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Background and Purpose: The underlying transcriptomic signatures driving brain functional alterations in MS and neuromyelitis optica spectrum disorder (NMOSD) are still unclear., Materials and Methods: Regional fractional amplitude of low-frequency fluctuation (fALFF) values were obtained and compared among 209 patients with MS, 90 patients with antiaquaporin-4 antibody (AQP4)+ NMOSD, 49 with AQP4- NMOSD, and 228 healthy controls from a discovery cohort. We used partial least squares (PLS) regression to identify the gene transcriptomic signatures associated with disease-related fALFF alterations. The biologic process and cell type-specific signature of the identified PLS genes were explored by enrichment analysis. The correlation between PLS genes and clinical variables was explored. A prospective independent cohort was used to validate the brain fALFF alterations and the repeatability of identified genes., Results: MS, AQP4+ NMOSD, and AQP4- NMOSD showed decreased fALFF in cognition-related regions and deep gray matter, while NMOSD (both AQP4+ and AQP4-) additionally demonstrated lower fALFF in the visual region. The overlapping PLS1- genes (indicating that the genes were overexpressed as regional fALFF decreased) were enriched in response to regulation of the immune response in all diseases, and the PLS1- genes were specifically enriched in the epigenetics profile in MS, membrane disruption and cell adhesion in AQP4+ NMOSD, and leukocyte activation in AQP4- NMOSD. For the cell type transcriptional signature, microglia and astrocytes accounted for the decreased fALFF. The fALFF-associated PLS1- genes directly correlated with Expanded Disability Status Scale of MS and disease duration across disorders., Conclusions: We revealed the functional activity alterations and their underlying shared and specific gene transcriptional signatures in MS, AQP4+ NMOSD, and AQP4- NMOSD., (© 2024 by American Journal of Neuroradiology.)

Grey matter (GM) atrophies are observed in multiple sclerosis, neuromyelitis optica spectrum disorders [NMOSD; both anti-aquaporin-4 antibody-positive (AQP4+) and -negative (AQP4-) subtypes] and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Revealing the pathogenesis of brain atrophy in these disorders would help their differential diagnosis and guide therapeutic strategies. To determine the neurobiological underpinnings of GM atrophies in multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD and MOGAD, we conducted a virtual histology analysis that links T1-weighted image derived GM atrophy and gene expression using a multicentre cohort of 324 patients with multiple sclerosis, 197 patients with AQP4+ NMOSD, 75 patients with AQP4- NMOSD, 47 patients with MOGAD and 2169 healthy control subjects. First, interregional GM atrophy profiles across the cortical and subcortical regions were determined using Cohen's d between patients with multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD or MOGAD and healthy controls. The GM atrophy profiles were then spatially correlated with the gene expression levels extracted from the Allen Human Brain Atlas, respectively. Finally, we explored the virtual histology of clinical-feature relevant GM atrophy using a subgroup analysis that stratified by physical disability, disease duration, number of relapses, lesion burden and cognitive function. Multiple sclerosis showed a severe widespread GM atrophy pattern, mainly involving subcortical nuclei and brainstem. AQP4+ NMOSD showed an obvious widespread pattern of GM atrophy, predominately located in occipital cortex as well as cerebellum. AQP4- NMOSD showed a mild widespread GM atrophy pattern, mainly located in frontal and parietal cortices. MOGAD showed GM atrophy mainly involving the frontal and temporal cortices. High expression of genes specific to microglia, astrocytes, oligodendrocytes and endothelial cells in multiple sclerosis, S1 pyramidal cells in AQP4+ NMOSD, as well as S1 and CA1 pyramidal cells in MOGAD, had spatial correlations with GM atrophy profile, while no atrophy profile-related gene expression was found in AQP4- NMOSD. Virtual histology of clinical feature-relevant GM atrophy pointed mainly to the shared neuronal and endothelial cells, among the four neuroinflammatory diseases. The unique underlying virtual histology patterns were microglia, astrocytes and oligodendrocytes for multiple sclerosis; astrocytes for AQP4+ NMOSD; and oligodendrocytes for MOGAD. Neuronal and endothelial cells were shared potential targets across these neuroinflammatory diseases. These findings may help the differential diagnoses of these diseases and promote the use of optimal therapeutic strategies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Spinal cord and brain atrophy are common in neuromyelitis optica spectrum disorder (NMOSD) and relapsing-remitting multiple sclerosis (RRMS) but harbor distinct patterns accounting for disability and cognitive impairment., Methods: This study included 209 NMOSD and 304 RRMS patients