Quinolinic acid, a kynurenine/tryptophan pathway metabolite, associates with impaired cognitive test performance in systemic lupus erythematosus

Abstract

Objectives: Interferon-alpha, an important contributor to SLE pathogenesis, induces the enzyme indoleamine 2,3-dioxygenase in the kynurenine/tryptophan (KYN/TRP) pathway. This leads to a potentially neurotoxic imbalance in the KYN/TRP pathway metabolites, quinolinic acid (QA), an N-methyl D-aspartate glutamatergic receptor (NMDAR) agonist, and kynurenic acid (KA), an NMDAR antagonist. We determined whether QA/KA ratios associate with cognitive dysfunction (CD) and depression in SLE.

Methods: This cross-sectional study included 74 subjects with SLE and 74 healthy control (HC) subjects; all without history of neuropsychiatric disorders. Serum metabolite levels (KYN, TRP, QA, KA) were measured concurrently with assessments of cognition (Automated Neuropsychological Assessment Metrics (ANAM), 2×2 array), mood and pain, and compared between SLE and HC. Multivariable modelling in SLE was used to evaluate associations of metabolites with cognitive performance and depression.

Results: Serum KYN/TRP and QA/KA ratios were elevated in SLE versus HC (p<0.0001). SLE performed worse than HC on four of five ANAM tests (all p≤0.02) and the 2×2 array (p<0.01), and had higher depression scores (p<0.01). In SLE, elevated QA/KA ratios correlated with poor performance on Match to Sample (MTS), a working memory and visuospatial processing task (p<0.05). Subjects with SLE with elevated QA/KA ratios also had slightly higher odds of depression, but this did not reach significance (p=0.09). Multivariable modelling in SLE confirmed an association between QA/KA ratios and poor MTS performance when considering potentially confounding factors (p<0.05).

Conclusions: Elevated serum KYN/TRP and QA/KA ratios confirm KYN/TRP pathway activation in SLE. The novel association between increased QA/KA ratios and poor cognitive performance supports further study of this pathway as a potential biomarker or therapeutic target for SLE-mediated CD.

Keywords: autoimmunity; cytokines; inflammation; lupus erythematosus; systemic.

Figure 1

The kynurenine/tryptophan (KYN/TRP) pathway. This is a simplified schematic of the KYN/TRP pathway, highlighting the intermediates and enzymes involved in the production of quinolinic acid (QA) and kynurenic acid (KA). The enzyme IDO is stimulated by inflammatory cytokines, such as IFN⍺, that results in the breakdown of TRP into KYN. KYN may be further metabolised by KMO ultimately to QA, an NMDAR agonist, or by KAT to KA, an NMDAR antagonist. Since the enzyme KMO has higher affinity for KYN than KAT, metabolism proceeds preferentially towards the production of QA in the setting of inflammation. IDO, indoleamine 2,3-dioxygenase; IFNα, interferon-alpha; IFNγ, interferon-gamma; NMDAR, N-methyl D-aspartate glutamatergic receptor; TNFα, tumor necrosis factor-alpha.

Figure 2

KYN/TRP pathway metabolite ratios in subjects with SLE compared with healthy controls (HC). Serum metabolite ratios measured by HPLC-MS in 74 subjects with SLE and 74 HC. Subjects with SLE demonstrate a significantly higher KYN/TRP ratio (A) and QA/KA ratio (B) than HC. HPLC-MS, high-performance liquid chromatography-mass spectrometry; KA, kynurenic acid; KYN, kynurenine; QA, quinolinic acid; TRP, tryptophan.