Parkinson’s disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction
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<sub>6</sub> 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.
Authors
- Michelle S. Swarovski (ORCID: https://orcid.org/0009-0009-0375-3298)
- Cyrus P. Zabetian (ORCID: https://orcid.org/0000-0002-7739-4306)
- Nicole K. Corso (ORCID: https://orcid.org/0000-0002-8004-5617)
- Lü Tian (ORCID: https://orcid.org/0000-0002-5893-0169)
- Anthony D. Wagner (ORCID: https://orcid.org/0000-0003-0624-4543)
- Frank M. Longo (ORCID: https://orcid.org/0000-0002-9514-7325)
- Geoffrey A. Kerchner (ORCID: https://orcid.org/0000-0001-7674-0695)
- Arve Ulvik (ORCID: https://orcid.org/0000-0003-1574-9690)
- Carolyn Fredericks (ORCID: https://orcid.org/0000-0002-7051-6382)
- Per Magne Ueland (ORCID: https://orcid.org/0000-0002-1903-0571)
- Tony Wyss‐Coray (ORCID: https://orcid.org/0000-0001-5893-0831)
- Katrin I. Andreasson (ORCID: https://orcid.org/0000-0001-8391-4155)
- Nima Aghaeepour (ORCID: https://orcid.org/0000-0002-6117-8764)
- David A. Wolk (ORCID: https://orcid.org/0000-0002-3554-3481)
- Edward Norman Wilson (ORCID: https://orcid.org/0000-0003-0640-5247)
- Paras S. Minhas (ORCID: https://orcid.org/0000-0002-7741-3327)
- Brenna Cholerton (ORCID: https://orcid.org/0000-0002-2139-987X)
- Nora E. Gray (ORCID: https://orcid.org/0000-0001-6848-859X)
- Kathleen L. Poston (ORCID: https://orcid.org/0000-0003-3424-7143)
- Øivind Midttun (ORCID: https://orcid.org/0000-0003-2937-5351)
- Divya Channappa
- Sharon J. Sha (ORCID: https://orcid.org/0000-0002-3666-1463)
- Alice Chen‐Plotkin (ORCID: https://orcid.org/0000-0002-3387-2038)
- Thomas J. Montine (ORCID: https://orcid.org/0000-0002-1346-2728)
- Jaime Mendiola (ORCID: https://orcid.org/0000-0002-0657-9346)
- Elizabeth C. Mormino (ORCID: https://orcid.org/0000-0002-4542-6537)
- Edward D. Plowey (ORCID: https://orcid.org/0000-0001-9016-4751)
- Marian Shahid (ORCID: https://orcid.org/0000-0002-8515-3238)
- Siddhita D. Mhatre (ORCID: https://orcid.org/0000-0001-9939-780X)
- Joseph F. Quinn (ORCID: https://orcid.org/0000-0001-7305-2256)
- Victor W. Henderson (ORCID: https://orcid.org/0000-0003-1198-9240)
- Patricia Linortner
- Jacob Umans (ORCID: https://orcid.org/0000-0001-9826-5573)
- Qian Wang (ORCID: https://orcid.org/0000-0001-5504-0008)
Institutions
- Roche (Switzerland) (CH)
- Oregon Health & Science University (US)
- Neurosciences Institute (US)
- University of Washington (US)
- Portland VA Medical Center (US)
- Yale University (US)
- VA Puget Sound Health Care System (US)
- Stanford Health Care (US)
- Chan Zuckerberg Initiative (United States) (US)
- Stanford Medicine (US)
- Bevital (Norway) (NO)
- University of Pennsylvania (US)
- Stanford University (US)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-04-26
- DOI
- https://doi.org/10.1038/s41531-025-00964-7
- Citations
- 13
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 7.51
Funders
- Michael J. Fox Foundation for Parkinson's Research
- American Heart Association
- University of Pennsylvania
- Jean Perkins Foundation
- National Institutes of Health
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke