“Changes in soluble CD163 indicate monocyte involvement in cognitive deficits in Parkinson’s disease”

Abstract

Parkinson's disease is a neurodegenerative disorder with a significant immune component. Numerous studies have reported alterations on immune biomarkers in CSF and serum that associate with symptoms in PD patients. However, it is unclear, which specific immune cells are responsible for the changes in those biomarkers; since most of these cytokines or chemokines, can be produced by a variety of immune cells, or even neurons or glia cells in the brain. Here, we investigate a monocyte/macrophage-specific biomarker: sCD163, the soluble form of the receptor CD163. Our data from tow cohorts show that the CSF-sCD163 increases as the disease progresses, together with a correlated increase in PD-specific as well as neurodegeneration-associated disease biomarkers: alpha-synuclein, tau, and phosphorylated-Tau. Moreover, CSF-sCD163 levels were inversely correlated to the cognitive scores MMSE and MOCA, with higher sCD163 indicating lower cognitive capacity. sCD163 was also increased in serum, although only in female PD patients, suggesting a gender distinctive monocyte-related immune response. CSF-sCD163 also correlated with molecules associated with endothelial cells, tissue infiltration, and activation of B cells and T cells in the PD patients. This suggests activation of both the adaptive and the innate immune system along with recruitment of lymphocytes and monocytes to sites of inflammation in the brain. In serum, sCD163 was associated with pro-inflammatory cytokines and acute phase proteins, suggesting a relation to chronic systemic inflammation. Interestingly, our in vitro study suggests that sCD163 might enhance alpha-synuclein uptake by myeloid cells without direct binding, thus participating in the clearance of alpha-synuclein. Accordingly, our data supports sCD163 as a potential cognition-related biomarker in PD and corroborates a role for monocytes both in peripheral and brain immune responses that could have direct consequences in the handling of alpha-synuclein

Changes in CD163+, CD11b+, and CCR2+ peripheral monocytes relate to Parkinson’s disease and cognition

“…We and others have shown that MNP-associated changes seem particularly relevant for cognition in PD (26, 37, 40). Elevated CCR2 expression is a signature of newly-generated immature Mos from the bone marrow, marked for migration to blood and tissue.…”

“…In HCs, plasma sCD163 correlates negatively with CD163 MFI, but not with CD163 + cell counts (64). With our previous finding of increased serum sCD163 levels in females with PD (26), we anticipated a decrease in CD163 MFI on MNPs from females with PD. However, we observed a significant increased CD163 MFI in PwP for both sexes, indicating a PD-associated upregulation of CD163, in parallel to the increased shedding observed in serum (in females) and CSF (both sexes) (26).…”

“…With our previous finding of increased serum sCD163 levels in females with PD (26), we anticipated a decrease in CD163 MFI on MNPs from females with PD. However, we observed a significant increased CD163 MFI in PwP for both sexes, indicating a PD-associated upregulation of CD163, in parallel to the increased shedding observed in serum (in females) and CSF (both sexes) (26). This seems specific for PD since in multiple sclerosis, increased sCD163 was parallel to decreased CD163 MFI (65).…”

“…We have previously shown that PwP’s blood immune cells in vitro have reduced ability to downregulate CD163 expression on CD14 + Mos upon exposure to α-syn (18); and that PwP have increased soluble (s)CD163 levels in serum (females only) and in CSF (both sexes), with CSF sCD163 levels associated with α-syn and cognitive deficits (26). Based on these findings, we aimed to analyze the ex vivo CD163 expression on MNPs from PwP.…”

“…Despite the relatively high MoCA scores in the cohort, we observed that the combined absence of both migration markers was associated with better cognition, and accordingly, an increased percentage of CCR2 + MNPs correlated with reduced cognition in late PD. Furthermore, increased expression of CCR2 was in females with PD also correlated with cognitive impairment, suggesting that monocytes with migratory capacity are associated with cognitive decline in PD (26, 37, 39). Indeed a significant immune response in limbic areas and cortex is associated to dementia in PD (56).…”