Objective: To determine the longitudinal relationship between immune parameters and Parkinson’s progression; and immune predictors of motor and cognitive milestones.

Background: PD progression is highly heterogenous, with half developing dementia and 2/3 developing postural instability within 10 years¹. Validated biomarkers to predict or track progression are lacking. Early inflammation in PD may drive faster motor progression and is associated with dementia risk^2-4. Here we present 5-year data from a longitudinal multimodal immune marker study.

Method: Blood, CSF and neuroimaging markers of immune activation/inflammation were measured in 36 newly diagnosed PD cases and 35 age/sex-matched controls at baseline and 3 years. Immunophenotyping was performed using flow cytometry on PBMCs and CSF. Serum and CSF cytokines were measured using Mesoscale Discovery assays. Neuroinflammation was measured using ¹¹C-PK11195 PET. Clinical data was collected over 5 years (MDS-UPDRS, ACE-III).

Results: Linear mixed-effects models demonstrated increased CSF IL-1ß, increased blood monocytes and memory B cells, decreased blood CD8+ T cells and increased ¹¹C-PK11195 binding in the amygdala were longitudinally associated with motor impairment (UPDRS-III; p<0.05). Increased blood CD4+ T cells and decreased CSF:blood ratio of naive B cells was longitudinally associated with cognitive decline in PD (p<0.05), but not controls. Cox regression with covariate adjustment was used to determine baseline markers predicting motor (postural instability/gait disturbance) and cognitive (MCI/dementia) milestones. Predictors of time to motor milestones included increased ¹¹C-PK11195 binding in the amygdala, hippocampus and substantia nigra; decreased CSF:blood ratio of naïve B cells; increased blood IgA+ B cells and CD4+ memory T cells; decreased blood naïve CD4+ T cells and intermediate monocytes (p<0.05). Time to cognitive impairment was predicted by increased ¹¹C-PK11195 binding in the substantia nigra; increased blood naïve CD8+ T cells and IgA+ B cells; increased CSF:blood CD8+CD28+ T cells and CD8+CD28loCD57hi T cells (p<0.05).

Conclusion: Multiple blood, CSF and imaging-based immune markers longitudinally track and predict motor and cognitive outcomes in PD. This emphasizes the immune contribution to PD progression. Further work is needed to identify optimally performing biomarkers in larger datasets.

References: 1 Williams-Gray, C. H. et al. The CamPaIGN study of Parkinson’s disease: 10-year outlook in an incident population-based cohort. Journal of Neurology, Neurosurgery & Psychiatry 84, 1258-1264 (2013).
2 Kouli, A. et al. Neuroinflammation is linked to dementia risk in Parkinson’s disease. Brain 147, 923-935 (2024).
3 Kouli, A., Camacho, M., Allinson, K. & Williams-Gray, C. H. Neuroinflammation and protein pathology in Parkinson’s disease dementia. Acta neuropathologica communications 8, 1-19 (2020).
4 Scott, K. et al. Multimodal markers of immune activation predict cognitive outcomes in Parkinson’s disease. Brain, behavior, and immunity, (2025): 129:165-78.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/multimodal-immune-biomarkers-of-parkinsons-disease-progression/