Peripheral Inflammation Is Associated with Dopaminergic Degeneration in Parkinson's Disease.

BACKGROUND: Peripheral inflammatory immune responses are suggested to play a major role in dopaminergic degeneration in Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR) is a well-established biomarker of systemic inflammation in PD. Degeneration of the nigrostriatal dopaminergic system can be assessed in vivo using [123 I]FP-CIT single photon emission computed tomography imaging of striatal dopamine transporter (DAT) density. OBJECTIVES: To assess the relationship between the peripheral immune profile (NLR, lymphocytes, and neutrophils) and striatal DAT density in patients with PD. METHODS: We assessed clinical features, the peripheral immune profile, and striatal [123 I]FP-CIT DAT binding levels of 211 patients with PD (primary-cohort). Covariate-controlled associations between the immune response and striatal DAT levels were assessed using linear regression analyses. For replication purposes, we also studied a separate cohort of 344 de novo patients with PD enrolled in the Parkinson's Progression Markers Initiative (PPMI-cohort). RESULTS: A higher NLR was significantly associated with lower DAT levels in the caudate (primary-cohort: ß = -0.01, p < 0.001; PPMI-cohort: ß = -0.05, p = 0.05) and the putamen (primary-cohort: ß = -0.05, p = 0.02; PPMI-cohort: ß = -0.06, p = 0.02). Intriguingly, a lower lymphocyte count was significantly associated with lower DAT levels in both the caudate (primary-cohort: ß = +0.09, p < 0.05; PPMI-cohort: ß = +0.11, p = 0.02) and the putamen (primary-cohort: ß = +0.09, p < 0.05, PPMI-cohort: ß = +0.14, p = 0.01), but an association with the neutrophil count was not consistently observed (caudate; primary-cohort: ß = -0.05, p = 0.02; PPMI-cohort: ß = 0, p = 0.94; putamen; primary-cohort: ß = -0.04, p = 0.08; PPMI-cohort: ß = -0.01, p = 0.73). CONCLUSIONS: Our findings across two independent cohorts suggest a relationship between systemic inflammation and dopaminergic degeneration in patients with PD. This relationship was mainly driven by the lymphocyte count. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Peripheral inflammatory immune response differs among sporadic and familial Parkinson's disease.

Peripheral inflammatory immune responses are thought to play a major role in the pathogenesis of Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation, has been reported to be higher in patients with PD than in healthy controls (HCs). The present study was aimed at determining if the peripheral inflammatory immune response could be influenced by the genetic background of patients with PD. We included a discovery cohort with 222 patients with PD (132 sporadic PD, 44 LRRK2-associated PD (with p.G2019S and p.R1441G variants), and 46 GBA-associated PD), as well as 299 HCs. Demographic and clinical data were recorded. Leukocytes and their subpopulations, and the NLR were measured in peripheral blood. Multivariate lineal regression and post-hoc tests were applied to determine the differences among the groups. Subsequently, a replication study using the Parkinson's Progression Markers Initiative cohort was performed which included 401 patients with PD (281 sPD patients, 66 LRRK2-PD patients, 54 GBA-PD patients) and a group of 174 HCs. Patients with sporadic PD and GBA-associated PD showed a significantly lower lymphocyte count, a non-significantly higher neutrophil count and a significantly higher NLR than HCs. The peripheral inflammatory immune response of patients with LRRK2-associated PD did not differ from HCs. Our study supports the involvement of a peripheral inflammatory immune response in the pathophysiology of sPD and GBA-associated PD. However, this inflammatory response was not found in LRRK2-associated PD, probably reflecting different pathogenic inflammatory mechanisms.