Abstract
BACKGROUND: Cross-sectional studies have suggested that patients with Parkinson's disease (PD) have significantly lower heart rate variability (HRV) than healthy controls. However, the role of ultra-short HRV (usHRV) as an early biomarker for PD remains unclear. The objective of this study was to investigate the association between usHRV and PD risk and its underlying mechanisms. METHODS: In a prospective cohort study based on the UK Biobank, participants without PD and dementia at baseline who had available 15-second resting electrocardiogram data (n = 48 202) were included. The participants were followed up for an average of 12.24 years, and some were diagnosed with PD (n = 307). Cox proportional hazards models were used to examine the association between usHRV parameters and PD risk. A nested case-control study was conducted within the cohort to further investigate temporal trends in HRV. Mediation analysis was used to explore the underlying mechanisms driven by brain structure, peripheral inflammation, and proteomic biomarkers. RESULTS: We found that lower usHRV parameters were significantly associated with an increased PD risk. Notably, an L-shaped association was observed between the corrected root mean square of successive differences and PD risk. Temporal trend analysis suggested usHRV levels of patients with PD started to decline approximately 10 years before diagnosis. Mediation analysis revealed that thalamus-related fiber tracts, plasma inflammatory, and neuroendocrine markers mediated the association between usHRV and PD risk. CONCLUSIONS: Our findings provide evidence supporting that usHRV may serve as an early, convenient, and noninvasive biomarker of PD risk up to a decade before diagnosis.