and 436 healthy controls. Non-negative matrix factorization was used to parse differences in spinal cord and brain atrophy at subject level into distinct patterns based on structural MRI. The weights of patterns were obtained using a linear regression model and associated with Expanded Disability Status Scale (EDSS) and cognitive scores. Additionally, patients were divided into cognitive impairment (CI) and cognitive preservation (CP) groups., Results: Three patterns were observed in NMOSD: (1) Spinal Cord-Deep Grey Matter (SC-DGM) pattern was associated with high EDSS scores and decline of visuospatial memory function; (2) Frontal-Temporal pattern was associated with decline of language learning function; and (3) Cerebellum-Brainstem pattern had no observed association. Patients with CI had higher weights of SC-DGM pattern than CP group. Three patterns were observed in RRMS: (1) DGM pattern was associated with high EDSS scores, decreased information processing speed, and decreased language learning and visuospatial memory functions; (2) Frontal-Temporal pattern was associated with overall cognitive decline; and (3) Occipital pattern had no observed association. Patients with CI trended to have higher weights of DGM and Frontal-Temporal patterns than CP group., Conclusion: This study estimated the heterogeneity of spinal cord and brain atrophy patterns in NMOSD and RRMS patients at individual level, and evaluated the clinical relevance of these patterns, which may contribute to stratifying participants for targeted therapy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: The cerebellum plays key roles in the pathology of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), but the way in which these conditions affect how the cerebellum communicates with the rest of the brain (its connectome) and associated genetic correlates remains largely unknown., Methods: Combining multimodal MRI data from 208 MS patients, 200 NMOSD patients and 228 healthy controls and brain-wide transcriptional data, this study characterized convergent and divergent alterations in within-cerebellar and cerebello-cerebral morphological and functional connectivity in MS and NMOSD, and further explored the association between the connectivity alterations and gene expression profiles., Results: Despite numerous common alterations in the two conditions, diagnosis-specific increases in cerebellar morphological connectivity were found in MS within the cerebellar secondary motor module, and in NMOSD between cerebellar primary motor module and cerebral motor- and sensory-related areas. Both diseases also exhibited decreased functional connectivity between cerebellar motor modules and cerebral association cortices with MS-specific decreases within cerebellar secondary motor module and NMOSD-specific decreases between cerebellar motor modules and cerebral limbic and default-mode regions. Transcriptional data explained > 37.5% variance of the cerebellar functional alterations in MS with the most correlated genes enriched in signaling and ion transport-related processes and preferentially located in excitatory and inhibitory neurons. For NMOSD, similar results were found but with the most correlated genes also preferentially located in astrocytes and microglia. Finally, we showed that cerebellar connectivity can help distinguish the three groups from each other with morphological connectivity as predominant features for differentiating the patients from controls while functional connectivity for discriminating the two diseases., Conclusions: We demonstrate convergent and divergent cerebellar connectome alterations and associated transcriptomic signatures between MS and NMOSD, providing insight into shared and unique neurobiological mechanisms underlying these two diseases., (© 2023. The Author(s).)

Objective: To evaluate the clinical significance of deep learning-derived brain age prediction in neuromyelitis optica spectrum disorder (NMOSD) relative to relapsing-remitting multiple sclerosis (RRMS)., Methods: This cohort study used data retrospectively collected from 6 tertiary neurological centres in China between 2009 and 2018. In total, 199 patients with NMOSD and 200 patients with RRMS were studied alongside 269 healthy controls. Clinical follow-up was available in 85 patients with NMOSD and 124 patients with RRMS (mean duration NMOSD=5.8±1.9 (1.9-9.9) years, RRMS=5.2±1.7 (1.5-9.2) years). Deep learning was used to learn 'brain age' from MRI scans in the healthy controls and estimate the brain age gap (BAG) in patients., Results: A significantly higher BAG was found in the NMOSD (5.4±8.2 years) and RRMS (13.0±14.7 years) groups compared with healthy controls. A higher baseline disability score and advanced brain volume loss were associated with increased BAG in both patient groups. A longer disease duration was associated with increased BAG in RRMS. BAG significantly predicted Expanded Disability Status Scale worsening in patients with NMOSD and RRMS., Conclusions: There is a clear BAG in NMOSD, although smaller