous alternation Y-maze test, and novel object recognition test. In a separate batch of animals, in vivo striatal microdialysis was performed, and tryptophan, kynurenine, quinolinic acid, and kynurenic acid (KYNA) in the dialysate were measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: Dual-LPS treatment decreased spontaneous locomotion, exaggerated d-amphetamine-induced locomotor activity, and impaired recognition memory in male Sprague-Dawley rats. In vivo microdialysis showed that dual-LPS treatment elicited metabolic disturbances in the kynurenine pathway with increased extracellular levels of kynurenine and KYNA in the striatum. CONCLUSION: The present study further supports the feasibility of using the dual-LPS model to investigate inflammation-related psychotic disorders and cognitive impairments.

Peripheral and central kynurenine pathway abnormalities in major depression.

Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro-inflammatory cytokines facilitate metabolism of tryptophan along the kynurenine pathway (KP) putatively resulting in reduced neuroprotective and increased neurotoxic KP metabolites in MDD, in addition to modulating metabolic and immune function. This central nervous system hypothesis has, however, only been tested in the periphery. Here, we measured KP-metabolite levels in both plasma and cerebrospinal fluid (CSF) of depressed patients (n = 63/36 respectively) and healthy controls (n = 48/33). Further, we assessed the relation between KP abnormalities and brain-structure volumes, as well as body mass index (BMI), an index of metabolic disturbance associated with atypical depression. Plasma levels of picolinic acid (PIC), the kynurenic/quinolinic acid ratio (KYNA/QUIN), and PIC/QUIN were lower in MDD, but QUIN levels were increased. In the CSF, we found lower PIC in MDD. Confirming previous work, MDD patients had lower hippocampal, and amygdalar volumes. Hippocampal and amygdalar volumes were correlated positively with plasma KYNA/QUIN ratio in MDD patients. BMI was increased in the MDD group relative to the control group. Moreover, BMI was inversely correlated with plasma and CSF PIC and PIC/QUIN, and positively correlated with plasma QUIN levels in MDD. Our results partially confirm previous peripheral KP findings and extend them to the CSF in MDD. We present the novel finding that abnormalities in KP metabolites are related to metabolic disturbances in depression, but the relation between KP metabolites and depression-associated brain atrophy might not be as direct as previously hypothesized.

GRK3 deficiency elicits brain immune activation and psychosis.

The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3-/- mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1ß, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3-/- mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.

Two-day fasting affects kynurenine pathway with additional modulation of short-term whole-body cooling: a quasi-randomised crossover trial.

Metabolites of the kynurenine (KYN) pathway of tryptophan (TRP) degradation have attracted interest as potential pathophysiological mediators and future diagnostic biomarkers. A greater knowledge of the pathological implications of the metabolites is associated with a need for a better understanding of how the normal behaviour and physiological activities impact their concentrations. This study aimed to investigate whether fasting (FAST) and whole-body cold-water immersion (CWI) affect KYN pathway metabolites. Thirteen young women were randomly assigned to receive the 2-d FAST with two 10-min CWI on separate days (FAST-CWI), 2-d FAST without CWI (FAST-CON), 2-d two CWI on separate days without FAST (CON-CWI) or the 2-d usual diet without CWI (CON-CON) in a randomised crossover fashion. Changes in plasma concentrations of TRP, kynurenic acid (KYNA), 3-hydroxy-kynurenine (3-HK), picolinic acid (PIC), quinolinic acid (QUIN) and nicotinamide (NAA) were determined with ultra-performance liquid chromatography-tandem mass spectrometer. FAST-CWI and FAST-CON lowered TRP concentration (P < 0·05, ηp2 = 0·24), and increased concentrations of KYNA, 3-HK and PIC (P < 0·05, ηp2 = 0·21-0·71) with no additional effects of CWI. The ratio of PIC/QUIN increased after FAST-CWI and FAST-CON trials (P < 0·05) but with a blunted effect in the FAST-CWI trial (P < 0·05) compared with the FAST-CON trials (ηp2 = 0·67). Concentrations of QUIN and NAA were unaltered. This study demonstrated that fasting for 2 d considerably impacts the concentration of several metabolites in the KYN pathway. This should be considered when discussing the potential of KYN pathway metabolites as biomarkers.

Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial.

