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AIMS: To explore large-scale brain network alterations and examine their clinical and neuropsychological relevance in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: Twenty-four patients with anti-NMDAR encephalitis and 26 matched healthy controls (HCs) were enrolled in our study. Based on the multimodal MRI dataset, individual morphological, structural, and functional brain networks were constructed and compared between the two groups at multiple levels. The associations with clinical/neuropsychological variables and the discriminant ability of significant alterations were further studied. RESULTS: Multimodal network analysis revealed that anti-NMDAR encephalitis mainly affected morphological and structural networks, but subtle alterations were observed in functional networks. Intriguingly, decreased network local efficiency was observed for both morphological and structural networks and increased nodal centrality in the lateral orbital gyrus was convergently observed among the three types of networks in the patients. Moreover, the alterations, particularly those from structural networks, accounted largely for cognitive deficits of the patients and could distinguish the diseased individuals from the HCs with excellent performance (area under the curve =0.933). CONCLUSIONS: The current study provides a comprehensive view of characteristic multimodal network dysfunction in anti-NMDAR encephalitis, which is crucial to establish new diagnostic biomarkers and promising therapeutic targets for the disease.

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Objective: To investigate the rich-club organization in clinically isolated syndrome (CIS) and multiple sclerosis (MS), and to characterize its relationships with physical disabilities and cognitive impairments. Methods: We constructed high-resolution white matter (WM) structural networks in 41 CIS, 32 MS and 35 healthy controls (HCs) using diffusion MRI and deterministic tractography. Group differences in rich-club organization, global and local network metrics were investigated. The relationship between the altered network metrics, brain lesions and clinical variables including EDSS, MMSE, PASAT, disease duration were calculated. Additionally, reproducibility analysis was performed using different parcellation schemes. Results: Compared with HCs, MS patients exhibited a decreased strength in all types of connections (rich-club: p < 0.0001; feeder: p = 0.0004; and local: p = 0.0026). CIS patients showed intermediate values between MS patients and HCs and exhibited a decreased strength in feeder and local connections (feeder: p = 0.019; and local: p = 0.031) but not in rich-club connections. Compared with CIS patients, MS patients showed significant reductions in rich-club connections (p = 0.0004). The reduced strength of rich-club and feeder connections was correlated with cognitive impairments in the MS group. These results were independent of lesion distribution and reproducible across different brain parcellation schemes. Conclusion: The rich-club organization was disrupted in MS patients and relatively preserved in CIS. The disrupted rich-club connectivity was correlated with cognitive impairment in MS. These findings suggest that impaired rich-club connectivity is an essential feature of progressive structural network disruption, heralding the development of clinical disability in MS.

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Purpose: To investigate spontaneous brain activity amplitude alterations in single and relapsing optic neuritis (sON and rON, respectively) and their relationships with clinical variables. Methods: In total, 42 patients with sON, 35 patients with rON and 50 healthy volunteers were recruited. Resting-state functional Magnetic Resonance Imaging (rs-fMRI) scans were acquired for all participants and compared to investigate the changes in the amplitude of low-frequency fluctuations (ALFFs) among the three groups. The relationships between the ALFFs in regions with significant differences in the groups and clinical variables, including the logarithm of minimal angle of resolution (LogMAR), Expanded Disability Status Scale (EDSS) score and disease duration, were further explored. Results: Compared with healthy volunteers, the sON and rON patients showed significantly decreased ALFFs in several regions of the occipital and temporal lobes (i.e., inferior occipital gyrus and superior temporal gyrus; corrected p < 0.01 using AlphaSim). The sON patients showed significantly increased ALFFs in the left caudate and certain regions in the frontal lobes (i.e., medial frontal gyrus), whereas the rON patients showed increased ALFFs in the bilateral inferior temporal gyrus and left medial frontal gyrus (corrected p < 0.01 using AlphaSim). Significantly decreased ALFFs were observed in the right inferior parietal lobule (IPL), left posterior cingulate and precuneus in the rON patients compared with those in the sON patients (corrected p < 0.01 using AlphaSim). Significant correlations were observed between the disease duration and ALFF in the left middle temporal gyrus, left inferior occipital gyrus, right lingual gyrus and right IPL (p < 0.05). Conclusion: Functional impairment and adaptation occurred in both the sON and rON patients. Impairment mainly involved the occipital cortex, and functional adaptions predominantly occurred in the frontal lobe. Functional damage was more severe in the rON patients than in the sON patients and correlated with the disease duration.

