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.


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This project was a retrospective study, including a discovery cohort with patients with Parkinson's disease (PD) from the Movement Disorder Clinic at Hospital Universitario Virgen del Rocio in Seville, Spain. PD was diagnosed following the Movement Disorder Society Clinical Diagnostic Criteria (Postuma et al. 2015). Patients with PD were classified into three subgroups according to their genetic background: 132 sPD patients, 44 LRRK2-PD patients and 46 GBA-PD patients. sPD patients did not have any variants in the PD-associated genes. The LRRK2-PD group included 33 LRRK2 p.G2019S PD patients and 11 LRRK2 p.R1441G PD patients. The list of GBA pathogenic variants considered for the inclusion of patients in the GBA-PD group is shown in Table 4. For our discovery cohort, patients with PD were recruited from the Movement Disorder Clinic at Hospital Universitario Virgen del Rocio (Seville, Spain). Healthy controls were volunteers from the same geographical area, and they were not considered for the study if they had any neurodegenerative disorder, a family history of PD, or a variant in LRRK2 or GBA genes. For validating the peripheral immune profile in PD according to their genetic background, we used as replication cohort the Parkinson's Progression Markers Initiative (PPMI) cohort: an international, multisite, prospective, longitudinal cohort study. The PPMI data used in this study were downloaded on June 2, 2022.
We obtained consent from the local ethics committee (Hospital Universitario Virgen del Rocío, Seville, Spain) in accordance with the Declaration of Helsinki, and written informed consent from all the participants in the study. The PPMI study was approved by the local institutional review boards of all participating sites.
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Sample size
This project was a retrospective study. No sample size calculation was performed. All patients with Parkinson's disease genetically characterized were included, and then selection criteria were applied. Total leukocyte count and subpopulations (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) in peripheral blood were measured in the Central Laboratory of our center using Sysmex XN automated haematology analyser (at Hospital Universitario Virgen del Rocio, Seville, Spain).

Data exclusions
Data of patients with Parkinson's disease and data of healthy controls were excluded following the pre-established exclusion criteria. Also, data of those individuals with missing values were excluded too Replication A replication cohort was used for validating our results. The Parkinson's Progressive Markers Initiative cohort was used.

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No randomization was performed.

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Investigators were blinded during retrospective data collection (demographic and clinical data from both healthy controls and patients with Parkinson's disease) and analysis.
For assessing a possible sex influence of peripheral inflammatory immune response, Sex-stratified analyses were also performed in both cohorts. All data is shown in the results section and in supplementary information part B.

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