Tryptophan Metabolites Are Associated With Symptoms and Nigral Pathology in Parkinson's Disease

Abstract

A BS TRACT: Background: The objective of this study was to determine whether neurotoxic kynurenine metabolites, induced by inflammation, in plasma and cerebrospinal fluid (CSF) are associated with symptom severity and nigral pathology in Parkinson's disease (PD). Methods: Clinical and MRI data were obtained from 97 PD and 89 controls. We used ultra-performance liquid chromatography to quantify kynurenine metabolites and high-sensitivity multiplex assays to quantify inflammation in plasma and CSF. We evaluated group-wise differences as well as associations between the biomarkers, motor and nonmotor symptoms, and nigral R2* (MRI metric reflecting iron content). Results: PD subjects had >100% higher 3-hydroxykynurenine and 14% lower 3-hydroxyanthranilic acid in plasma. The 3-HK in plasma was closely associated with both symptom severity and disease duration. PD subjects also had 23% lower kynurenic acid in the CSF. Higher CSF levels of the excitotoxin quinolinic acid were associated with more severe symptoms, whereas lower levels of the neuroprotective kynurenic acid were linked to olfactory deficits. An elevated quinolinic acid/picolinic acid ratio in the CSF correlated with higher R2* values in the substantia nigra in the entire cohort. Plasma C-reactive protein and serum amyloid alpha were associated with signs of increased kynurenine pathway activity in the CSF of PD patients, but not in controls. Conclusions: In PD, the kynurenine pathway metabolite levels are altered in both the periphery and the central nervous system, and these changes are associated with

Gut Microbiota Dysbiosis Is Associated with Elevated Bile Acids in Parkinson’s Disease

“…We report significant increases in Burkholderiales which is a bacterial genus with a broad environmental distribution [ 41 ]. Burkholderia can cause severe inflammation in immunocompromised individuals [ 41 ] and produce kynurenine and quinolinate [ 42 ], which are proinflammatory metabolites associated with symptom severity in PD [ 43 ]. Burkholderia has also been reported to infect the brain [ 44 , 45 ].…”

Is COVID-19 a Perfect Storm for Parkinson’s Disease?

“…Several studies have demonstrated elevated interleukin (IL)-6 levels in COVID-19, and one report suggested that the kynurenine pathway is perturbed [ 8 ]. Interestingly, these are both mechanisms that have been associated with PD [ 2 , 9 ].…”

Tryptophan Metabolism and Gut-Brain Homeostasis

“…Recent work has also revealed that tryptophan metabolism is deranged in PD and represents a potential therapeutic target. PD patients have markedly elevated 3-HK in plasma and reduced 3-HANA [ 110 ]. KA is significantly reduced and QA levels correlated with disease severity in these patients, indicating a potential pathogenic role of TPH metabolites in exacerbating excitotoxic injury, though a causal role remains to be established.…”