Clinical and dopaminergic profiling identifies four different subtypes in de novo Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a multitude of motor and non-motor symptoms. The diverse patterns of dopaminergic and non-dopaminergic degeneration may underlie its heterogeneous manifestations and varied prognostic trajectories. Despite the need to identify clinical PD subtypes that can help in the development of new disease modifying treatment no standardized criteria for describing PD heterogeneities is yet available. In this work we aim to phenotype a cohort of de novo PD patients based on dopaminergic and motor dysfunction and investigate 1) the association of the identified subgroups with clinical, genetic and dopaminergic denervation anomalies and 2) the longitudinal progression of the disease. We selected from the Parkinson's Progression Markers Initiative (PPMI) database a group of 249 early de novo PD subjects - disease duration ≤2, H&Y 1-2, without cognitive impairment (MoCa score >26) and with baseline [123I]FP-CIT-SPECT acquisition available. We performed cluster analysis based on clinical and dopaminergic parameters. Four subgroups emerged: n=44 [M+D+], n=85 [M-D-], n= 44 [M+D-], and n=76 [M-D+]. Demographic, clinical, neuroimaging and genetic information were compared at baseline among the four subgroups. Mixed-linear model assessed the rate of change of motor, cognitive and neuropsychological variables over time. Findings revealed that [M+D+] was associated with a more malignant motor and cognitive phenotype at baseline, and faster clinical progression. This group also showed severe posterior cortical thinning. [M+D-] exhibited the most severe rigidity; however, it showed no morphological differences compared to controls. [M-D+] displayed gray matter reduction involving the anterior portion of the brain. [M-D-] presented the most benign phenotype with lower clinical and neuropsychological deficits and slower progression and cortical thinning restricted to the caudate. These findings demonstrated that PD can be subdivided into different subgroups based on basic motor and dopaminergic information and shed light on the importance of both motor dysfunction and dopaminergic denervation in determining clinical trajectories and morphological abnormalities in PD.