Multimodal MRI Study Of Neuropsychiatric Lupus

Objectives:Systemic lupus erythematosus(SLE)is a chronic,multi-organ-involved autoimmune disease with a recurrence-remission form.It occurs predominantly in young women(female:male is 7-9:1).Neuropsychiatric systemic lupus(NPSLE)is one of the most common clinical manifestations of SLE and one of the main causes of disability and motality in SLE.The clinical manifestations of NPSLE are varied.The incidence of NPSLE is about 25%-70%in SLE patients,while only the central nervous system is involved in about 90%of NPSLE patients.At present,the pathomechanism and clinical typing of NPSLE are not completely clear.The current diagnostic methods can not completely distinguish NPSLE from nonNPSLE[1,2],There is still a grey area in the ACR naming standard.In recent years,the development of neuroimaging has led to the development of NPSLE research,especially the development of magnetic resonance imaging technology,such as structural magnetic resonance imaging(structural MRI),diffusion tensor imaging(DTI),which is from qualitative to quantitative,multi-angle analysis of the pathophysiology and pathogenesis of the disease.It provides a more comprehensive and accurate imaging basis for the clinical diagnosis,differential diagnosis,prognosis evaluation and curative effect evaluation of NPSLE.A single-center NPSLE neuroimaging cohort was established in this study.It is expected that the overall study will be divided into cross-sectional feature study and prospective cohort study based on this.This study is the starting point of the overall research,namely,cross sectional characteristic research.The aim of this study is to analyze the cerebral structural characteristics of female patients with primary central nervous system NPSLE with multimodal MRI technique;to explore the correlations of clinical factors with and the risk factors of MRI structural manifestations of SLE patients;and to serch the potential neuroimaging markers for the differentiation of NPSLE from nonNPSLE and health controls.Methods:From 2017 to 2018,32 female primary NPSLE patients(32.75±12.68 years)were enrolled in the NPSLE group with a median course of 55.5 months(12.0 to 162.10 months);25 female SLE patients without neuropsychiatric manifestations(29.24±9.84 years)in the nonNPSLE group with a median course of 29.10 months(10.5 to 72.10 months);and 34 healthy female control subjects(32.50±10.57 years).Medical history was collected(including major clinical manifestations,past risk factors for vascular diseases,laboratory immunological/neurological indicators,medications,etc.).clinical scores(including SLEDAI-2000,International Collaborative Group on Systemic Lupus Erythematosus/American Society of Rheumatology Injury Index(S)LICC/ACR damage index,SDI)were evaluated.Cerebral conventional MRI,structural MRI scan(3.0TMR scanner)were carried out.T1-weighted 3D BRAVO sequence data were used to calculate the volume/thickness of brain area segmentation by FreeSurfer software and FA/MD value of DTI image.Voxel-based morphological analysis(VBM)and DTI-based TBSS analysis were performed.Single factor multivariate analysis of variance was used for inter-group comparison;Spearman correlation analysis was used for correlation analysis;binary and ordered multivariate logistic regression analysis were used to determine the risk factors;ROC curve analysis was used to determine the optimal combination of structural MRI parameters to distinguish NPSLE from non-NPSLE and healthy controls.Results:The median SLEDAI scores of NPSLE patients was 6 points(3.0-12.0 points),and SDI median scores was 1 points(0-1 points).The median SLEDAI of NonNPSLE patients was 4 points(1.0-8.0 points),and SDI median was 0 points.There was no significant difference between groups.The main neuropsychiatric symptoms in NPSLE group were epilepsy(40.69%),cognitive impairment(40.6%)and psychosis(34.4%),etc.Neuropsychiatric symptoms in NPSLE patients occurred at median 7.5 months(0-120 months)after onset of SLE.The median interval between the onset of neuropsychiatric symptoms and MRI scan was 15 months(3.25-48.5 months).Eleven patients(34.4%)were in the acute stage of NPSLE(NP-SLEDAI≥8),and some patients had different degrees of cognitive impairment(NP-SLICC≥1).2.The brain parameters of NPSLE group were lower than those of healthy control group,and some of the parameters were significantly different from those of non-NPSLE group(p<0.05).Statistically significant brain regions were the ventricular system(third ventricle),subcortical gray matters(thalamus,hippocampus),prefrontal lobe(superior frontal gyrus,anterior middle frontal gyrus),anterior central gyrus,and marginal lobe.VBM analysis:The abnormal areas between the control group and the nonNPSLE group(p=0.001 corrected)included:paracentral gyrus,parietal lobe(right anterior cuneate lobe,angular gyrus),temporal lobe(middle temporal gyrus),occipital lobe(cuneate lobe,supracoccipital gyrus).3.The gray matter/white matter atrophy of