Sara K. Olsson

Bio: Sara K. Olsson is an academic researcher from Karolinska Institutet. The author has contributed to research in topics: Kynurenic acid & Kynurenine. The author has an hindex of 13, co-authored 15 publications receiving 1119 citations.

Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia

Abstract: Background: The kynurenic acid (KYNA) hypothesis for schizophrenia is partly based on studies showing increased brain levels of KYNA in patients. KYNA is an endogenous metabolite of tryptophan (TRP ...

Elevation of cerebrospinal fluid interleukin-1ß in bipolar disorder.

Abstract: Background: In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention. Although bipolar disorder appears to be associated with altered serum cytokine levels, a putative immunological contribution to its pathophysiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed. Methods: We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar disorder type I (n = 15) or type II (n = 15) and healthy volunteers (n = 30) using an immunoassay-based protein array multiplex system. Results: The mean interleukin (IL)-1 beta level (4.2 pg/mL, standard error of the mean [SEMI 0.5) was higher and the IL-6 level (1.5 pg/mL, SEM 0.2) was lower in euthymic bipolar patients than in healthy volunteers (0.8 pg/mL, SEM 0.04, and 2.6 pg/mL, SEM 0.2, respectively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1 beta (6.2 pg/mL, SEM 0.8; n = 9) than patients without a recent manic/hypomanic episode (3.1 pg/mL, SEM 1.0; n = 10). Limitations: All patients were in an euthymic state at the time of sampling. Owing to the large variety of drugs prescribed to patients in the present study, influence of medication on the cytokine profile cannot be ruled out. Conclusion: Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1 beta in bipolar disorder.

Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders.

Abstract: The kynurenine pathway constitutes the main route of tryptophan degradation and generates the production of several neuroactive compounds; quinolinic acid is an excitotoxic NMDA receptor agonist, 3-hydroxykynurenine is a free-radical generator and kynurenic acid (KYNA) is an antagonist at glutamate and nicotinic receptors. In low micromolar concentrations, KYNA blocks the glycine site of the NMDA receptor and the nicotinic α7* acetylcholine receptor. Knowledge regarding kynurenine metabolites and their involvement in neurophysiological processes has increased dramatically in recent years. In particular, endogenous KYNA appears to tightly control firing of midbrain dopamine neurons and to be involved in cognitive functions. Thus, decreased endogenous levels of rat brain KYNA have been found to reduce firing of these neurons, and mice with a targeted deletion of kynurenine aminotransferase II display low endogenous brain KYNA levels concomitant with an increased performance in cognitive tests. It is also suggested that kynurenines participate in the pathophysiology of psychiatric disorders. Thus, elevated levels of KYNA have been found in the CSF as well as in the post-mortem brain of patients with schizophrenia. Advantages in understanding how kynurenines can be pharmacologically manipulated may provide new possibilities in the treatment of psychiatric disorders, such as schizophrenia.

The KMO allele encoding Arg 452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression

Abstract: The KMO allele encoding Arg 452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression

Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder

Abstract: Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder

A polygenic burden of rare disruptive mutations in schizophrenia

Abstract: Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

Kynurenines in the mammalian brain: when physiology meets pathology

Abstract: The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.

Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond

Abstract: L-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative. This Review summarizes the physiological and pathophysiological roles of Trp metabolism, highlighting the vast opportunities and challenges for drug development in multiple diseases.