Low lymphocyte count is a risk factor for Parkinson’s disease

Abstract

Importance: Biomarkers for the early detection of Parkinsons disease (PD) are needed; emerging evidence implicates immune dysregulation. Altered leukocyte differentials and C-reactive protein (CRP), common markers of immune function, occur in patients with PD. Whether these changes drive pathogenesis remains unclear. Objectives: We sought to identify whether peripheral immune dysregulation can be seen as a pre-diagnostic feature of PD, and whether it appears to play a causal role. Design: We examined the relationship between differential leukocyte count and other markers of acute inflammation at enrolment, and incident cases of PD, in UK Biobank, a longitudinal cohort study. We used Mendelian randomization to establish whether differences in leukocyte subsets have a causal influence on risk of PD. Setting: The UK Biobank; a population-based cohort with over 500,000 participants aged 40-69 recruited in the UK between 2006 and 2010. Participants: PD cases were defined as individuals with an ICD-10 coded diagnosis of PD. Cases were defined as incident if their age at diagnosis was greater than their age at recruitment to UKB. Controls were defined as all other individuals in the dataset after applying the above exclusions. After applying exclusion criteria for pre-existing health conditions that can influence blood counts, 507 incident PD cases and 328,280 controls were included in the analysis. Exposure: Blood cell markers (absolute and relative counts) and other markers of inflammation (CRP and albumin) were obtained from blood tests of participants taken at the initial assessment visit. Results: Lower lymphocyte count was associated with increased risk of incident PD. There was weaker evidence of association between lower eosinophil and monocyte counts, lower CRP, and higher neutrophil counts on risk of incident PD. The association between lymphopenia and incident PD remained robust to sensitivity analyses. Mendelian randomization did not reveal a clear causal effect of low lymphocyte count on PD risk, but a weak trend in that direction was seen. Conclusions and relevance: In this large, prospective setting, lower lymphocyte count was associated with higher risk of subsequent PD diagnosis. The absence of a clear causal effect indicates that lymphopenia might be a consequence of prodromal PD.

Peripheral Immune Cell Numbers and C-Reactive Protein in Parkinson’s Disease: Results from a Population-Based Study

“…Differences between our study and the studies by Yazdani et al and Jensen et al [14,15] which reported a lower lymphocyte count to be associated with an increased risk of incident PD could be explained by several factors. First, these two previous studies [14,15] used hospital discharge international classification of diseases (ICD) codes or self-reported PD to define incident events. Both studies reported a significant delay of multiple years between the first symptom onset and the date of incident PD recorded in the study [14,15,49].…”

“…In addition to the effect of lymphocytes, we found that participants with a higher GLR, PLR, and adapted SII [19,42] monocytes and the risk of PD [14,15]. Because of these conflicting previous findings and the wide confidence intervals around our estimates, the association between monocyte count and PD warrants further investigation.…”

“…For the lymphocyte count, a marker previously shown to be associated with the risk of incident PD [14,15], we analyzed the temporal average evolution in people with versus without PD using a nested case-control design. The aim of this analysis was to determine at which point in time the lymphocyte count in people with PD starts deviating from controls.…”

“…First, these two previous studies [14,15] used hospital discharge international classification of diseases (ICD) codes or self-reported PD to define incident events. Both studies reported a significant delay of multiple years between the first symptom onset and the date of incident PD recorded in the study [14,15,49]. We defined the date of diag- The main limitation of the current study includes the small number of PD events.…”

“…At an earlier stage of pathogenesis, infectious agents have been suggested to act as a trigger of auto-immune responses against dopaminergic neurons [13]. Indeed, alterations in differential leukocyte counts and cytokine levels have already been described before the onset of clinical PD [14][15][16][17].…”