Connectivity-Based Subtyping of De Novo Parkinson Disease: Biomarkers, Medication Effects and Longitudinal Progression

Parkinson's disease (PD) is characterized by divergent clinical symptoms and prognosis, suggesting the presence of distinct subtypes. Identifying these subtypes is crucial for understanding the underlying pathophysiology, predicting disease progression, and developing personalized treatments. In this study, we propose a connectivity-based subtyping approach, which measures each patient's deviation from the reference structural covariance networks established in healthy controls. Using data from the Parkinson's Progression Markers Initiative, we identified two distinct subtypes of de novo PD patients: 248 patients with typical cortical-striato-thalamic dysfunctions and 41 patients showing weakened dorsal raphe nucleus (DRN)-to-cortical/striatal projections. The proposed subtyping approach demonstrated high stability in terms of random sampling of healthy or diseased population and longitudinal prediction at follow-up visits, outperforming the traditional motor phenotypes. Compared to the typical PD, patients with the DRN-predominant subtype were characterized by less server motor symptoms at baseline and distinct imaging biomarkers, including larger striatal volumes, higher concentration of cerebrospinal fluid amyloid-β and amyloid-β/t(p)-tau ratio. Subtype-specific associations and drug effects were identified that the DRN subtype exhibited more pronounced medication effects on motor symptoms, potentially regulated by DRN serotonergic modulation through striatal dopaminergic neurons. The DRN serotonergic inputs also regulated non-motor symptoms, the aggregation of CSF biomarkers and the conversion to more severe disease states. Our findings suggest that the DRN-predominant subtype represents a unique clinical and biological phenotype of PD characterized by an enhanced response to anti-parkinsonian treatment, more favorable prognosis and slower progression of dopamine depletion. This study may contribute to clinical practice of precision medicine, early invention and individualized treatments in PD and other neurodegenerative diseases.