BACKGROUND: Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects. METHODS: The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18-40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models. RESULTS: Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP. CONCLUSIONS: Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway. TRIAL REGISTRATION: This study is based on a study registered at ClinicalTrials.gov, NCT03392701 . Registered 21 December 2017.

Twin study shows association between monocyte chemoattractant protein-1 and kynurenic acid in cerebrospinal fluid.

Preclinical studies indicate a link between the kynurenine pathway and monocyte chemoattractant protein-1 (MCP-1), but there is a lack of clinical studies examining this further. We here perform a secondary analysis of kynurenine metabolites and MCP-1 in cerebrospinal fluid of 23 twins affected from schizophrenia, bipolar disorder or unaffected. We show an association between MCP-1 and kynurenic acid (KYNA), driven by unique environmental influences and a less pronounced association between MCP-1 and tryptophan. No association was detected between MCP-1 and quinolinic acid. Further studies on the mechanism behind the putative relationship between KYNA and MCP-1 are needed.

Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria.

BACKGROUND: One-fourth of children with cerebral malaria (CM) retain cognitive sequelae up to 2 years after acute disease. The kynurenine pathway of the brain, forming neuroactive metabolites, e.g. the NMDA-receptor antagonist kynurenic acid (KYNA), has been implicated in long-term cognitive dysfunction in other CNS infections. In the present study, the association between the kynurenine pathway and neurologic/cognitive complications in children with CM was investigated. METHODS: Cerebrospinal fluid (CSF) concentrations of KYNA and its precursor kynurenine in 69 Ugandan children admitted for CM to Mulago Hospital, Kampala, Uganda, between 2008 and 2013 were assessed. CSF kynurenine and KYNA were compared to CSF cytokine levels, acute and long-term neurologic complications, and long-term cognitive impairments. CSF kynurenine and KYNA from eight Swedish children without neurological or infectious disease admitted to Astrid Lindgren's Children's Hospital were quantified and used for comparison. RESULTS: Children with CM had significantly higher CSF concentration of kynurenine and KYNA than Swedish children (P < 0.0001 for both), and CSF kynurenine and KYNA were positively correlated. In children with CM, CSF kynurenine and KYNA concentrations were associated with coma duration in children of all ages (P = 0.003 and 0.04, respectively), and CSF kynurenine concentrations were associated with worse overall cognition (P = 0.056) and attention (P = 0.003) at 12-month follow-up in children ≥5 years old. CONCLUSIONS: CSF KYNA and kynurenine are elevated in children with CM, indicating an inhibition of glutamatergic and cholinergic signaling. This inhibition may lead acutely to prolonged coma and long-term to impairment of attention and cognition.

Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients.

BACKGROUND: Neuroinflammation is increasingly recognized as contributing to the pathogenesis of depression. Key inflammatory markers as well as kynurenic acid (KYNA) and quinolinic acid (QUIN), both tryptophan metabolites, have been associated with depressive symptoms and suicidality. The aim of the present study is to investigate the peripheral concentration of cytokines and tryptophan and kynurenine metabolites in patients with unipolar treatment-resistant depression before and after electroconvulsive therapy (ECT), the most effective treatment for depression. METHODS: Cytokines in plasma from patients with major depressive disorder (MDD; n = 19) and healthy volunteers (n = 14) were analyzed with electrochemiluminescence detection. Tryptophan and kynurenine metabolites were detected with high-performance liquid chromatography (HPLC) and LC/MS. KYNA was analyzed in a second healthy control cohort (n = 22). RESULTS: Patients with MDD had increased plasma levels of interleukin (IL)-6 compared to healthy volunteers (P < 0.05). We also found an altered kynurenine metabolism in these patients displayed by decreased plasma levels of KYNA (P < 0.0001) as well as a significantly increased QUIN/KYNA ratio (P < 0.001). Plasma levels of tryptophan, kynurenine, and QUIN did not differ between patients and controls. Treatment with ECT was associated with a significant decrease in the plasma levels of tryptophan (P < 0.05), kynurenine (P < 0.01), and QUIN (P < 0.001), whereas plasma levels of KYNA did not change. The QUIN/KYNA ratio was found to significantly decrease in ECT-treated patients (P < 0.05). There was a significant inverse correlation between symptom severity and kynurenine levels at baseline (r = -0.67, P = 0.002). CONCLUSIONS: This study confirms an imbalanced kynurenine pathway in MDD supporting the hypothesis of a netstimulation of N-methyl-D-aspartic acid (NMDA) receptors in the disorder. Treatment with ECT profoundly decreased QUIN, an NMDA-receptor agonist previously suggested to be implicated in the pathogenesis of depression, an effect that might have bearing for the good clinical outcome of ECT.

