Striatal dopamine depletion drives disease progression and network topology aberrations specifically by impairing left M1 network

BackgroundStratal dopamine depletion contributes to both motor and non-motor symptoms of patients with Parkinsons disease (PD). The objective of current study is to explore whether stratal dopamine depletion shapes clinical heterogeneity by impairing brain networks of PD patients. MethodsIn this cross-sectional study, PD participants undergoing functional magnetic resonance imaging from Parkinsons Progression Markers Initiative (PPMI) database were investigated. According to the levels of striatal binding ratio (SBR) in bilateral striatum, PD patients were classified into lower quartile group (SBR level rank: 0%[~]25%), interquartile group (SBR level rank: 26%[~]75%), and upper quartile group (SBR level rank: 76%[~]100%) based on their SBR level quartiles to examine how stratal dopamine depletion affects clinical manifestations and brain networks. FindingsPD patients in the lower quartile group showed more severe motor and non-motor symptoms compared to upper quartile group. Additionally, topological metrics in both structural and functional network were significantly different between upper quartile group and lower quartile group. Furthermore, the functional network of left primary motor cortex (M1) was specifically impaired in lower quartile group, which resulted in topological disruptions in functional network. Importantly, impaired left M1 network in PD patients mediated the effects of striatal dopamine depletion on both motor and non-motor symptoms. InterpretationStriatal dopamine depletion specifically impaired left M1 network, which contributed to aberrant functional network topology and dopamine-dependent motor and non-motor symptoms. FundingNational Natural Science Foundation of China (Grant No. 81873778, 82071415) and National Research Center for Translational Medicine at Shanghai (Grant No. NRCTM(SH)-2021-03).