Cerebrospinal Fluid Kynurenic Acid Levels Research Articles

Kynurenic Acid Levels are Increased in the CSF of Alzheimer's Disease Patients.

Kynurenic acid (KYNA) is a product of the tryptophan (TRP) metabolism via the kynurenine pathway (KP). This pathway is activated in neurodegenerative disorders, such as Alzheimer´s disease (AD). KYNA is primarily produced by astrocytes and is considered neuroprotective. Thus, altered KYNA levels may suggest an inflammatory response. Very recently, significant increases in KYNA levels were reported in cerebrospinal fluid (CSF) from AD patients compared with normal controls. In this study, we assessed the accuracy of KYNA in CSF for the classification of patients with AD, cognitively healthy controls, and patients with a variety of other neurodegenerative diseases, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy (PSP). Averaged KYNA concentration in CSF was higher in patients with AD when compared with healthy subjects and with all the other differentially diagnosed groups. There were no significant differences in KYNA levels in CSF between any other neurodegenerative groups and controls. These results suggest a specific increase in KYNA concentration in CSF from AD patients not seen in other neurodegenerative diseases.

Normal Pressure Hydrocephalus, Dementia and Kynurenic Acid

A female 49 years old patient with vestibular schwannoma developed normal pressure hydrocephalus. Patient complained about gait disturbance, urinary incontinence and memory impairment. Investigation of clinical parameter and measurement of kynurenic acid in the cerebrospinal fluid (CSF) and serum in patients with normal pressure hydrocephalus and in corresponding controls (CO; N=15) were performed. Within investigated parameters significant increase of protein and IgG levels in CSF were found in patient with normal pressure hydrocephalus. Furthermore, kynurenic acid was increased in the CSF by 60% and in the serum by 40%, comparing to CO subjects. Kynurenic acid level in CO was in the CSF and serum 2.77 ± 0.23 and 53.4 ± 4.0 nM, respectively. Three lumbar punctures were applied to patient with normal pressure hydrocephalus and clinical parameters partially normalized and lowering of kynurenic acid levels in CSF and serum were observed. Patient was improving after each lumbar puncture but the effect was transient, therefore permanent CSF shunting was recommended. After that a complete remission of symptoms occurred. Revealed data indicate a significant advantage of single punctures in management of treatment for normal pressure hydrocephalus. Increase of kynurenic acid in CSF represents interesting parameter. It is questionable if occurrence of cognition impairment and/or dementia in patients with normal pressure hydrocephalus might be related to an enhancement of kynurenic acid in the CNS.

Distress Intolerance, Kynurenic Acid, and Schizophrenia

Distress Intolerance, Kynurenic Acid, and Schizophrenia

Kynurenic Acid levels in cerebrospinal fluid from patients with Alzheimer's disease or dementia with lewy bodies.

Kynurenic acid (KYNA) is implicated in cognitive functions. Altered concentrations of the compound are found in serum and cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD). Further studies to determine whether KYNA serves as a biomarker for cognitive decline and dementia progression are required. In this study, we measured CSF KYNA levels in AD patients (n = 19), patients with dementia with Lewy bodies (DLB) (n = 18), and healthy age-matched controls (Ctrls)) (n = 20) to further explore possible correlations between KYNA levels, cognitive decline, and well-established AD and inflammatory markers. Neither DLB patients nor AD patients showed significantly altered CSF KYNA levels compared to Ctrls. However, female AD patients displayed significantly higher KYNA levels compared to male AD patients, a gender difference not seen in the Ctrl or DLB group. Levels of KYNA significantly correlated with the AD-biomarker P-tau and the inflammation marker soluble intercellular adhesion molecule-1 (sICAM-1) in the AD patient group. No associations between KYNA and cognitive functions were found. Our study shows that, although KYNA was not associated with cognitive decline in AD or DLB patients, it may be implicated in AD-related hyperphosphorylation of tau and inflammation. Further studies on larger patient cohorts are required to understand the potential role of KYNA in AD and DLB.

The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression

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.