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia--significance for activation of the kynurenine pathway.

BACKGROUND: Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway. METHODS: We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were analyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry. RESULTS: We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA. LIMITATIONS: The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age. CONCLUSION: We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA in patients with schizophrenia.

Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment--role of brain kynurenic acid.

Exposure to infections in early life is considered a risk-factor for developing schizophrenia. Recently we reported that a neonatal CNS infection with influenza A virus in mice resulted in a transient induction of the brain kynurenine pathway, and subsequent behavioral disturbances in immune-deficient adult mice. The aim of the present study was to investigate a potential role in this regard of kynurenic acid (KYNA), an endogenous antagonist at the glycine site of the N-methyl-D-aspartic acid (NMDA) receptor and at the cholinergic α7 nicotinic receptor. C57BL/6 mice were injected i.p. with neurotropic influenza A/WSN/33 virus (2400 plaque-forming units) at postnatal day (P) 3 or with L-kynurenine (2×200 mg/kg/day) at P7-16. In mice neonatally treated with L-kynurenine prepulse inhibition of the acoustic startle, anxiety, and learning and memory were also assessed. Neonatally infected mice showed enhanced sensitivity to D-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as adults. Neonatally L-kynurenine treated mice showed enhanced sensitivity to D-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as well as mild impairments in prepulse inhibition and memory. Also, D-amphetamine tended to potentiate dopamine release in the striatum in kynurenine-treated mice. These long-lasting behavioral and neurochemical alterations suggest that the kynurenine pathway can link early-life infection with the development of neuropsychiatric disturbances in adulthood.

Kynurenine Metabolites in CSF and Plasma in Healthy Males.

In recent years, kynurenine metabolites generated by tryptophan catabolism have gained increasing attention in the context of brain diseases. The question of importance is whether there is a relationship between peripheral and central levels of these metabolites. Some of these compounds do not cross the blood-brain barrier; in particular, kynurenic acid, and most analyses of kynurenines from psychiatric patients have been performed using plasma samples. In the present study, we recruited 30 healthy volunteers with no history of psychiatric or neurological diagnosis, to analyze tryptophan, kynurenine, kynurenic acid, and quinolinic acid levels in CSF and plasma. In addition, kynurenic acid was analyzed in urine. The most important finding of this study is that CSF kynurenic acid levels do not correlate with those in plasma or urine. However, we found a correlation between plasma kynurenine and CSF kynurenic acid. Further, plasma kynurenine and plasma quinolinic acid were correlated. Our findings clarify the distribution of tryptophan and its metabolites in various body compartments and may serve as a guide for the analysis of these metabolites in humans. The most significant finding of the present study is that a prediction of brain kynurenic acid by of the analysis of the compound in plasma cannot be made.

The Tryptophan Metabolite Indole-3-Propionic Acid Raises Kynurenic Acid Levels in the Rat Brain In Vivo.

Alterations in the composition of the gut microbiota may be causally associated with several brain diseases. Indole-3-propionic acid (IPrA) is a tryptophan-derived metabolite, which is produced by intestinal commensal microbes, rapidly enters the circulation, and crosses the blood-brain barrier. IPrA has neuroprotective properties, which have been attributed to its antioxidant and bioenergetic effects. Here, we evaluate an alternative and/or complementary mechanism, linking IPrA to kynurenic acid (KYNA), another neuroprotective tryptophan metabolite. Adult Sprague-Dawley rats received an oral dose of IPrA (200 mg/kg), and both IPrA and KYNA were measured in plasma and frontal cortex 90 minutes, 6 or 24 hours later. IPrA and KYNA levels increased after 90 minutes and 6 hours (brain IPrA: ~56- and ~7-fold; brain KYNA: ~4- and ~3-fold, respectively). In vivo microdialysis, performed in the medial prefrontal cortex and in the striatum, revealed increased KYNA levels (~2.5-fold) following the administration of IPrA (200 mg/kg, p.o), but IPrA failed to affect extracellular KYNA when applied locally. Finally, treatment with 100 or 350 mg IPrA, provided daily to the animals in the chow for a week, resulted in several-fold increases of IPrA and KYNA levels in both plasma and brain. These results suggest that exogenously supplied IPrA may provide a novel strategy to affect the function of KYNA in the mammalian brain.

