Functional Magnetic Resonance Imaging Biomarkers Predicting Cognitive Progression in Parkinson Disease: Protocol for a Prospective Longitudinal Cohort Study

Background: Cardinal features of Parkinson disease (PD) are motor symptoms, but nonmotor features such as mild cognitive impairment (MCI) are common early in the disease process. MCI can progress and convert to dementia in advanced stages, creating significant disability and reduced quality of life. The primary pathological substrate for cognitive decline in PD is unclear, and there are no reliable biomarkers predicting the risk of conversion to dementia. A subgroup of PD patients with visual hallucinations may display more rapid conversion to dementia, suggesting that regional markers of visuoperceptual dysfunction may be sensitive to pathologic density in posterior cortical regions. Objective: The purpose of this project is to characterize PD-MCI and evaluate the utility of genetic and neuroimaging biomarkers in predicting cognitive outcomes with a prospective longitudinal study. We will evaluate whether accelerated cognitive progression may be reflected in biomarkers of early posterior cortical changes reflective of alpha-synuclein deposition. Methods: We will evaluate a cohort of early-stage PD patients with the following methods to predict cognitive progression: (1) serial neuropsychological evaluations including detailed visuoperceptual functioning across 4 years; (2) genetic analysis of SNCA (alpha-synuclein), MAPT (microtubule-associated tau), and APOE (apolipoprotein E); (3) an event-related functional magnetic resonance imaging paradigm of object recognition memory; and (4) anatomical and regional brain activation changes (resting-state functional magnetic resonance imaging) across 4 years. Results: The project received funding from the National Institutes of Health in August 2017, and data collection began in February 2018. Enrollment is ongoing, and subjects will be evaluated annually for 4 years extended across a 5-year project including data analysis and image processing. Conclusions: Cognitive, genetic, and structural and functional magnetic resonance imaging will characterize neural network changes predictive of cognitive progression in PD across 4 years. Identification of biomarkers with sensitivity for early prediction and estimation of risk for conversion to dementia in PD will pave the way for effective intervention with neuroprotective therapies during the critical stage when treatment can have the greatest impact.