Sustained Elevation of Kynurenic Acid in the Cerebrospinal Fluid of Patients with Herpes Simplex Virus Type 1 Encephalitis

Herpes simplex virus (HSV) type 1 encephalitis (HSE) is a viral infectious disease with commonly occurring neurodegeneration and neurological/cognitive long-term sequelae. Kynurenic acid (KYNA) is a neuroactive tryptophan metabolite, which is elevated in the cerebrospinal fluid (CSF) during viral infection as a result of immune activation. The aim of the study was to investigate the role of endogenous brain KYNA for the long-term outcome of the disease. CSF KYNA concentration was analyzed in 25 HSE patients along the course of the disease and compared with that of 25 age-matched healthy volunteers. Within 3 weeks of admission CSF KYNA of HSE patients was markedly elevated (median 33.6 nM) compared to healthy volunteers (median 1.45 nM). Following a decline observed after 1–2 months, levels of CSF KYNA were elevated more than 1 year after admission (median 3.4 nM range: 1–9 years). A negative correlation was found between initial CSF KYNA concentrations and severity of the long-term sequelae.This study show a marked elevation in CSF KYNA from patients with HSE, most pronounced during the acute phase of the disease and slowly declining along the recovery. We propose that brain KYNA might potentially protect against neurodegeneration while causing a long-lasting loss in cognitive function associated with the disease.

Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder

Kynurenic acid (KYNA), an end metabolite of tryptophan degradation, antagonizes glutamatergic and cholinergic receptors in the brain. Recently, we reported elevated levels of cerebrospinal fluid (CSF) KYNA in male patients with bipolar disorder. Here, we investigate the relationship between symptomatology and the concentration of CSF KYNA in patients with bipolar I disorder. CSF KYNA levels from euthymic male {n = 21; mean age: 41 years [standard deviation (SD) = 14]} and female [n = 34; mean age: 37 years (SD = 14)] patients diagnosed with bipolar I disorder were analyzed using high-performance liquid chromatography (HPLC). Euthymic bipolar I disorder patients with a lifetime occurrence of psychotic features had higher CSF levels of KYNA {2.0 nm [standard error of the mean (SEM) = 0.2]; n = 43} compared to patients without any history of psychotic features [1.3 nm (SEM = 0.2); n = 12] (p = 0.01). Logistic regression, with age as covariate, similarly showed an association between a history of psychotic features and CSF KYNA levels [n = 55; odds ratio (OR) = 4.9, p = 0.03]. Further, having had a recent manic episode (within the previous year) was also associated with CSF KYNA adjusted for age (n = 34; OR = 4.4, p = 0.03), and the association remained significant when adjusting for a lifetime history of psychotic features (OR = 4.1, p = 0.05). Although the causality needs to be determined, the ability of KYNA to influence dopamine transmission and behavior, along with previous reports showing increased brain levels of the compound in patients with schizophrenia and bipolar disorder, may indicate a possible pathophysiological role of KYNA in the development of manic or psychotic symptoms.

Elevated cerebrospinal fluid kynurenic acid levels in patients with tick‐borne encephalitis

Kynurenic acid (KYNA) is a neuroactive metabolite of tryptophan that is thought to regulate cognitive functions. Previous studies have shown that levels of KYNA increase during virus infection and that this metabolite interacts with the immune system. The aim of the study was to investigate whether patients with tick-borne encephalitis (TBE), a viral infectious disease associated with long-term cognitive impairment, have increased levels of KYNA in the cerebrospinal fluid (CSF). CSF KYNA was analysed using high-performance liquid chromatography in 108 patients with TBE and 52 age-matched controls. Patients were classified according to the severity of TBE: mild (47%), moderate (44%) or severe (9%). Concentrations of CSF KYNA were considerably higher in patients with TBE (5.3 nmol L(-1) ) than in control subjects (0.99 nmol L(-1) ). KYNA concentration in the CSF varied greatly amongst individuals with TBE and increased (P < 0.05) with the severity of disease. This is the first study to demonstrate increased levels of CSF KYNA in patients with TBE. The importance of brain KYNA in both immune modulation and neurotransmission raises the possibility that abnormal levels of the compound in TBE might play a part in the pathophysiology of the disease. A detailed knowledge of endogenous brain KYNA during the course of CNS infection might yield further insights into the neuroimmunological role of the compound and may also provide new pharmacological approaches for the treatment of cognitive symptoms.

Acute psychotic symptoms in HIV-1 infected patients are associated with increased levels of kynurenic acid in cerebrospinal fluid

Human immunodeficiency virus type 1 (HIV-1) infection is associated with psychiatric complications including cognitive impairment, affective disorders, and psychosis. Previous studies have revealed a disturbed kynurenine metabolism in these patients leading to increased levels of neuroactive compounds acting at glutamatergic neurotransmission. Kynurenic acid (KYNA), one of these metabolites is a glutamate-receptor antagonist, preferentially blocking the glycine site of the N-methyl- d-aspartate (NMDA) receptor. Increased levels of brain KYNA have been suggested to induce a NMDA receptor hypofunction that is associated with psychotic symptoms. In the present study, we analyze the concentration of KYNA in the cerebrospinal fluid (CSF) from HIV-1 infected patients ( n = 22), including HIV-1 infected patients with psychotic symptoms ( n = 8) and HIV-1 infected patients without psychiatric symptoms ( n = 14). We found that HIV-1 infected patients had significantly higher median concentration of CSF KYNA (3.02 nM) compared to healthy controls (1.17 nM). Furthermore, CSF KYNA levels were significantly elevated in HIV-1 infected patients with psychotic symptoms (4.54 nM) compared to patients with HIV-1 without psychiatric symptoms (2.28 nM). Present results indicate that increased levels of CSF KYNA may be associated with development of psychotic symptoms in HIV-1 infected patients.