Mood, Cognitive Function, and Plasma Kynurenine Metabolites Responses Following Severe Changes in Physical Activity.

PURPOSE: To monitor changes in mood, cognitive function, brain electrical activity, and circulating kynurenine pathway metabolites in response to a three-week severe physical activity restriction, followed by three weeks of resumed activity adding resistance and high-intensity interval exercise training. METHODS: Twenty healthy participants (14 males, six females; 25.4 ± 5.2 years) underwent three weeks of limited physical activity using forearm crutches with one leg suspended (INACT) and then three weeks of resumed activity plus supervised resistance and high-intensity interval training sessions (ACT, three to six sessions per week). At baseline, after INACT, and then after ACT, venous blood was sampled for analysis of major kynurenine pathway metabolites, a short version of the International Physical Activity Questionnaire (IPAQ-SF), Hospital Anxiety and Depression Scale (HADS) and Profile of Mood States (POMS) questionnaires were completed, and cognitive tests with EEG were performed. RESULTS: During INACT, the depression score on the HADS scale tended to increase (3.5 to 6.8; p = 0.065), while it was reduced with ACT compared with after INACT (2.8; p = 0.022). On the POMS scale, depression, fatigue, and confusion increased within INACT (p < 0.05). Notably, subjects exhibited considerable variability, and those experiencing depression symptoms recorded by the HADS scale (n = 4) displayed distinct mood disturbances on POMS. All HADS and POMS scores were fully restored to baseline with ACT. Neither INACT nor ACT induced significant changes in cognition, brain electrical activity, or kynurenine pathway metabolites (p > 0.05). CONCLUSIONS: While young healthy individuals with three weeks of severely restricted physical activity do not undergo changes in circulating kynurenine pathway metabolites, cognitive performance, and brain electrical activity, their mood response is quite variable, and depression develops in some. Three weeks of resuming mobility plus exercise training reversed the mood profile.

Long-term neurological and neurocognitive impairments after tick-borne encephalitis in Lithuania - a prospective study.

BACKGROUND: The aim of this study was to characterise long-term neurological and neurocognitive sequelae after tick-borne encephalitis (TBE) in adults. METHODS: 98 prospective consecutive TBE patients, classified by disease severity, were included. Immediate outcomes were evaluated with Glasgow Outcome Scale (GOS) and Rankin Scale (RS). After 6 and 18 months, long-term disability was evaluated using Modified Rankin Scale (MRS) and neurocognitive assessment was performed with Matrics Consensus Cognitive Battery (MCCB), measuring processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving and social cognition. The MCCB results were compared to healthy age, gender and education-matched controls. RESULTS: Mild, moderate, and severe TBE was diagnosed in 53.1%, 38.8%, and 8.2% of cases, respectively. At discharge, 25.5% of the patients had major or moderate impairments (GOS) and various levels of disability in 34.7% (RS). Up to 18 months from the onset of TBE, over 20% remained with slight to moderate disability (MRS). GOS, RS and MRS scores correlated with disease severity. At 6 months after the onset, TBE patients scored significantly lower than controls in processing speed, verbal, and visual learning. Two latter domains were significantly more impaired in patients with mild TBE. Patients aged 18-39 performed significantly worse in attention/vigilance and working memory, whereas aged 60+ in verbal learning. A year later, significant improvement was observed in six of seven cognitive domains. CONCLUSIONS: Long-term neurological sequelae persist in a substantial proportion of TBE patients with significant impairment in several cognitive domains, especially in younger patients and even after mild TBE.

Cognitive impairments correlate with increased central nervous system immune activation after allogeneic haematopoietic stem cell transplantation.

