Longitudinal brain morphometry in Parkinson's disease clinical subtypes: Distinct signatures forecast behavioral change within subtypes

Background: Parkinson's disease (PD) is clinically heterogenous. We previously identified a multi-domain classification of distinct PD subtypes in participants without dementia, yielding Motor Only, Psychiatric & Motor, and Cognitive & Motor subtypes. These PD subtypes may exhibit different rates of brain atrophy. We aim to determine baseline and longitudinal morphometric brain signatures of PD clinical subtypes and their relationship to behavioral change. Methods: 213 PD and 73 control participants completed T1-weighted structural MRIs and motor, cognitive, and psychiatric measures at baseline and every 1–3 years. We used FreeSurfer-v7.3 to obtain cortical thickness and brain volume measures, with manual edits as necessary. We used hierarchical linear models for longitudinal analyses–modeling time, subtype and their interaction; predictors include baseline age, motor symptom duration, sex, and education. Results: Morphological brain MRI measures differentiate PD clinical subtypes at baseline, and the subtypes demonstrate different longitudinal rates of atrophy. The Motor Only subtype has preserved baseline morphometry and slow rate of atrophy, the Psychiatric & Motor has widespread baseline cortical thinning and slow rate of atrophy, and the Cognitive & Motor has baseline global and regional volume loss and fast rate of atrophy. Additionally, baseline morphometric measures predict longitudinal behavioral change within the Cognitive & Motor subtype. Conclusion: Multi-domain PD clinical subtypes exhibit distinct baseline brain morphometric patterns and predictable longitudinal volumetric changes that substantiate previous observations of differential risks of progression, dementia, and death. These findings suggest underlying biological differences across subtypes that may help inform clinical expectations and guide clinical trial design.