{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:12:26Z","timestamp":1790644346743,"version":"4.1.0"},"reference-count":67,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"Singapore National Medical Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Open Fund Large Collaborative Grant","award":["MOH-OFLCG24may-0004"],"award-info":[{"award-number":["MOH-OFLCG24may-0004"]}]},{"name":"Singapore Translational Research (STaR) Investigator Award","award":["NMRC\/STaR\/0030\/2018"],"award-info":[{"award-number":["NMRC\/STaR\/0030\/2018"]}]},{"name":"Open Fund-Individual Research Grant","award":["OF-IRG, MOH-001506"],"award-info":[{"award-number":["OF-IRG, MOH-001506"]}]},{"name":"Clinician Scientist-Individual Research Grants","award":["MOH-001091"],"award-info":[{"award-number":["MOH-001091"]}]},{"name":"Clinician Scientist-Individual Research Grants","award":["CIRG23jul-0006"],"award-info":[{"award-number":["CIRG23jul-0006"]}]},{"name":"HLCA2024","award":["HLCA24Mar-0019"],"award-info":[{"award-number":["HLCA24Mar-0019"]}]},{"DOI":"10.13039\/501100001809","name":"Singhealth-Duke-NUS AM Position grant and National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971185"],"award-info":[{"award-number":["81971185"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Singhealth-Duke-NUS AM Position grant and National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171243"],"award-info":[{"award-number":["82171243"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Singhealth-Duke-NUS AM Position grant and National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82401481"],"award-info":[{"award-number":["82401481"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder shaped by genetic factors such as LRRK2 and GBA1 mutations, as well as dietary and metabolic influences. Food-derived plasma metabolites\u2014including caffeine, paraxanthine, trigonelline, piperine, and sitosteryl hexoside\u2014have emerged as promising, accessible biomarkers for early detection, progression monitoring, and therapeutic targeting, yet their longitudinal behavior and genetic interactions remain insufficiently characterized. Using the Parkinson\u2019s Progression Markers Initiative (PPMI) cohort (n = 455; 303 PD patients, 152 controls), we quantified plasma levels of these metabolites by quantitative LC-MS\/MS with batch correction, examining sporadic PD and genetically defined subgroups (LRRK2-PD [PDL], GBA1-PD [PDG], dual-mutation PD [PDGL], and prodromal equivalents). Baseline one-way ANOVA showed significantly lower caffeine and paraxanthine in PDL (p = 0.0467, p = 0.0178) and PDG (p = 0.0408), reduced piperine in PDL (p = 0.0009), PDG (p = 0.0257), and prodromal LRRK2 (p = 0.0168), and elevated sitosteryl hexoside in PDG (p = 0.0184). Longitudinal regression analyses revealed that in sporadic PD, caffeine negatively correlated with MDS-UPDRS parts I (\u03b2 = \u22122, p = 0.0475) and III (\u03b2 = \u22127.2, p = 0.007), trigonelline declined over time and was inversely associated with part III (\u03b2 = \u22121.7, p = 0.0069), and sitosteryl hexoside negatively correlated with parts II (\u03b2 = \u221268.3, p = 0.042) and III (\u03b2 = \u221274.1, p = 0.0425). In PDL, sitosteryl hexoside inversely correlated with part I (\u03b2 = \u221254.2, p = 0.0049), while in PDGL, paraxanthine showed negative associations with part II (\u03b2 = \u221218.5, p = 0.00327). These findings demonstrate subgroup-specific alterations in food-derived metabolites and consistent inverse associations with PD severity, supporting their potential as non-invasive biomarkers, particularly in LRRK2\/GBA1 mutation carriers, and highlighting the need for longitudinal validation and dietary intervention trials to advance personalized PD management.<\/jats:p>","DOI":"10.3390\/ijms27010016","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T12:59:57Z","timestamp":1766149197000},"page":"16","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Plasma Levels of Food-Derived Metabolites as Biomarkers of Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"27","author":[{"given":"Xiaoxue","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.86, Wujin Road, Shanghai 200080, China"},{"name":"Department of Neurology, National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilong","family":"Zheng","sequence":"additional","affiliation":[{"name":"SingHealth PGY1 Program, Singapore General Hospital, Outram Road, Singapore 169608, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn Ting Ying","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Biological Science, Nanyang Technological University, 50 Nanyang Ave, Singapore 639798, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7842-7034","authenticated-orcid":false,"given":"Qiao Yang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2986-4980","authenticated-orcid":false,"given":"Bin","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore"},{"name":"Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eng King","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore"},{"name":"Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857, Singapore"},{"name":"Department of Neurology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Cheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.86, Wujin Road, Shanghai 200080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0251-4163","authenticated-orcid":false,"given":"Zhi Dong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore"},{"name":"Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s disease","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"key":"ref_2","unstructured":"GBD 2016 Neurology Collaborators (2019). 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