Peripheral immune cell response to stimulation stratifies Parkinson’s disease progression from prodromal to clinical stages

The motor stage of Parkinson's disease (PD) can be preceded for years by a prodromal stage characterized by non-motor symptoms like REM sleep behavior disorder (RBD), hyposmia, and constipation. Here, we show that multiple stages of idiopathic PD, including the pre-motor prodromal stage, can be stratified according to the inflammatory responses to stimulation of peripheral blood mononuclear cells ex vivo. IFNγ stimulation of isolated monocytes reveals increased stimulation-dependent secretion of TNF, IL-1β, and IL-8 in prodromal PD relative to moderate stage PD. Additionally, T cells stimulated with CD3/CD28 co-stimulatory beads show diminished proinflammatory cytokine secretion in early-moderate PD relative to prodromal. Receiver operating characteristic curves demonstrate that several cytokines produced by stimulated monocytes show high predictive utility for distinguishing prodromal PD individuals from neurologically healthy controls. Moreover, immune stimulation reveals deficits in CD8⁺ T-cell mitochondrial health in moderate PD, with relative mitochondrial health in CD8⁺ T cells being positively correlated with stimulation-dependent secretion of IL-1β, IL-8, and IL-10 in T cells from prodromal PD subjects. Dysregulated mitochondrial health in immune cells may contribute to peripheral inflammation and PD progression, and ex vivo stimulation-based assays have the potential to reveal novel biomarkers for patient stratification and progression with immune endophenotypes.