The Imaging Study Of Neuromyelitis Optica Spectrum Disorder And Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease

Objective:The purpose of this study is to explore the imaging characteristics of neuromyelitis optica spectrum disorder（NMOSD）and myelin oligodendrocyte glycoprotein antibody-associated disease（MOGAD）,and to search for imaging markers distinguishing the two diseases with magnetic resonance imaging（MRI）and positron emission computed tomography（PET）techniques.The results may address the value of PET/MR technology in facilitating the diagnosis and evaluation of NMOSD and MOGAG.Methods:1)MRI images of 88 patients with NMOSD,MOGAD,and multiple sclerosis（MS,disease control）were retrospectively analyzed.First,a semi-automatic segmentation approach was used to obtain lesions with T2/FLAIR-hyperintensity and lateral ventricles following by a periventricular lesion（PVL）algorithm.The quantitative and volumetric characteristics of PVL and non-PVL（NPVL）were calculated and compared among the three diseases.Finally,a classification model was established using Logistic regression and its classification performance was tested.2)PET/MR scans were performed on patients with NMOSD and MOGAD using 18-fluoro-2-deoxy-d-glucose（18F-FDG）,translocator protein（TSPO）ligand 18F-PRB06,and 11C-acetate.To explore the characteristics and differences of neuroinflammation among different conditions,the standard uptake value ratio（SUVR）and Z scores were calculated for lesions,physiologically meaningful brain area and the gray/white matter by various methods.The abnormalities of NMOSD and MOGAD were compared with MS,the disease control,and healthy controls.3)To further verify the relationship between PET imaging results and pathological substrates,the NMOSD mouse model mediated by AQP4 antibody from complete Freund’s adjuvant combined with plasma exchange fluid and the EAE mouse model induced by MOG_35-55 peptide were constructed.The brain uptake value of NMOSD mice and EAE mice and healthy mice were compared by small animal PET/CT.Subsequently,the PET/CT results were verified by histopathology.Results:1)In the first part which aimed to create the disease discrimination model based on the morphology and distribution of MRI lesions,lesion-based comparison yielded that the proportion of PVL in patients with NMOSD and MOGAD was significantly lower than that in the MS group.The PVL volume of the three groups of diseases was larger than NPVL,among which the NPVL volume of patients with NMOSD was smaller than that of patients with MS and MOGAD.Comparison at the subject level found that the count of PVL,total lesion volume,and PVL volume in MS patients are higher than those of the other two diseases.The proportion of PVL in NMOSD patients was significantly lower than that in MS;The total number of lesions and the proportion of NPVL lesions in patients with MOGAD were significantly lower than those in the other two groups.The classification models established by combining the quantitative and volumetric lesion characteristics exhibited better classification performances,with a high area under the curve（AUC）（MOGAD-MS:0.90,NMOSD-MS:0.81,and MOGAD-NMOSD:0.71）.2)For the second part of the molecular imaging study,a total of 16 patients（NMOSD,6;MOGAD,5;MS,5）were included in the study,of which 13 patients had lesions on their brain MRI.Comparatively,PET examination showed that all patients had abnormal changes in PET imaging with at least one probe.This data indicated a higher sensitivity of PET imaging than conventional MRI.18F-FDG uptake decreased across the overall lesions of NMOSD,MOGAD,and MS consistently,while newly-formed lesions can exhibit a pattern of increased 18F-FDG uptake.Whole brain-based analysis showed that the median Z scores of 18-FDG uptake in the corpus callosum,lingual gyrus,and ventricles were lower than those in the control group,but the brainstem,putamen,frontal orbital gyrus,posterior central gyrus,and superior temporal gyrus showed a pattern of increased uptake.The 18F-PBR06uptake ratio in lesions was higher than that of healthy controls,with the most significant increase in acute new lesions in the MS subgroup.Globally,there was a relative increase in the Z score of 18F-PBR06 in the brainstem and parietal regions of patients with three diseases.In the NMOSD patients,the 11C-acetate SUVR of overall lesions and newly-formed lesions were lower than that of HC and the other two diseases.In the other sites of the brain,11C-acetate showed increased uptake in the bilateral thalamus and temporal lobes,while there was a decrease in uptake in the third ventricle.The comparison of gray and white matter results shows that there is an increase in 18F-FDG,18F-PBR06,and 11C-acetate in the SUVR of white matter and white matter/gray matter ratio in MS patients,suggesting that white matter involvement characterized MS.Patients showed an abnormal pattern of decreased FA and T1T2R compared to the contralateral normal tissue,indicating myelin injury at the lesion site.3)Motor dysfunction was observed in EAE mice and NMOSD mice.Whole body PET/CT showed that 18F-FDG-SUVR in the brain of EAE mice was higher than that of CTL mice,while it was similar between NMOSD and CTL mice.The results of H&E staining showed significant lymphocyte infiltration in the EAE mice brain.The large number of lymphocytes involved in neuroinflammation may be associated with the increased 18F-FDG uptake.The mean 18F-PBR06-SUVR of EAE mice and the maximum SUVR of NMOSD significantly differed from CTL mice.Immunohistochemistry and immunofluorescence analysis showed the wide activation of cerebral microglia in the NMOSD mice and EAE mice brains,and the up-regulated expression of TSPO compared with the CTL mice.Microglia accounts for the main source of TSPO.There was no significant difference in brain 11C-acetate uptake levels among NMOSD,EAE,and CTL mice.Conclusion:1)The quantity and volumetric characteristics of PVL/NPVL are valuable in identifying three types of central nervous system inflammatory demyelinating diseases.Based on these parameters,we proposed novel classification models to distinguish three diseases entities optimizing the diagnostic strategy for conventional MRI;2)In this study,18F-PBR06 uptake alternations were found in the brain lesions of patients with NMOSD,MOGAD and MS,revealing the whole brain-wide neuroinflammation,especially in the lesions.There was a decrease in 11C-acetate uptake within the acute NMOSD lesions,which was consistent with the pathological characteristics of astrocyte loss.11C-acetate may serve as a potential radiological biomarker for NMOSD.3)The PET results for animal models further supported the previous findings and demonstrated that microglia are the main source of TSPO.In summary,the optimization of MRI lesion analysis strategies improved the discriminatory capabilities.The joint application of 18F-FDG,18F-PBR06,and 11C-acetate PET/MR noninvasively displayed the pathological substrates of the brain neuroinflammation,showing great potential in assisting the accurate diagnosis of NMOSD and MOGAD.