Objective: To investigate the peripheral inflammatory cytokine levels and their associations with clinical severity, dopaminergic presynaptic degeneration in asymptomatic carriers and PD patients with LRRK2 mutation.To investigate the peripheral inflammatory cytokine levels and their associations with clinical severity, dopaminergic presynaptic degeneration in asymptomatic carriers and PD patients with LRRK2 mutation.

Background: LRRK2 mutations cause familial/sporadic Parkinson’s disease (PD), with emerging links to inflammation. While peripheral inflammation is observed in LRRK2 carriers and PD patients, its relationship with dopaminergic degeneration across disease stages remains unclear.

Method: We analyzed peripheral inflammation in 24 asymptomatic LRRK2 carriers, 30 LRRK2-PD, 25 sporadic PD, and 20 controls. Assessments included 18F-FP-DTBZ PET, serum cytokines (IL-10/IL-8/IL-4/IFN-γ/IL-22/IL-12p70/IL-2), T-cell subsets (Th1/Th2/Th17), and standardized clinical scales.

Results: Asymptomatic LRRK2 carriers, LRRK2-PD, and idiopathic PD had higher IL-10 levels than controls (P = 0.025, 0.040, 0.028). Asymptomatic LRRK2 carriers also had higher IL-8 (P = 0.032), IL-4 (P = 0.021), and IFN-γ (P = 0.022) compared to LRRK2-PD, and higher IL-22 than controls (P = 0.033), after adjusting for age. LRRK2-PD had more T helper cells than idiopathic PD (P = 0.015) and controls (P = 0.031). LRRK2-PD also had increased Th2 cells (P = 0.032), while PD had more Th1 cells (P = 0.008) than controls. In asymptomatic LRRK2 carriers, IL-12p70 correlated with depression (R = 0.54, P = 0.006) and IL-4 with RBDQHK scores (R = 0.46, P = 0.043). No significant correlation was found between inflammatory cytokines and dopaminergic degeneration. In LRRK2-PD, IFN-γ was negatively correlated with Hoehn and Yahr stage (R = -0.53, P = 0.003) and MDS-UPDRS III (R = -0.49, P = 0.0006), while IL-2 was negatively correlated with cognitive scores (R = -0.45, P = 0.037).

Conclusion: In this study, elevated cytokines in asymptomatic LRRK2 carriers indicate early immune changes. And, we highlight distinct immune profiles in LRRK2-PD and iPD, with Th2 and Th1 biases, respectively, suggesting different inflammatory mechanisms. However, given the small sample size, larger longitudinal studies are needed to validate these findings and their clinical relevance.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/inflammatory-profile-in-lrrk2-associated-prodromal-and-clinical-pda-cross-sectional-study/