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This study aims to determine whether and how diffusion alteration occurs in the earliest stage of multiple sclerosis (MS) and the differences in diffusion metrics between CIS and MS by using the tract-based spatial statistics (TBSS) method based on diffusion tensor imaging (DTI). Thirty-six CIS patients (mean age ±â€¯SD: 34.0 years ±â€¯12.6), 36 relapsing-remitting multiple sclerosis (RRMS) patients (mean age ±â€¯SD: 35.0 years ±â€¯9.4) and 36 age- and gender-matched normal controls (NCs) were included in this study. Voxel-wise analyses were performed with TBSS using multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ1) and radial diffusivity (λ23). In the CIS patients, TBSS analyses revealed diffusion alterations in a few white matter (WM) regions including the anterior thalamic radiation, corticospinal tract, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, body and splenium of the corpus callosum, internal capsule, external capsule, and cerebral peduncle. MS patients showed more widespread diffusion changes (decreased FA, increased λ1, λ23 and MD) than CIS. Exploratory analyses also revealed the possible associations between WM diffusion metrics and clinical variables (Expanded Disability Status Scale and disease duration) in the patients. This study provided imaging evidence for DTI abnormalities in CIS and MS and suggested that DTI can improve our knowledge of the path physiology of CIS and MS and clinical progression.

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OBJECTIVE: To investigate the longitudinal spinal cord and brain changes in neuromyelitis optica (NMO) and multiple sclerosis (MS) and their associations with disability progression. PATIENTS AND METHODS: We recruited 28 NMO, 22 MS, and 20 healthy controls (HC), who underwent both spinal cord and brain MRI at baseline. Twenty-five NMO and 20 MS completed 1-year follow-up. Baseline spinal cord and brain lesion loads, mean upper cervical cord area (MUCCA), brain, and thalamus volume and their changes during a 1-year follow-up were measured and compared between groups. All the measurements were also compared between progressive and non-progressive groups in NMO and MS. RESULTS: MUCCA decreased significantly during the 1-year follow-up in NMO not in MS. Percentage brain volume changes (PBVC) and thalamus volume changes in MS were significantly higher than NMO. MUCCA changes were significantly different between progressive and non-progressive groups in NMO, while baseline brain lesion volume and PBVC were associated with disability progression in MS. MUCCA changes during 1-year follow-up showed association with clinical disability in NMO. CONCLUSION: Spinal cord atrophy changes were associated with disability progression in NMO, while baseline brain lesion load and whole brain atrophy changes were related to disability progression in MS. KEY POINTS: • Spinal cord atrophy progression was observed in NMO. • Spinal cord atrophy changes were associated with disability progression in NMO. • Brain lesion and atrophy were related to disability progression in MS.

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Previous studies have revealed brain adaptations to injury that occurs in optic neuritis (ON); however, the mechanisms underlying the functional connectivity (FC) and gray matter volume (GMV) changes in ON have not been clarified. Here, 51 single attack ON patients and 45 recurrent attacks ON patients were examined using structural MRI and resting-state functional MRI (RS-fMRI), and compared to 49 age- and gender-matched healthy controls (HC). FC analysis with a seed in primary visual cortex (V1 area) was used to assess the differences among three groups. Whole brain GMV was assessed using voxel-based morphometry (VBM). Correlation analyses were performed between FC results, structural MRI and clinical variables. We found positive correlations between the Paced Auditory Serial Addition Test (PASAT) score and FC in V1 area with bilateral middle frontal gyrus. Disease duration is significantly negatively related to FC in V1 area with the left inferior parietal lobule. Compared to the HC, single attack ON patients were found to have decreased FC values in the frontal, temporal lobes, right inferior occipital gyrus, right insula, right inferior parietal lobule, and significant increased FC values in the left thalamus. Recurrent attacks ON patients had the same pattern with single attack ON. No significant differences were found in brain GMV among three groups. This study provides the imaging evidence that impairment and compensation of V1 area connectivity coexist in ON patients, and provides important insights into the underlying neural mechanisms of ON.

