Disrupted topological properties of structural brain networks presents a glutamatergic neuropathophysiology in narcolepsy patients

Study objectives Growing evidence have reported a number of abnormalities in the white matter bundles of narcolepsy patients. We sought to evaluate topological properties of brain structural networks, and their association with sleepiness and neuropathophysiological features in narcolepsy patients. Methods Diffusion tensor imaging (DTI) was conducted for 30 narcolepsy patients and matched healthy controls as well as sleepiness assessment and polysomnography. Structural connectivity for each patient was generated to analyze global and regional topological properties and their correlation with narcolepsy features. Further human brain transcriptome was extracted and spatially registered for connectivity vulnerability. Genetic functional enrichment analysis was performed and further clarified using in vivo emission computed tomography data. Results A wide and dramatic decrease in structural connetivities was observed in narcolepsy patients, with descending global network degree and global efficiency. These metrics were not only correlated with sleep latency and awakenning features, but also reflects alterations of sleep macrostructure in narcolepsy patients. Further network-based statistics identified a small hyperenhanced subnetwork of cingulate gyrus that is closely related to rapid eye movement sleep behavior disorder (RBD) in narcolepsy. Conclusions Narcolepsy patients endured a remarkable decrease in the structural architecture, which is not only be closely related to sleepiness symptoms but also glutamatergic signatures. Statement of Significance Growing evidence have identified a widespread disrupted white matter integrity of narcolepsy patients, so that connectome properties and neuropathophysiological features underlying these abnormalities have become a topic of increasing interest. This report extends on findings regarding the structural wirings and architectural topology of narcolepsy patients and inferring their clinical correlation with sleepiness assessment, polysomnography features and sleep macrostructure. Further imaging genetics analysis suggested glutamatergic signatures were responsible for the preferential vulnerability of connectivity alterations, while additional PET/SPECT data verified that structural alteration was significantly correlated with metabotropic glutamate receptor 5 (mGlutR5) and N-methyl-D-aspartate receptor (NMDA). Our findings, therefore, converge structural network and genetic signatures for in patients with narcolepsy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work has been supported by the Key R&D Program of Shaanxi Province (Grant no. 2022ZDLSF03-07). ### 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: Ethics Committee of the Second Affiliated Hospital in Air Force Medical University gave ethical approval for this work. 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 data produced in the present study are available upon reasonable request to the authors.All code produced are available online at .