A reliable subtyping of de novo Parkinson disease: biomarkers, medication effects and longitudinal progression

Divergent clinical symptoms and pathological progression suggest multiple subtypes of Parkinson disease (PD). Here, we proposed a reliable PD subtyping approach that quantifies the disturbance of an individual patient to the reference structural covariance networks derived from healthy controls. We revealed two subtypes of de novo PD patients by using longitudinal data from the PPMI dataset. Compared to the conventional clinical TD/PIGD phenotypes, our subtyping was highly stable in 5 years' visits. The two subtypes of PD showed significant differences in motor symptoms, medication effects, CSF biomarkers, and longitudinal progression. Moreover, patients of subtype 2 showed widespread lower cortical-to-dorsal raphe nucleus (DRN) connections and higher medication effects on motor symptoms which was regulated by 5-HT neurons in DRN. Our results suggest distinct neuropathological pathways underlying the two subtypes, such that, in contrast to the typical PD subtype, patients of subtype 2 may be affected by serotonergic modulation on dopaminergic neurons in striatum. Our study opens new avenue to precision medicine and personalized treatments in PD and may be applicable to other neurodegenerative diseases.