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OBJECTIVE: To investigate structural and functional alterations of gray matter (GM) and examine their clinical relevance in neuromyelitis optica (NMO) using multimodal magnetic resonance imaging (MRI) techniques. METHODS: A total of 35 NMO and 36 healthy controls (HC) were recruited in this study. Cortical lesions were investigated by double inversion recovery technique. Five voxel-wise MRI measurements were obtained for each participant in the GM including gray matter volume (GMV), fractional anisotropy (FA), mean diffusivity (MD), amplitude of low-frequency fluctuation (ALFF), and weighted functional connectivity strength (wFCS). Between-group differences, cross-modality relationships, and MRI-clinical correlations were examined. RESULTS: No cortical lesions were found in NMO. Compared to HC, NMO patients exhibited significantly decreased GMV in deep GM and cortical regions involving visual function and cognition. Diffusion GM abnormalities were widespread in the patients. Decreased ALFF and wFCS were observed in the patients in sensorimotor, visual, cognition, and cerebellar sites. GM structural alterations were correlated with cognitive but not physical disability scores of the patients. CONCLUSION: Despite the lack of focal cortical lesions, patients with NMO exhibit both structural and functional alterations of GM in cerebrum and cerebellum that predominantly involve deep GM, visual, motor, and cognitive regions. GM alterations are associated with cognitive impairment but not physical disability.

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Background Previous studies with a small sample size have not reported metabolic changes in neuromyelitis optica (NMO). Metabolic changes, such as decreased N-acetylaspartate (NAA), are well-established in patients with multiple sclerosis (MS). It remains unknown whether different patterns of metabolic changes occur in NMO and MS. Purpose To investigate the metabolic changes in normal-appearing white matter (NAWM) in NMO, compared with MS patients and healthy controls (HC), and correlate these changes with clinical disability. Material and Methods We recruited 27 patients with NMO, 24 patients with MS, and 24 HC. Each participant underwent chemical shift imaging with a 1H-MR spectroscopy operating in a 1.5 T magnetic resonance imaging (MRI) scanner. The absolute concentrations of NAA, choline (Cho), creatine (Cr) as well as the metabolite ratios of NAA/Cr, Cho/Cr, and NAA/Cho were measured and compared among the groups. The correlations between the metabolic concentrations, disease duration, and clinical disability (Expanded Disability Status Scale, EDSS) were further explored. Results Compared with HC, a mild increase of Cho without significant NAA changes was observed in NMO patients, while both a significant reduction of NAA and an increase of Cho were observed in MS patients. The absolute concentration of NAA and NAA/Cho ratio were significantly decreased in MS patients in a direct comparison with NMO patients. In MS patients, the EDSS was correlated with the NAA/Cr and Cho/Cr ratios. Conclusion A reduction of NAA was not observed in NMO, implying axonal or neuronal damage may be absent in NAWM for NMO, which is different from MS. A mild increase in Cho was observed in NAWM of NMO patients, suggesting that subtle metabolic changes occur in NMO.

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Purpose To investigate the topological organization of functional brain networks in clinically isolated syndrome (CIS) and multiple sclerosis (MS) and examine the clinical relevance. Materials and Methods The institutional review board of Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China, approved the study, and written informed consent was obtained from each participant. Functional brain networks were constructed for 34 patients with MS, 34 patients with CIS, and 36 matched healthy control subjects by using resting-state functional magnetic resonance (MR) imaging data. Graph-based network measures were then calculated, followed by performance of between-group comparison and brain-behavior correlation analysis. Results Decreased whole-brain network efficiency was observed for patients with MS when compared with healthy control subjects, with intermediate values for the patients with CIS (P < .05, corrected). Regionally, both patient groups showed decreased nodal efficiency in the left rolandic operculum and insula and the superior temporal gyrus of the bilateral temporal pole (P < .05, corrected). Moreover, impaired functional connectivity involving the occipital, temporal, and frontal cortices and the insula was identified in MS (P = .007), and a similar but smaller component was observed in CIS (P = .032). The disrupted functional connectivity correlated with disease duration of the patients (r = 0.312, P = .011) and served to distinguish the patients from healthy control subjects with high performance (area under the curve for MS, 0.825 [P < .001]; area under the curve for CIS, 0.789 [P < .001]). These findings were reproducible across several different analytical strategies and were largely independent of white matter lesions and gray matter atrophy. Conclusion The results of this study demonstrate that disrupted network organization already emerges in CIS, with a lesser degree relative to MS. © RSNA, 2016 Online supplemental material is available for this article.

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The brain connectome of multiple sclerosis (MS) has been investigated by several previous studies; however, it is still unknown how the network changes in clinically isolated syndrome (CIS), the earliest stage of MS, and how network alterations on a functional level relate to the structural level in MS disease. Here, we investigated the topological alterations of both the structural and functional connectomes in 41 CIS and 32 MS patients, compared to 35 healthy controls, by combining diffusion tensor imaging and resting-state functional MRI with graph analysis approaches. We found that the structural connectome showed a deviation from the optimal pattern as early as the CIS stage, while the functional connectome only showed local changes in MS patients, not in CIS. When comparing two patient groups, the changes appear more severe in MS. Importantly, the disruptions of structural and functional connectomes in patients occurred in the same direction and locally correlated in sensorimotor component. Finally, the extent of structural network changes was correlated with several clinical variables in MS patients. Together, the results suggested early disruption of the structural brain connectome in CIS patients and provided a new perspective for investigating the relationship of the structural and functional alterations in MS.