Cerebrospinal fluid kynurenic acid in male and female controls – Correlation with monoamine metabolites and influences of confounding factors

The concentrations of the tryptophan metabolite kynurenic acid (KYNA) and the monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were determined in the cerebrospinal fluid (CSF) from 43 healthy volunteers (30 males and 13 females). Healthy female controls displayed higher CSF concentration of KYNA (1.91 nM ± 0.20) compared to healthy male controls (1.06 nM ± 0.07) and lower CSF levels of HMPG (39.2 nM ± 2.0 and 43.4 ± 1.2, respectively). CSF levels of HVA and 5-HIAA did not differ between females (181.3 nM ± 21.9 and 93.7 nM ± 11.4, respectively) and males (138.9 nM ± 12.6 and 74.8 nM ± 5.9, respectively). Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA while CSF content of HMPG did not correlate with KYNA or the other monoamine metabolites in CSF. A negative correlation was found between back length and CSF concentrations of KYNA, HVA and 5-HIAA and also between CSF KYNA levels and body height. The results of the present study suggest that concentrations of KYNA and the monoamine metabolites in CSF from healthy controls are dependent on gender and back length, which must be taken in consideration when analysing mixed groups of men and women. The higher KYNA concentration found in female controls compared to male might be attributed to a shorter back in women compared to men. Furthermore, these findings suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover.

Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia

Previous studies have shown that endogenous brain levels of kynurenic acid (KYNA), a glutamate receptor antagonist, are elevated in patients with schizophrenia. Here we analyse KYNA in the cerebrospinal fluid (CSF) from a large cohort, including male healthy controls (n=49) and male patients with schizophrenia (n=90). We found that male patients with schizophrenia had significantly higher levels of CSF KYNA compared to healthy male controls (1.45 nM±0.10 vs. 1.06 nM±0.06 in the control group). Furthermore, when the patients with schizophrenia were divided into subgroups we found that CSF KYNA levels were significantly elevated in drug-naïve, first episode patients (1.53 nM±0.19, n=37) and in patients undergoing treatment with antipsychotic drugs (1.53 nM±0.17, n=34) compared to healthy male controls. No elevated CSF KYNA levels were detected in drug-free patients with schizophrenia, i.e. patients previously undergoing antipsychotic medications but drug-free at time of sampling (1.16 nM±0.10, n=19). Present results confirm that CSF KYNA concentration is elevated in patients with schizophrenia and are consistent with the hypothesis that KYNA contributes to the pathophysiology of the disease.

Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients

The present study was undertaken to measure cerebrospinal fluid (CSF) levels of kynurenic acid (KYNA) in patients with relapsing-onset multiple sclerosis (MS) during remission or not progressing for at least 2 months. In these patients the levels of CSF KYNA were found to be significantly lower compared with subjects with non-inflammatory neurological diseases, as well as those with inflammatory disease (median (interquartile range): 0.41 (0.3–0.5) pmol/ml, n=26 vs. 0.67 (0.5–1.1), n=23, P<0.01 and 1.7 (1.5–2.6), n=16, P<0.001, respectively). These results provide further evidence of the alterations in the kynurenine pathway during remitting-onset MS.

Studies on cerebrospinal fluid kynurenic acid concentrations in epileptic children

Kynurenic acid (KYA), the only known endogenous antagonist of the excitatory amino acids, is a metabolite of kynurenine. In the present study the levels of KYA were measured in the cerebrospinal fluid (CSF) of epileptic children and age-matched controls to investigate the relationship between various forms of epilepsy and KYA levels. CSF samples from four patients with West syndrome (WS), four patients with epilepsy with grand mal seizures on awakening (EGSA), and four patients with childhood epilepsy with occipital paroxysms (CEOP) were collected by lumbar puncture before treatment. The concentration of CSF KYA was analyzed by HPLC with electrochemical detection and compared with those of age-matched controls. The levels of CSF KYA were significantly lower (P < 0.05) in patients with WS compared with controls. The levels of CSF KYA in patients with EGSA and with CEOP did not differ significantly from control levels. These results suggest that the presence of seizures in WS is associated with altered kynurenine metabolism. The possibility that seizures in WS may be related to decreased production of KYA is discussed.

