Parkinson’s disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction
Edward N. Wilson, Jacob Umans, Michelle S. Swarovski, Paras S. Minhas, Jaime Mendiola, Øivind Midttun, Arve Ulvik, Marian Shahid, Patricia Linortner, Siddhita D. Mhatre, Qian Wang, Divya Channappa, Nicole K. Corso, Lü Tian, Carolyn Fredericks, Geoffrey A. Kerchner, Edward D. Plowey, Brenna Cholerton, Per Magne 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
Abstract
Abstract Recent studies demonstrate that Parkinson’s disease (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). Here, we used mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. We found increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B 6 deficiency. Furthermore, increased QA tracked with CSF tau, CSF soluble TREM2 (sTREM2) and severity of both motor and non-motor PD clinical symptoms. Finally, PD patient subgroups with distinct KP profiles displayed distinct PD clinical features. These data validate the KP as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.