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OBJECTIVE: To investigate brain functional connectivity (FC) alterations in patients with clinically isolated syndromes (CIS) presenting without conventional brain MRI lesions, and to identify the FC differences between the CIS patients who converted to multiple sclerosis (MS) and those not converted during a 5-year follow-up. METHODS: We recruited 20 CIS patients without conventional brain lesions, 28 patients with MS and 28 healthy controls (HC). Normalized voxel-based functional connectivity strength (nFCS) was determined using resting-state fMRI (R-fMRI) and compared among groups. Furthermore, 5-years clinical follow-up of the CIS patients was performed to examine the differences in nFCS between converters and non-converters. RESULTS: Compared to HC, CIS patients showed significantly decreased nFCS in the visual areas and increased nFCS in several brain regions predominately in the temporal lobes. MS patients revealed more widespread higher nFCS especially in deep grey matter (DGM), compared to CIS and HC. In the four CIS patients converting to MS, significantly higher nFCS was found in right anterior cingulate gyrus (ACC) and fusiform gyrus (FG), compared to non-converted patients. CONCLUSION: We demonstrated both functional impairment and compensation in CIS by R-fMRI. nFCS alteration in ACC and FG seems to occur in CIS patients at risk of developing MS. KEY POINTS: • Both functional impairment and compensation occur in CIS without conventional brain lesions. • MS patients revealed more widespread higher nFCS especially in deep grey matter. • nFCS alteration may help stratifying CIS at risk of developing MS.

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PURPOSE: To systematically investigate structural and functional alterations of the thalamus and its subregions through a multimodal magnetic resonance (MR) imaging technique and examine its clinical relevance in multiple sclerosis (MS) and neuromyelitis optica (NMO). MATERIALS AND METHODS: The institutional review board approved this study, and written informed consent was obtained from each participant. Thirty-seven patients with MS, 39 patients with NMO, and 40 healthy control subjects were recruited. Six MR imaging measurements were obtained for each participant and compared between groups in the thalamus and its seven subregions, including gray matter (GM) volume, fractional anisotropy, mean diffusivity, amplitude of low-frequency fluctuation, cross-correlation coefficient of spontaneous low frequency, and weighted functional connectivity strength. Partial correlation was used to estimate the MR imaging-clinical relationships. RESULTS: Both MS and NMO exhibited widespread GM atrophy (GM volume in MS, 0.244; NMO, 0.297; and control subjects, 0.329; P < .001) and diffusion abnormalities (fractional anisotropy in MS, 0.293; NMO, 0.323; and control subjects, 0.355; P < .001) in the whole thalamus and several subregions, while MS showed more severe changes than NMO. Decreased cross-correlation coefficient of spontaneous low-frequency and weighted functional connectivity strength was observed in several thalamus subregions in MS (P < .05), but no significant functional abnormalities were identified in NMO. GM volume, fractional anisotropy, and mean diffusivity, not functional changes of the thalamus and thalamic subregions, correlated with the patients' clinical variables and exhibited high discriminative power in distinguishing the three groups. CONCLUSION: Similar patterns of thalamic structural alteration were identified in MS and NMO, but MS showed more severe pathologic changes. The thalamus is a key node for functional disconnection in MS but not in NMO.

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OBJECTIVE: To investigate spinal cord and brain atrophy in neuromyelitis optica (NMO), and its relationship with other MRI measurements and clinical disability, compared with patients with multiple sclerosis (MS) and healthy controls (HC). METHODS: We recruited 35 patients with NMO, 35 patients with MS, and 35 HC, who underwent both spinal cord and brain MRI. Mean upper cervical cord area (MUCCA), brain parenchymal fraction (BPF), gray matter fraction (GMF), white matter fraction (WMF), and spinal cord and brain lesion loads were measured and compared among groups. Multivariate associations between MUCCA and brain volume measurement and clinical variables were assessed by partial correlations and multiple linear regression. RESULTS: Patients with NMO showed smaller MUCCA than HC (p = 0.004), and patients with MS had a trend of smaller MUCCA compared to HC (p = 0.07), with no significant difference between the patient groups. Patients with NMO showed lower BPF than HC, and patients with MS had lower BPF and GMF than patients with NMO. In NMO, MUCCA was correlated with Expanded Disability Status Scale score (EDSS), number of relapses, and total spinal cord lesion length, while in MS, MUCCA was correlated with WMF and EDSS. MUCCA was the only independent variable for predicting clinical disability measured by EDSS in NMO (R(2) = 0.55, p < 0.001) and MS (R(2) = 0.17, p = 0.013). CONCLUSION: NMO showed predominately spinal cord atrophy with mild brain atrophy, while MS demonstrated more brain atrophy, especially in the gray matter. MUCCA is the main MRI-derived parameter for explaining clinical disability in NMO and MS, and may serve as a potential biomarker for further clinical trials, especially in NMO.

