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

Background Stratal dopamine depletion contributes to both motor and non-motor symptoms of patients with Parkinson’s disease (PD). The objective of current study is to explore whether stratal dopamine depletion shapes clinical heterogeneity by impairing brain networks of PD patients. Methods In this cross-sectional study, PD participants undergoing functional magnetic resonance imaging from Parkinson’s 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. Findings PD 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. Interpretation Striatal dopamine depletion specifically impaired left M1 network, which contributed to aberrant functional network topology and dopamine-dependent motor and non-motor symptoms. Funding National Natural Science Foundation of China (Grant No. 81873778, 82071415) and National Research Center for Translational Medicine at Shanghai (Grant No. NRCTM(SH)-2021-03). ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants from National Natural Science Foundation of China (Grant No. 81873778, 82071415) and National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (Grant No. NRCTM(SH)-2021-03). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Committee of all participating sites approved the PPMI study. The informed consents have been signed by all study participants, which can be obtained from the site investigators. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All the raw data used in the preparation of this Article were downloaded from PPMI database ([www.ppmi-info.org/data][1]).All data produced in the present study are available upon reasonable request to the authors. [1]: http://www.ppmi-info.org/data