Disrupted topological properties of structural brain networks present a glutamatergic neuropathophysiology in people with narcolepsy

Study objectives Growing evidences have documented various abnormalities of the white matter bundles in people with narcolepsy. We sought to evaluate topological properties of brain structural networks, and their association with symptoms and neuropathophysiological features in people with narcolepsy. Methods Diffusion tensor imaging (DTI) was conducted for people with narcolepsy (n = 30) and matched healthy controls as well as symptoms assessment. Structural connectivity for each participant was generated to analyze global and regional topological properties and their correlations with narcoleptic 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 connectivities was observed in people with narcolepsy, with descending network degree and global efficiency. These metrics were not only correlated with sleep latency and awakening features, but also reflected alterations of sleep macrostructure in people with narcolepsy. Network-based statistics identified a small hyperenhanced subnetwork of cingulate gyrus that was closely related to rapid eye movement sleep behavior disorder (RBD) in narcolepsy. Further imaging genetics analysis suggested glutamatergic signatures were responsible for the preferential vulnerability of connectivity alterations in people with narcolepsy, 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). Conclusions People with narcolepsy endured a remarkable decrease in the structural architecture, which was not only be closely related to narcolepsy symptoms but also glutamatergic signatures. Statement of Significance Growing evidences have identified a widespread disrupted white matter integrity of people with narcolepsy, 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 people with narcolepsy and inferring their clinical correlation with sleepiness assessment, polysomnography features and sleep macrostructure. Further imaging genetics analysis suggests glutamatergic signatures are responsible for the preferential vulnerability of connectivity alterations, while additional PET/SPECT data verifies that structural alteration is 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 people 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 .