Murine studies indicate that, after allogeneic haematopoietic stem cell transplantation (aHSCT), donor-derived macrophages replace damaged microglia and alloreactive T-cells invade the central nervous system (CNS). The clinical relevance of this is unknown. We assessed CNS immune surveillance and metabolic activity involved in neuronal survival, in relation to fatigue and cognitive dysfunction in 25 long-term survivors after aHSCT. Patients with cognitive dysfunction exhibited increased proportions of activated T-cells and CD16 + NK-cells in the cerebrospinal fluid (CSF). Immune cell activation was paralleled with reduced levels of anti-inflammatory factors involved in T-cell suppression (transforming growth factor-ß, programmed death ligand-1), NK-cell regulation (poliovirus receptor, nectin-2), and macrophage and microglia activation (CD200, chemokine [C-X3-C motif] ligand-1). Additionally, the CSF mRNA expression pattern was associated with neuroinflammation and oxidative stress. Furthermore, proteomic, and transcriptomic studies demonstrated decreased levels of neuroprotective factors, and an upregulation of apoptosis pathway genes. The kynurenine pathway of tryptophan metabolism was activated in the CNS of all aHSCT patients, resulting in accumulation of neurotoxic and pro-inflammatory metabolites. Cognitive decline and fatigue are overlooked but frequent complications of aHSCT. This study links post-transplant CNS inflammation and neurotoxicity to our previously reported hypoactivation in the prefrontal cortex during cognitive testing, suggesting novel treatment targets.

Lipopolysaccharide-induced changes in the kynurenine pathway and symptoms of sickness behavior in humans.

Metabolites of the kynurenine pathway are hypothesized to be implicated in inflammation-associated depression, but there is a lack of experimental studies in humans assessing the kinetics of kynurenine metabolites in relation to experimentally-induced sickness. The aim of the present study was to assess changes in the kynurenine pathway and to explore its relation to symptoms of sickness behavior during an acute experimental immune challenge. This double-blind placebo-controlled randomized cross-over study included 22 healthy human participants (n = 21 both sessions, Mage = 23.4, SD = 3.6, nine women) who received an intravenous injection of 2.0 ng/kg lipopolysaccharide (LPS) and saline (placebo) on two different occasions in a randomized order. Blood samples (0 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h post-injection) were analyzed for kynurenine metabolites and inflammatory cytokines. The intensity of symptoms of sickness behavior was assessed using the 10-item Sickness Questionnaire at 0 h, 1.5 h, 3 h, 5 h, and 7 h post-injection. LPS induced significantly lower concentrations of plasma tryptophan (at 2 h, 4 h, 5 h, and 7 h post-injection), kynurenine (at 2 h, 3 h, 4 h, and 5 h post-injection), nicotinamide (at 4 h, 5 h, and 7 h post-injection), and higher levels for quinolinic acid at 5 h post-injection as compared to placebo. LPS did not affect kynurenic acid, 3-hydroxykynurenine, and picolinic acid. The development of the sickness symptoms was largely similar across items, with the highest levels around 1.5-3 h post-injection. Changes in plasma levels of kynurenine metabolites seem to coincide rather than precede or follow changes in subjective sickness. Exploratory analyses indicate that higher Sickness Questionnaire total scores at 1.5-5 h post-injection were correlated with lower kynurenic acid and nicotinamide levels. These results lend further support for LPS-induced changes in the kynurenine pathway, but may not, as interpreted from blood levels, causally link to LPS-induced acute symptoms of sickness behavior. Future research may consider a larger sample to further scrutinize the role of the kynurenine pathway in the sickness response.

CSF dopamine is elevated in first-episode psychosis and associates to symptom severity and cognitive performance.

BACKGROUND: The hypothesis of dopamine dysfunction in psychosis has evolved since the mid-twentieth century. However, clinical support from biochemical analysis of the transmitter in patients is still missing. The present study assessed dopamine and related metabolites in the cerebrospinal fluid (CSF) of first-episode psychosis (FEP) subjects. METHODS: Forty first-episode psychosis subjects and twenty healthy age-matched volunteers were recruited via the Karolinska Schizophrenia Project, a multidisciplinary research consortium that investigates the pathophysiology of schizophrenia. Psychopathology, disease severity, and cognitive performance were rated as well as cerebrospinal fluid concentrations of dopamine and related metabolites were measured using a sensitive high-pressure liquid chromatography assay. RESULTS: CSF dopamine was reliably detected in 50 % of healthy controls and in 65 % of first-episode psychosis subjects and significantly higher in first-episode psychosis subjects compared to age-matched healthy controls. No difference in CSF dopamine levels was observed between drug-naive subjects and subjects with short exposure to antipsychotics. The dopamine concentrations were positively associated with illness severity and deficits in executive functioning. CONCLUSIONS: Dopamine dysfunction has long been considered a cornerstone of the pathophysiology of schizophrenia, although biochemical support for elevated brain dopamine levels has been lacking. The results of the present study, showing that FEP subjects have increased CSF dopamine levels that correlate to disease symptoms, should fill the knowledge gap in this regard.