Peripheral-central immune crosstalk in Parkinson’s disease and its association with clinical severity

Abstract:

Background: Increasingly, the immune system is implicated in the aetiology and progression of Parkinson's disease (PD). Immune activation is seen both peripherally in the blood, with a tendency towards a pro-inflammatory profile, and centrally in the cerebrospinal fluid and brain parenchyma, with microglial activation and increased numbers of immune cells in the central nervous system. However, the relationship between this peripheral and central immune profile, as well as the association with clinical measures of disease severity is not clear. Methods: 61 people with PD, within three years of diagnosis and no immune comorbidities, and 51 matched controls underwent detailed blood immunophenotyping using a flow cytometry panel with markers to characterise adaptive and innate immune populations. In the PD cohort, 35 also had cerebrospinal fluid (CSF) immune cell analysis and 31 underwent positron emission tomography (PET) brain imaging with the radioligand [¹¹C]-PK11195 to assess microglial activation. PD participants were assessed with the Movement Disorder Society-Unified Parkinson's disease rating Scale (MDS-UPDRS) and the Addenbrooke's Cognitive Examination (ACE-III). The immune profiles of PD and control participants were compared. In the PD group, relationships between peripheral and CSF immune cell populations, [¹¹C]-PK11195 binding, and clinical measures were investigated in exploratory analyses using multiple linear regression. Results: Compared to controls, PD participants had a pro-inflammatory profile in the blood with an elevated Systemic Inflammatory Index (SII) (p = 0.049), a higher percentage of classical monocytes (p = 0.046), and decreased expression of functional markers of T regulatory cells (FoxP3 (p = 0.030) and Helios (p = 0.015)) and B regulatory cells (CD1d (p = 0.031)). Immune cell subset numbers in blood and CSF were correlated for CD8+ cells (rho = 0.42, p = 0.011), CD16+ NK cells (rho = 0.49, p = 0.004) and classical monocytes (rho = −0.38, p = 0.028). CSF immune populations were also correlated with [¹¹C]-PK11195 binding in disease-relevant regions of interest. Several blood and CSF immune cell subsets and regional [¹¹C]-PK11195 binding showed relationships with motor and cognitive scores, with a consistent trend of pro-inflammatory markers being related to a more severe disease phenotype. Increased Toll-like receptor 2 expression on classical monocytes in the CSF and [¹¹C]-PK11195 binding in the substantia nigra independently predicted motor score (MDS-UPDRS-III). Conclusion: This exploratory study suggests that peripheral and central immune changes are closely linked in PD, and relevant to clinical disease severity. These findings warrant further validation and exploration to identify immune biomarkers linked to disease state, as well as candidate therapeutic targets.