Plasma MIA, CRP, and albumin predict cognitive decline in Parkinson's Disease

Objective: Using a multi-cohort, Discovery-Replication-Validation design, we sought new plasma biomarkers that predict which PD individuals will experience cognitive decline. Methods: In 108 Discovery Cohort PD individuals and 83 Replication Cohort PD individuals, we measured 940 plasma proteins on an aptamer-based platform. Using proteins associating with subsequent cognitive decline in both cohorts, we trained a logistic regression model to predict which PD patients showed fast (>=1 point drop/year on Montreal Cognitive Assessment (MoCA)) vs. slow (<1 point drop/year on MoCA) cognitive decline in the Discovery Cohort,testing it in the Replication Cohort. We developed alternate assays for the top three proteins and confirmed their ability to predict cognitive decline - defined by change in MoCA or development of incident Mild Cognitive Impairment (MCI) or dementia - in a Validation Cohort of 118 PD individuals. We investigated the top plasma biomarker for causal influence by Mendelian randomization. Results: A model with only three proteins (Melanoma Inhibitory Activity Protein (MIA), C-Reactive Protein (CRP), albumin) separated Fast vs. Slow cognitive decline subgroups with an AUC of 0.80 in the Validation Cohort. Validation Cohort PD individuals in the top quartile of risk for cognitive decline based on this model were 4.4 times more likely to develop incident MCI or dementia than those in the lowest quartile. Genotypes at MIA SNP rs2233154 associated with MIA levels and cognitive decline, providing evidence for MIA's causal influence. Conclusions: An easily-obtained plasma-based predictor identifies PD individuals at risk for cognitive decline. MIA may participate causally in development of cognitive decline.