Focal and diffuse clinical subtypes in early-stage Parkinson’s disease: a one-year longitudinal study

Abstract Heterogeneity in Parkinson’s disease (PD) presents a barrier to understanding disease mechanisms and developing new treatments. This challenge may be partially overcome by stratifying patients into clinically meaningful subtypes. A recent subtyping scheme classifies de novo PD patients into three subtypes: mild-motor predominant, intermediate, or diffuse-malignant, based on motor impairment, cognitive performance, REM-sleep behavior disorder, and autonomic function. We aimed to validate this approach in a large longitudinal cohort of early-stage PD (n=517). Furthermore, we assessed the influence of subtype on clinical motor phenotype and on one-year clinical disease progression. Diffuse-malignant patients (14%) differed from mild-motor predominant patients (48%) in three ways: involvement of more clinical domains, more diffuse hypokinetic-rigid symptoms (less lateralization, less hand/foot focality), and faster one-year progression. These findings extend the classification of diffuse-malignant and mild-motor predominant subtypes to early-stage PD and suggest that different pathophysiological mechanisms (focal versus diffuse cerebral propagation) may play a role.