Peripheral immunoinflammatory markers and clinical correlations in Parkinson's disease patients carrying LRRK2 G2385R and R1628P variants

Peripheral inflammation in Parkinson's disease (PD) remains poorly characterised among carriers of Asian-prevalent LRRK2 G2385R and R1628P variants. We investigated plasma immunoinflammatory markers (i.e., IL-6, TNF-, CCL2, CX3CL1, CCL5, and VCAM-1) via multiplex immunoassay in 240 participants: PD-G2385R (n=53), PD-R1628P (n=58), PD-G2385R+R1628P (n=5), idiopathic PD (iPD; n=62), and controls (n=62), and their clinicobiological correlates including monocyte LRRK2 kinase activity (pRab10Thr73). Compared with iPD and/or controls, TNF-, CCL2, CX3CL1, and CCL5 were lower in PD-G2385R, while IL-6, TNF-, CCL2, and CCL5 were lower in PD-R1628P. Higher LRRK2 kinase activity correlated with lower TNF-. CX3CL1 correlated with greater motor severity in iPD but less disability in both variant groups. CCL5 correlated with less motor complications in PD-G2385R, while IL-6 and VCAM-1 correlated with worse disability and/or cognition in PD-R1628P. These findings suggest that immunoinflammatory profiles and their clinical relevance in PD differ by genotype, with implications for stratification in future immunomodulatory trials.