Parkinson’s disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction
Year: 2025
Type: article
Study design: Observational Study
Abstract: Parkinson's disease (PD) is a complex multisystem disorder clinically characterized by motor, non-motor, and premotor manifestations. Pathologically, PD involves neuronal loss in the substantia nigra, striatal dopamine deficiency, and accumulation of intracellular inclusions containing aggregates of α-synuclein. Recent studies demonstrate that PD is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). This multicenter study used highly sensitive liquid chromatography-tandem mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. Results indicate that increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau and severity of both motor and non-motor PD clinical dysfunction. Importantly, plasma and CSF kynurenine metabolites classified PD participants with a high degree of accuracy (AUC = 0.897). Finally, analysis of metabolite data revealed subgroups with distinct KP profiles, and these were subsequently found to display distinct PD clinical features. Together, these data further support the hypothesis that the KP serves as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.
Source: npj Parkinson s Disease
Authors: Edward N. Wilson, Jacob Umans, Michelle S. Swarovski, Paras S. Minhas, Justin H. Mendiola, Øivind Midttun, Arve Ulvik, Marian Shahid-Besanti, Patricia Linortner, Siddhita D. Mhatre, Qian Wang, Divya Channappa, Nicole K. Corso, Lu Tian, Carolyn A. Fredericks, Geoffrey A. Kerchner, Edward D. Plowey, Brenna Cholerton, Per M. Ueland, Cyrus P. Zabetian, Nora E. Gray, Joseph F. Quinn, Thomas J. Montine, Sharon J. Sha, Frank M. Longo, David A. Wolk, Alice Chen-Plotkin, Victor W. Henderson, Tony Wyss-Coray, Anthony D. Wagner, Elizabeth C. Mormino, Nima Aghaeepour, Kathleen L. Poston, Katrin I. Andreasson
Language: English
Subfield: Biological Psychiatry
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,890
Funders: U.S. Department of Health and Human Services, Michael J. Fox Foundation for Parkinson's Research, American Heart Association, Cooley's Anemia Foundation, University of Pennsylvania, Jean Perkins Foundation, National Institutes of Health, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
Awards: G1151654597, G1172598993, G1260893416, G1421846007, G1530735441, G1531775036, G1793654115, Machine Learning for Integrative Modeling of the Immune System in Clinical Settings, Hippocampal-dependent memory decline in aging and early Alzheimer's disease, G2502777568, Pacific Udall Center, G2665291689, G3476377297, G348743638, Immunomodulation to promote cerebrovascular and cognitive health, G3953550094, G3956270474, Targeting the kynurenine pathway in Alzheimer's disease, Basal Ganglia Modulation of Cognitive Systems in Parkinson's disease, G4675765292, Biomarkers of cognitive decline in Parkinson's Disease, G4740819463, G4989757568, G5002805933, G5020466020, G504619356, G5212296653, G5453232361, G5459524459, G5617737820, G6098828385, G6250057130, The impact of early Tau pathology on cognitive progression and neuropsychiatric symptoms in Parkinson's disease, G662559107, G6714493491, Regulation of immune cell metabolism in aging and Alzheimer's disease: role of the kynurenine pathway, Penn Alzheimer's Disease Research Center (ADRC), G7157548431, G7470994556, G7686398897, G807536817, High-resolution imaging of hippocampal mechanisms in age-related memory decline., G8344366917, G8466051252, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), G869356358, Oregon Alzheimer's Disease Research Center, G9000004438, G9000021280, G9000023826, G9000026598, G9000063279, G9000065952, G9000095919, G9000154978, G9000180489, G9000202291, G9000217334, G9000226412, G9000226643, G9000315395, Mechanisms Underlying Heterogeneity of Cognitive Outcomes in Synucleinopathy, Center of Excellence in Environmental Toxicology, Stanford Alzheimer's Disease Research Center
OpenAlex ID: W4409835317