than in RRMS. The BAG is a clinically relevant MRI marker in NMOSD and RRMS., Competing Interests: Competing interests: FB acts as a consultant for Combinostics, Biogen-Idec, Janssen, IXICO, Merck-Serono, Novartis and Roche. He has received grants, or grants are pending, from the Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) initiative, the Biomedical Research Centre at University College London Hospitals, the Dutch MS Society, ECTRIMS–MAGNIMS, EU-H2020, the Dutch Research Council (NWO), the UK MS Society and the National Institute for Health Research, University College London. He has received payments for the development of educational presentations from IXICO and his institution from Biogen-Idec and Merck. He is co-founder of Queen Square Analytics. He is on the editorial board of Radiology, Neuroradiology, Multiple Sclerosis Journal and Neurology. JHC is a scientific consultant to and shareholder in BrainKey and Claritas Healthcare, as has worked as a consultant to Queen Square Analytics., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Brain morphometric alterations involve multiple brain regions on progression of the disease in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) and exhibit age-related degenerative changes during the pathological aging. Recent advance in brain morphometry as measured using MRI have leveraged Person-Based Similarity Index (PBSI) approach to assess the extent of within-diagnosis similarity or heterogeneity of brain neuroanatomical profiles between individuals of healthy populations and validate in neuropsychiatric disorders. Brain morphometric changes throughout the lifespan would be invaluable for understanding regional variability of age-related structural degeneration and the substrate of inflammatory demyelinating disease. Here, we aimed to quantify the neuroanatomical profiles with PBSI measures of cortical thickness (CT) and subcortical volumes (SV) in 263 MS, 207 NMOSD, and 338 healthy controls (HC) from six separate central datasets (aged 11-80). We explored the between-group comparisons of PBSI measures, as well as the advancing age and sex effects on PBSI measures. Compared to NMOSD, MS showed a lower extent of within-diagnosis similarity. Significant differences in regional contributions to PBSI score were observed in 29 brain regions between MS and NMOSD (P < 0.05/164, Bonferroni corrected), of which bilateral cerebellum in MS and bilateral parahippocampal gyrus in NMOSD represented the highest divergence between the two patient groups, with a high similarity effect within each group. The PBSI scores were generally lower with advancing age, but their associations showed different patterns depending on the age range. For MS, CT profiles were significantly negatively correlated with age until the early 30 s (ρ = -0.265, P = 0.030), while for NMOSD, SV profiles were significantly negatively correlated with age with 51 year-old and older (ρ = -0.365, P = 0.008). The current study suggests that PBSI approach could be used to quantify the variation in brain morphometric changes in CNS inflammatory demyelinating disease, and exhibited a greater neuroanatomical heterogeneity pattern in MS compared with NMOSD. Our results reveal that, as an MR marker, PBSI may be sensitive to distribute the disease-associated grey matter diversity and complexity. Disease-driven production of regionally selective and age stage-dependency changes in the neuroanatomical profile of MS and NMOSD should be considered to facilitate the prediction of clinical outcomes and assessment of treatment responses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hippocampal involvement may differ between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD)., Objective: To investigate the morphometric, diffusion and functional alterations in hippocampus in MS and NMOSD and the clinical significance., Methods: A total of 752 participants including 236 MS, 236 NMOSD and 280 healthy controls (HC) were included in this retrospective multi-center study. The hippocampus and subfield volumes, fractional anisotropy (FA) and mean diffusivity (MD), amplitude of low frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and their associations with clinical variables were investigated., Results: The hippocampus showed significantly lower volume, FA and greater MD in MS compared to NMOSD and HC ( p < 0.05), while no abnormal ALFF or DC was identified in any group. Hippocampal subfields were affected in both diseases, though subiculum, presubiculum and fimbria showed significantly lower volume only in MS ( p < 0.05). Significant correlations between diffusion alterations, several subfield volumes and clinical variables were observed in both diseases, especially in MS ( R = -0.444 to 0.498, p < 0.05). FA and MD showed fair discriminative power between MS and HC, NMOSD and HC (AUC > 0.7)., Conclusions: Hippocampal atrophy and diffusion abnormalities were identified in MS and NMOSD, partly explaining how clinical disability and cognitive impairment are differentially affected.