NPSLE patients is related to SDI scores and has nothing to do with SLEDAI scores.Anti-ribosomal P protein antibody is associated with the atrophy of hippocampus and prefrontal cortex.Epilepsy is associated with ventricular dilatation and subcortical gray matter atrophy.Leukopenia,anemia,thrombocytopenia,cutaneous vasculitis,interstitial pneumonia(ischemia and hypoxia situations,and immunal inflammations)are also correlated with gray matter atrophy and ventricular dilatation.A variety of antinuclear antibodies and cutaneous vasculitis are related to atrophy of prefrontal cortex.DTI white matter lesions are associated with vascular perfusion factors(large vessel cerebrovascular events,focal NPSLE,anemia,thrombocytopenia,hypertension,etc.).4.Compared with the control group,the FA value decreased and MD value increased in the white matter areas of SLE patients,but only the FA value decreased with the MD value increased in the column and body part of fornix.There were significant differences among the three groups(FA:P<0.001,MD:P=0.007).The white matter areas with significantly different between groups FA values and no significant difference in MD values between groups are corpus callosum,superior cerebellar foot,cerebellar foot,left superior longitudinal tract(temporal lobe).The results of TBSS analysis in NPSLE group were not significantly different from those in non-NPSLE group and non-NPSLE group compared with those in healthy control group.5.The GCA scale was mainly correlated with subcortical gray matter and white matter atrophy;MTA scale was mainly correlated with cortical atrophy;Fazekas scale was correlated with white matter abnormalities on DTI images,especially white matter fiber bundles in the posterior regions.The three scales jointly distinguished the sensitivity and specificity of NPSLE and nonNPSLE and healthy controls by 83.9%and 80%respectively.The positive predictive value of GCA was 28.6-62.1%and the negative predictive value was 57.1-85.2%;the positive predictive value of MTA was 12.8%and the negative predictive value was 94.4%;the positive predictive value of Fazekas was 63.6%and the negative predictive value was 78.8%.6.Risk factors for brain atrophy in SLE patients:ventricular enlargement:SDI≥1(p=0.001,OR=9.642,95%CI 2.493-37.293);epileptic seizures(p=0.014,OR=8.025,95%CI 1.511-42.604);thrombocytopenia(p=0.040,OR=6.107,95%CI 1.083-34.438);age>31 years(p=0.053,OR=3.266,95%CI 0.983-10.855).Risk factors for subcortical gray matter nucleus atrophy:hippocampal atrophy:SDI≥1(p=0.023,OR=6.769,95%CI 1.302-35.204);anti-ribosomal P protein antibody positive(p=0.075,OR=3.150,95%CI 0.871-11.389).Thalamic atrophy:SDI≥ 1(p=0.026,OR=3.987,95%CI 1.178-13.495).Cortical atrophy risk factors:left anterior central gyrus:Fazekas score ≥3(p=0.043,OR=5.681,95%CI 1.053-30.663);leukopenia induced by SLE(p=0.018,OR=.945,95%CI 1.364-25.917);Hashimoto thyroiditis(p=0.046,OR=8.517,95%CI 1.035-70.065).WMHIs Fazekas≥2(p=0.005,OR=9.398,95%CI 1.948-45.349);age>31 years(p=0.043,OR=5.090,95%CI 1.054-24.585);duration of disease(p=0.099,OR=1.012,95%CI 0.998-1.027).Risk factors for abnormal white matter structure:fornix(column/body):SDI ≥ 1(p=0.079,OR=3.055,95%CI 0.878-10.633);intrathecal injection treatment of immunosuppressant and steroids(p=0.055,OR=5.851,95%CI 0.962-35.595).Left posterior thalamic radiation:SDI(p=0.020,OR=5.833,95%CI 1.328-25.628);lung involvement(p=0.027,OR=11.263,95%CI 1.309-96.882);hypertension(p=0.057,OR=6.380,95%CI 0.946-43.044);NP-SLEDAI(p=0.026,OR=1.292,95%CI 1.031-1.619).7.The optimal and simplest combination of MRI measurements that distinguish NPSLE from non-NPSLE and healthy controls is the third ventricular volume and the right pericalcarine thickness(AUC 0.848,sensitivity 78.1%,specificity 84.7%,95%CI 0.759-0.937).Conclusions:This study again confirmed that SLE patients had different degrees of brain atrophy and white matter lesions,even in SLE patients without neuropsychiatric symptoms,which are related to age,course of disease,SDI scores.Anti-ribosomal P protein antibody is a risk factor for hippocampal atrophy and is also associated with prefrontal lobe atrophy.It has been confirmed by imaging that this antibody is associated with central nervous system NPSLE(especially mental disorders),and that antibody-mediated autoimmune inflammation plays an important role in impairing neuronal function and leading to cognitive impairment of NPSLE.Hypoxia and hypertension are risk factors for abnormal white matter structure in the posterior circulation of SLE patients.Cortical atrophy mainly involved the parieto-occipital lobe,prefrontal lobe,libmic lobe cortex in SLE patients,with Fazekas score is a risk factor,which consistent with the characteristics of cerebral small vessel disease.It again confirmed the role of vascular factors in the pathogenesis of NPSLE.The volume of the third ventricle combined with the thickness of the right pericalcarine is a satisfied MRI marker for differentiating NPSLE from nonNPSLE and healthy controls.