Objective: To investigate plasma cytokines and chemokines with clinical correlations between Parkinson’s disease (PD) patients carrying LRRK2 p.G2385R and/or p.R1628P variants, idiopathic PD (iPD), and healthy controls.

Background: Peripheral inflammation is one of the pathological features in PD yet understanding of inflammation in Asian-prevalent LRRK2 p.G2385R and p.R1628P variants, each affecting 5-10% of PD patients, remains limited.

Method: This study included 240 participants, comprising PD-G2385R (n=53), PD-R1628P (n=58), PD-G2385R+R1628P (n=5), age- and sex-matched iPD (n=62), and healthy controls (HC; n=62) who were negative for p.G2385R and p.R1628P. Exclusion criteria were recent vaccination, acute illness, presence of autoimmune diseases, use of steroids or immune-modulating therapy, and inability to complete assessments. Plasma IL-6, TNF-α, CCL2, CX3CL1, CCL5 and VCAM-1 were measured using multiplexed immunoassay. Clinical severity was evaluated using standardised MDS-UPDRS, CISI-PD, and MoCA ratings.

Results: Compared to iPD and/or HC, TNF-α, CX3CL1, and CCL5 were significantly lower in PD-G2385R and IL-6, TNF-α, CCL2, and CCL5 were reduced in PD-R1628P [figure1].  Among PD patients, lower plasma TNF-α levels were associated with higher LRRK2 kinase activity. Higher CX3CL1 was correlated with greater motor severity in iPD, but it indicated less disability in both PD-G2385R and PD-R1628P [figure2]. In PD-G2385R, higher plasma CCL5 was correlated with fewer motor response complications, whereas in PD-R1628P, IL-6 and VCAM-1 were correlated with greater disability and/or poorer cognition.

Conclusion: PD-G2385R and PD-R1628P patients exhibited a mild but significantly reduced peripheral inflammatory profile, distinct from that in iPD. These findings suggest that the inflammatory profile in PD differs by LRRK2 genotype and may not follow a straightforward, uniformly proinflammatory pattern, which is an important factor to consider in anti-inflammatory PD trials.

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References: [1] Morris, H. R., Spillantini, M. G., Sue, C. M., & Williams-Gray, C. H. (2024). The pathogenesis of Parkinson’s disease. Parkinson’s Disease, 403(10423), 293–304. https://doi.org/10.1016/S0140-6736(23)01478-2
[2] Simpson, C., Vinikoor-Imler, L., Nassan, F. L., Shirvan, J., Lally, C., Dam, T., & Maserejian, N. (2022). Prevalence of ten LRRK2 variants in Parkinson’s disease: A comprehensive review. Parkinsonism & Related Disorders, 98, 103–113. https://doi.org/10.1016/j.parkreldis.2022.05.012

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MDS Abstracts - https://www.mdsabstracts.org/abstract/peripheral-inflammatory-markers-and-clinical-correlations-in-parkinsons-disease-patients-carrying-lrrk2-g2385r-and-r1628p-variants/