Purpose: To investigate the brain MRI features in neuromyelitis optica spectrum disorders (NMOSD) and its clinical relevance in a large multi-center cohort in China., Methods: 270 NMOSD patients were recruited from seven centers. The brain MRI were classified as normal, NMOSD-specific lesions, multiple sclerosis-like, nonspecific white matter changes. Brain volumes including whole brain, white, gray matter, cortex and subcortex gray matter volume were measured. The relationship between MRI measures, clinical disability and cognitive impairment were investigated., Results: 98 patients (36.3%) had normal brain MRI; 48 patients (17.7%) had NMOSD-specific lesions located in dorsal brainstem, corticospinal tract corpus, callosum and periependymal lesions surrounding the ventricular system; 16 patients (6%) had multiple sclerosis-like lesions; and 108 patients (40%) had nonspecific white matter changes. NMOSD patients with brain lesions had a trend of lower subcortex gray matter volume compared to patients without lesions. 52.5% patients with normal brain MRI and 50.8% patients with abnormal brain MRI showed cognitive impairment. No significant differences were identified in brain volume between cognitive impairment and cognitive preserved groups., Conclusion: In this large multicenter NMOSD cohort, nonspecific white matter changes were the most common findings (40%). NMOSD patients with brain lesions demonstrated a trend of having lower brain volume than patients without lesions. Approximately 50% NMOSD patients presented cognitive impairment independent of brain lesions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Grey matter (GM) atrophies are observed in multiple sclerosis, neuromyelitis optica spectrum disorders [NMOSD; both anti-aquaporin-4 antibody-positive (AQP4+) and -negative (AQP4−) subtypes] and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Revealing the pathogenesis of brain atrophy in these disorders would help their differential diagnosis and guide therapeutic strategies. To determine the neurobiological underpinnings of GM atrophies in multiple sclerosis, AQP4+ NMOSD, AQP4− NMOSD and MOGAD, we conducted a virtual histology analysis that links T1-weighted image derived GM atrophy and gene expression using a multicentre cohort of 324 patients with multiple sclerosis, 197 patients with AQP4+ NMOSD, 75 patients with AQP4− NMOSD, 47 patients with MOGAD and 2169 healthy control subjects. First, interregional GM atrophy profiles across the cortical and subcortical regions were determined using Cohen's d between patients with multiple sclerosis, AQP4+ NMOSD, AQP4− NMOSD or MOGAD and healthy controls. The GM atrophy profiles were then spatially correlated with the gene expression levels extracted from the Allen Human Brain Atlas, respectively. Finally, we explored the virtual histology of clinical-feature relevant GM atrophy using a subgroup analysis that stratified by physical disability, disease duration, number of relapses, lesion burden and cognitive function. Multiple sclerosis showed a severe widespread GM atrophy pattern, mainly involving subcortical nuclei and brainstem. AQP4+ NMOSD showed an obvious widespread pattern of GM atrophy, predominately located in occipital cortex as well as cerebellum. AQP4− NMOSD showed a mild widespread GM atrophy pattern, mainly located in frontal and parietal cortices. MOGAD showed GM atrophy mainly involving the frontal and temporal cortices. High expression of genes specific to microglia, astrocytes, oligodendrocytes and endothelial cells in multiple sclerosis, S1 pyramidal cells in AQP4+ NMOSD, as well as S1 and CA1 pyramidal cells in MOGAD, had spatial correlations with GM atrophy profile, while no atrophy profile-related gene expression was found in AQP4− NMOSD. Virtual histology of clinical feature-relevant GM atrophy pointed mainly to the shared neuronal and endothelial cells, among the four neuroinflammatory diseases. The unique underlying virtual histology patterns were microglia, astrocytes and oligodendrocytes for multiple sclerosis; astrocytes for AQP4+ NMOSD; and oligodendrocytes for MOGAD. Neuronal and endothelial cells were shared potential targets across these neuroinflammatory diseases. These findings may help the differential diagnoses of these diseases and promote the use of optimal therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Hippocampal involvement may differ between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Objective: To investigate the morphometric, diffusion and functional alterations in hippocampus in MS and NMOSD and the clinical significance. Methods: A total of 752 participants including 236 MS, 236 NMOSD and 280 healthy controls (HC) were included in this retrospective multi-center study. The hippocampus and subfield volumes, fractional anisotropy (FA) and mean diffusivity (MD), amplitude of low frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and their associations with clinical variables were investigated. Results: The hippocampus showed significantly lower volume, FA and greater MD in MS compared to NMOSD and HC (p < 0.05), while no abnormal ALFF or DC was identified in any group. Hippocampal subfields were affected in both diseases, though subiculum, presubiculum and fimbria showed significantly lower volume only in MS (p < 0.05). Significant correlations between diffusion alterations, several subfield volumes and clinical variables were observed in both diseases, especially in MS (R = −0.444 to 0.498, p < 0.05). FA and MD showed fair discriminative power between MS and HC, NMOSD and HC (AUC > 0.7). Conclusions: Hippocampal atrophy and diffusion abnormalities were identified in MS and NMOSD, partly explaining how clinical disability and cognitive impairment are differentially affected. [ABSTRACT FROM AUTHOR]