Parkinson Disease Clinical Subtypes: Validation, Clinical Utility, and Biological Correlates

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ABSTRACT Parkinson disease (PD) is a progressive neurodegenerative disease characterized by motor, cognitive, and psychiatric manifestations resulting from abnormal protein deposition and neurotransmitter deficits. The variability in clinical presentation and progression likely reflects the underlying variability in brain pathology. Although current treatments provide dramatic motor benefit in PD, they fail to alleviate some aspects of gait impairment and non-motor symptoms and may exacerbate cognitive and psychiatric features. To develop more “personalized medicine” interventions to treat, forestall or prevent these features, classification of PD clinical subtypes and identification of the associated biological mechanisms are necessary for patient stratification, predicting progression, development and evaluation of novel treatments. Therefore, we propose to identify and validate PD clinical subtypes based on comprehensive motor, cognitive, and psychiatric evaluations; determine the predictive utility of PD clinical subtypes through longitudinal behavioral assessments; and examine biological markers of the PD clinical subtypes from multimodal neuroimaging, CSF, and autopsy data.