AbstractBackgroundLittle is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD).ObjectivesWe used data from a multi‐site, international, prospective cohort study to explore the impact of dopamine system‐related biomarkers on CI in PD.MethodsPD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut‐offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine‐123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system‐related biomarkers and CI, including persistent impairment.ResultsDemographic and clinical variables associated with CI were higher age, male sex, lower education, non‐White race, higher depression and anxiety scores and higher MDS‐UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values (Prange 0.003–0.005) and higher LEDD over time (Prange <0.001–0.01) were significantly associated with increased risk for CI.ConclusionsOur results provide preliminary evidence that alterations in the dopamine system predict development of clinically‐relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course.TRIAL REGISTRATIONParkinson's Progression Markers Initiative is registered withClinicalTrials.gov(NCT01141023).