Multimodal Magnetic Resonance Imaging Studies In Patients With Amyotrophic Lateral Sclerosis

Part 1 Multi-modal MRI studies of ALS patients with various levels of cognitive impairmentObjective:To characterize the brain structural,functional and perfusion patterns of ALS patients with various levels of cognitive impairment as measured by multi-modal MRI.Methods:A total of 50 ALS patients and 20 healthy controls(HC)were included,and all participants underwent neuropsychological assessments and multi-modal MRI scans.According to their cognitive performance,ALS patients were further subclassified into ALS with normal cognition(ALS-Cn,n=27),those with cognitive impairment(ALS-Ci,n=17)and ALS-FTD(n=11).Comparisons of voxel-based grey matter volume,cerebral blood flow,fractional anisotropy,mean diffusivity and resting state functional MRI data were conducted within the cognitive subgroups.Results:The whole-brain comparisons of grey matter volume,cerebral blood flow and functional MRI data between ALS-Ci,ALS-Ci and HC revealed no differences.The fractional anisotropy of cerebrospinal tracts of ALS patients was significantly decreased when compared with HC(P<0.001,uncorrected).The brain structure,function and perfusion in both motor and extra-motor areas of patients with ALS-FTD showed evident impairment when compared with the other three groups(P<0.05,FDR corrected),and the differences with ALS-Cn,ALS-Ci and HC increased in sequence.Conclusion:The brain structural,functional and perfusion patterns of ALS patients correlate with their cognitive function,and there is a gradient of disease burden across the ALS-Cn,ALS-Ci and ALS-FTD continuum.Multi-modal MRI might be helpful to explore the pathophysiological mechanism of ALS with cognitive impairment from various aspects.Part 2 The monitoring value of multi-modal MRI in the disease progression of amyotrophic lateral sclerosisObjective:To explore the monitoring value of multi-modal MRI in the disease progression of amyotrophic lateral sclerosis(ALS)and to find effective imaging markers.Methods:Twenty-seven ALS patients completed the MRI scans at baseline.The multi-modal MRI analyses included grey matter volume measured by voxel-based morphometry,integrity of white matter fiber tracts evaluated by diffusion tensor imaging,functional connectivity measured by resting state functional MRI,and cerebral vascular flow evaluated by arterial spin label.Correlation analyses between each imaging metrics and disease severity,disease duration and disease progression rate were carried out to find out brain regions that significantly correlated with clinical variables.Ten patients completed the follow-up MRI scans 6 months later.Comparisons were made between the imaging metrics of baseline and follow-up.We also compared the sensitivity of each imaging technique monitoring disease progression.Results:In the correlation analyses,the grey matter loss in the motor area was associated with disease severity;the integrity of the corticospinal tract in bilateral frontal lobe was associated with disease progression rate(P<0.001,uncorrected).In the longitudinal comparisons,the brain structure and perfusion in both motor and extra motor areas at follow-up were further impaired to different extent when compared with the baseline data(P<0.05,FDR corrected).The functional connectivity were increased in the motor areas and decreased in the extra-motor areas(P<0.001,uncorrected).No significant changes were detected in term of brain white matter measures.Conclusion:Multi-modal MRI can be used to monitor short-term brain changes in ALS patients,grey matter loss in the motor area might be more sensitive than the damage of corticospinal tract,and the hypoperfusion and decreased functional connectivity of the extra-motor areas might occur earlier than structural alterations.Part 3 Voxel-wise meta-analysis of grey matter changes in amyotrophic lateral sclerosisObjective:Increasing neuroimaging studies have revealed grey matter(GM)anomalies of several brain regions by voxel-based morphometry(VBM)studies in patients with amyotrophic lateral sclerosis(ALS).A voxel-wise meta-analysis was conducted to integrate the reported studies to determine the consistent GM alterations in ALS based on VBM methods.Methods:Ovid Medline,Pubmed,Emabase and BrainMap database were searched for relevant studies up to January,2017.Data were extracted by two independent researchers.Voxel-wise meta-analysis was performed using the effect-size signed differential mapping(ES-SDM)software.Results:Thirty-one VBM studies comprising 667 subjects with ALS and 659 healthy controls(HCs)met inclusion criteria,and 218 coordinates were collected.The global GM volumes of ALS patients were significantly decreased compared with those of HCs.GM reductions of ALS patients were mainly located in the right precentral gyrus,the left inferior frontal gyrus(opercular part),left anterior cingulate/paracingulate gyri and the right lenticular nucleus,putamen.The right precentral gyrus and the left inferior frontal gyrus might be potential anatomical biomarkers to evaluate the severity of the disease,and longer disease duration was associated with more GM atrophy in the right anterior cingulate/paracingulate gyri in ALS patients.Conclusion:The results support that ALS is a complex degenerative disease involving multisystems besides the motor system.The mechanism of asymmetric atrophy of the motor cortex and the implication of opercular part of left inferior frontal gyrus involvement in ALS need to be further elucidated in future studies.