Different patterns of structural network impairments in two amyotrophic lateral sclerosis subtypes driven by 18F-FDG PET/MR hybrid imaging

The structural network damages in amyotrophic lateral sclerosis (ALS) patients are evident but contradictory due to the high heterogeneity of disease. We hypothesized that patterns of structural network impairments would be different in ALS subtypes by a data-driven method using 18F-FDG PET/MR hybrid imaging. 50 patients with ALS and 23 healthy controls (HCs) were collected PET, structural MRI and diffusion tensor imaging data by a 18F-FDG PET/MR hybrid. Two ALS subtypes were identified as the optimal cluster based on gray matter volume and standardized uptake value ratio. Network metrics at the global, local and connection levels were compared to explore the impaired patterns of structural network in the identified subtypes. Compared with HCs, the two ALS subtypes displayed a pattern of a locally impaired structural network centralized in the sensorimotor network and a pattern of an extensively impaired structural network in the whole brain. When comparing the two ALS subgroups by a support vector machine classifier based on the decreases in nodal efficiency of structural network, the individualized network scores were obtained in every ALS patient and demonstrated a positive correlation with disease severity. We clustered two ALS subtypes by a data-driven method, which encompassed different patterns of structural network impairments. Our results imply that ALS may possess the intrinsic damaged pattern of white matter network and thus provide a latent direction for stratification in clinical research. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement the National Natural Science Foundation of China (No. 81671761 and 81871425); Fundamental Research Funds for the Central Universities (No. 2017XTCX04); Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning (No. CNLYB2001). ### 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 study was approved by the Medical Ethics Committee of the Chinese PLA General Hospital, Beijing, China (S2020-027-01). All participates provided a written informed consent. 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 * ### Abbreviations AAL : Automated anatomical labeling ALS : Amyotrophic lateral sclerosis ALS-bi : ALS with behavioral impairment ALS-cbi : ALS with cognitive and behavioral impairment ALS-ci : ALS with cognitive impairment ALSFRS-R : ALS Functional Rating Scale-Revised BNA : Brainnetome Atlas DeltaFS : Progression rate from disease-onset to baseline dNE : Nodal efficiency of DTI-based brain network EISN : Extensively impaired structural network FTD : Frontotemporal dementia GMV : Gray matter volume HC : Healthy control INS : Individualized network score LISN : Locally impaired structural network LOOCV : Leave-one-out cross validation NBS : Network-based statistics sMRI : Structural MRI SUVR : Standardized uptake value ratio SVM : Support vector machine WM : White matter