Multimodal markers of immune activation predict cognitive outcomes in Parkinson's disease

Inflammation is well described in the central nervous system (CNS) and the periphery in Parkinson's disease (PD) and has been implicated in dementia risk. Longitudinal studies to identify immune/inflammatory biomarkers predicting cognitive decline are lacking.

Peripheral blood mononuclear cells and cerebrospinal fluid (CSF)-derived immune cells were obtained from newly-diagnosed PD cases and healthy controls as part of the NET-PDD study. Immunophenotyping was performed using flow cytometry. CSF:blood ratios were calculated as a index of cell ingress to the CNS. Neuroinflammation was evaluated using ¹¹C-PK11195 positron emission tomography (PET) MRI scanning. Participants were then followed-up clinically for 3 years to determine cognitive outcomes.

Bivariate comparisons between PD cases who were cognitively impaired at 3 years (PD-CI N = 10), PD non cognitively impaired (PD-NCI, N = 25) and controls (N = 36) identified 22 blood/CSF immune variables that differed between groups. The differences with the largest effect sizes (Cliff's d) were a higher proportion of activated CD4 T cells in the blood (CD4 + CD28+, d = 0.63) and a higher CSF:blood ratio of memory B cells (d = 0.63) in PD-CI versus controls. The substantia nigra was the only brain region in which PD-CI versus controls showed a higher ¹¹C-PK11195 non-displaceable binding potential (BP_ND) (d = 0.45). In a multivariate regression model including age and gender, the CSF:blood memory B cell ratio and substantia nigra ¹¹C-PK11195 BP_ND at baseline predicted cognitive decline over 3 years. ROC analysis demonstrated that the lead blood, CSF and imaging markers individually predicted cognitive status at 3 years with good accuracy (AUC 0.79-0.85).

An increase in activated CD4 cells in the blood, transition of B cells to the CNS and inflammation in the substantia nigra were predictive of longitudinal cognitive outcomes in PD. These markers warrant further validation as biomarkers for immune/inflammatory stratification and add to the evidence supporting development of therapeutic strategies to reduce microglial inflammation or the recruitment of lymphocytes to the CNS in early PD.