Circulating branched-chain amino acids and multimodal signatures of incident Parkinson's disease: a prospective cohort study

The role of circulating branched-chain amino acids (BCAAs) in Parkinson’s disease (PD) remains unclear. We investigated the association between plasma BCAAs and incident PD and characterized their prediagnostic patterns and related biological signatures in 374,751 UK Biobank participants free of PD and other neurodegenerative diseases at baseline. Cox proportional hazards models were used to estimate associations of total BCAAs, leucine, isoleucine, and valine with incident PD.

Restricted cubic splines assessed dose-response relationships, and LOESS smoothing modeled control-standardized pseudotemporal patterns of baseline BCAA levels according to time to PD diagnosis. Fully adjusted linear regression models evaluated associations of BCAAs with PD-related plasma protein biomarkers, PhenoAge acceleration, and diffusion MRI-derived white matter microstructure. Higher circulating levels of total BCAAs, leucine, and valine were associated with lower incident PD risk, with approximately linear inverse dose-response relationships.

Baseline BCAA levels were lower among participants assessed at time points closer to subsequent PD diagnosis. Higher BCAA levels were also associated with lower PhenoAge acceleration, lower GFAP and NEFL levels, and more favorable white matter microstructural profiles. These findings suggest that altered BCAA metabolism may represent a prediagnostic metabolic feature of PD and support further investigation of its biological and translational relevance.

We sincerely thank all participants and researchers of the UK Biobank. Meiyan Chen for her assistance in preparing the study workflow presented in Figure 1. This project was funded by the National Natural Science Foundation of China (T2488101 and 82071417) and the State Key Laboratory of Infectious Disease Prevention and Control, China (2022SKLID306).

Human Brain & Tissue Bank, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China Zhiqing Chen, Bohan Zhang, Chuxin Huang, Liyuan Lu, Jinhui Yin, Yanli Zhang & Yue Huang Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China Centre for Healthy Brain Aging (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.

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