Kynurenic acid is decreased in cerebrospinal fluid of patients with infantile spasms

Cerebrospinal fluid (CSF) from 8 patients with symptomatic infantile spasms was collected before specific treatment for infantile spasms. The concentration of CSF kynurenic acid (KYA) and 3-hydroxykynurenine (3-OHKY) in infantile spasms was analyzed by high-performance liquid chromatography and compared with CSF KYA from 10 age-matched controls. The levels of CSF KYA were significantly lower in infantile spasm patients compared to controls ( P < .05). In contrast, the levels of CSF 3-OHKY were significantly higher in infantile spasm patients than in controls ( P < .05). These findings suggest that the presence of seizures in infantile spasms is associated with altered metabolism of 3-OHKY. The possibility that seizures may be related to increased or decreased production of certain kynurenine metabolites is discussed.

A mechanism for increased quinolinic acid formation following acute systemic immune stimulation

Mechanisms for increased levels of quinolinic acid (QUIN) following systemic immune stimulation were investigated. In gerbils, systemic administration of pokeweed mitogen (PWM) increased plasma and cerebrospinal fluid QUIN levels, while plasma kynurenic acid levels were decreased and cerebrospinal fluid kynurenic acid levels were unchanged. PWM also increased the QUIN concentrations of brain and systemic tissues. In slices of spleen, lung, liver, duodenum, and kidney, PWM caused marked increases in [13C6]QUIN formation from L-[13C6]tryptophan (but not from [13C6]anthranilic acid). PWM also increased QUIN excretion in the urine and enhanced the formation and excretion of [13C6]QUIN following an intraperitoneal injection of L-[13C6]tryptophan. Indoleamine-2,3-dioxygenase activity was increased in the brain, kidney, lung, spleen, and duodenum while hepatic L-tryptophan-2,3-dioxygenase activity was reduced, data consistent with in vitro L-kynurenine formation from L-tryptophan. Kynurenine-3-hydroxylase activity was increased in the duodenum, lung, and spleen, but not in the brain, kidney, or liver. Kynureninase activity was increased in the brain, lung, and duodenum, but not in the spleen, kidney, or liver. 3-Hydroxyanthranilate-3,4-dioxygenase activity was unchanged in the brain, lung, and liver. No change in kynurenine aminotransferase activity was observed in the brain or lung, while liver kynurenine aminotransferase activity was reduced. We conclude that increased activities of kynurenine pathway enzymes in various tissues following systemic immune stimulation, in conjunction with macrophage infiltration of the affected tissue, provide a mechanism to account for increased concentrations of QUIN.

Inter-relationships between quinolinic acid, neuroactive kynurenines, neopterin and β 2-microglobulin in cerebrospinal fluid and serum of HIV-1-infected patients

Quinolinic acid (QUIN) is an neurotoxic N- methyl- d- aspartate receptor agonist and an l-tryptophan metabolite of the kynurenine pathway. Increased concentrations of QUIN occur in both cerebrospinal fluid (CSF) and blood of patients infected with human immunodeficiency virus (HIV)-1, particularly those with neurologic disturbances. In the present study of HIV-1 infected patients in Walter Reed stages 4,5, and 6, reductions in l-tryptophan accompanied proportional increases in l-kynurenine and QUIN in both serum and CSF. Further, close inter-correlations exist between QUIN kynurenic acid and L-kynurenine with both β 2-microglobulin and neopterin in CSF and serum. These correlations support the hypotheses that the kynurenine pathway is activated in association with inflammation and induction of indoleamine-2,3-dioxygenase. There were no relationships between CSF QUIN, l-kynurenine or kynurenic acid with the ratio of serum: CSF albumin concentrations, which indicates that the increases in CSF QUIN, l-kynurenine or kynurenic acid were not dependent on a breakdown of the blood-brain barrier. Kynurenic acid is also a kynurenine pathway metabolite that can attenuate the excitotoxic effects of QUIN when present in higher molar concentrations. While CSF kynurenic acid levels were increased in HIV-1 infected patients, the magnitude of the increases were smaller than those of QUIN and the molar concentrations of kynurenic acid were consistently lower than QUIN by at least one order of magnitude. We conclude that immune activation increases the levels of neuroactive kynurenines within the central nervous system of HIV-1 infected patients secondary to activation of indoleamine-2,3-dioxygenase.