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OBJECTIVE: To compare thalamic functional connectivity (FC) in patients with multiple sclerosis (MS) and healthy controls (HC), and correlate these connectivity measures with other MRI and clinical variables. METHODS: We employed resting-state functional MRI (fMRI) to examine changes in thalamic connectivity by comparing thirty-five patients with MS and 35 age- and sex-matched HC. Thalamic FC was investigated by correlating low frequency fMRI signal fluctuations in thalamic voxels with voxels in all other brain regions. Additionally thalamic volume fraction (TF), T2 lesion volume (T2LV), EDSS and disease duration were recorded and correlated with the FC changes. RESULTS: MS patients were found to have a significantly lower TF than HC in bilateral thalami. Compared to HC, the MS group showed significantly decreased FC between thalamus and several brain regions including right middle frontal and parahippocampal gyri, and the left inferior parietal lobule. Increased intra- and inter-thalamic FC was observed in the MS group compared to HC. These FC alterations were not correlated with T2LV, thalamic volume or lesions. In the MS group, however, there was a negative correlation between disease duration and inter-thalamic connectivity (r=-0.59, p<0.001). CONCLUSION: We demonstrated decreased FC between thalamus and several cortical regions, while increased intra- and inter-thalamic connectivity in MS patients. These complex functional changes reflect impairments and/or adaptations that are independent of T2LV, thalamic volume or presence of thalamic lesions. The negative correlation between disease duration and inter-thalamic connectivity could indicate an adaptive role of thalamus that is gradually lost with increasing disease duration.

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OBJECTIVES: To compare spatial patterns of cortical thickness alterations in neuromyelitis optica (NMO) and multiple sclerosis (MS); and to investigate the correlations between cortical thinning and clinical variables in NMO and MS. METHODS: We studied 23 patients with NMO, 27 patients with MS and 26 healthy controls (HCs). The global, brain region and vertex-based cortical thickness (CTh) were analysed and compared among the three groups. A general linear model was used to investigate the correlations between cortical thinning and clinical measures. RESULTS: A limited number of cortical regions in visual cortex were found to be significantly thinner in NMO patients than in HCs. The MS patients exhibited more widespread cortical thinning compared with HCs, and significantly greater cortical thinning in the insula and the parahippocampus compared with NMO. The extent of cortical thinning in several brain regions correlated with cognitive measures in MS, but not in NMO. CONCLUSIONS: Neocortical thinning in NMO mainly affects visual cortex, while MS patients show much more extensive cortical thinning. Cognitive changes are correlated with cortical atrophy in MS not in NMO. The substrates of cognitive changes in MS and NMO could therefore be different. KEY POINTS: MS patients show much more extensive cortical thinning than NMO. Cortical thinning of insula and parahippocampus particularly distinguishes MS from NMO. Cognitive changes are correlated with cortical atrophy in MS but not in NMO.

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AIMS: To assess the demographic, clinical and spinal cord MRI characteristics of clinically definite neuromyelitis optica (NMO) patients for association with anti-aquaporin-4 (AQP4) antibody positivity in Chinese patients. METHODS: We recruited 72 consecutive patients with NMO. The clinical assessments, sera and spinal MRI scans were obtained within 1 week after the onset of symptoms of acute myelitis. The statistical significance of potential differences in demographic, clinical and spinal MRI lesion characteristics between the two groups (anti-AQP4 antibody positive vs. negative) was determined using the two-sample t test or Fisher's exact test. RESULTS: Forty-nine patients (49/72, 68.1%) were anti-AQP4 antibody positive and 23 patients (23/72, 31.9%) were anti-AQP4 antibody negative. The only characteristic that was significantly different between the groups was the presence of an enhancing spinal cord lesion (p < 0.001). CONCLUSION: We found a strong association between serum anti-AQP4 antibody positivity and lesional gadolinium enhancement in patients with clinically definite NMO. These findings support prior evidence that anti-AQP4 antibody could be pathogenic in NMO lesion development.

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