Table_1_Regional spinal cord volumes and pain profiles in AQP4-IgG + NMOSD and MOGAD.pdf

ObjectiveAquaporin-4-antibody-seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorder (MOGAD) are relapsing neuroinflammatory diseases, frequently leading to chronic pain. In both diseases, the spinal cord (SC) is often affected by myelitis attacks. We hypothesized that regional SC volumes differ between AQP4-IgG + NMOSD and MOGAD and that pain intensity is associated with lower SC volumes. To evaluate changes in the SC white matter (WM), gray matter (GM), and pain intensity in patients with recent relapses (myelitis or optic neuritis), we further profiled phenotypes in a case series with longitudinal imaging and clinical data.MethodsCross-sectional data from 36 participants were analyzed in this retrospective study, including 20 AQP4-IgG + NMOSD and 16 MOGAD patients. Pain assessment was performed in all patients by the Brief Pain Inventory and painDETECT questionnaires. Segmentation of SC WM, GM, cervical cord volumes (combined volume of WM + GM) was performed at the C2/C3 cervical level. WM% and GM% were calculated using the cervical cord volume as a whole per patient. The presence of pain, pain severity, and clinical disability was evaluated and tested for associations with SC segmentations. Additionally, longitudinal data were deeply profiled in a case series of four patients with attacks between two MRI visits within one year.ResultsIn AQP4-IgG + NMOSD, cervical cord volume was associated with mean pain severity within 24 h (β = −0.62, p = 0.009) and with daily life pain interference (β = −0.56, p = 0.010). Cross-sectional analysis showed no statistically significant SC volume differences between AQP4-IgG + NMOSD and MOGAD. However, in AQP4-IgG + NMOSD, SC WM% tended to be lower with increasing time from the last attack (β = −0.41, p = 0.096). This tendency was not observed in MOGAD. Our case series including two AQP4-IgG + NMOSD patients revealed SC GM% increased by roughly 2% with either a myelitis or optic neuritis attack between visits. Meanwhile, GM% decreased by 1–2% in two MOGAD patients with a myelitis attack between MRI visits.ConclusionIn AQP4-IgG + NMOSD, lower cervical cord volume was associated with increased pain. Furthermore, cord GM changes were detected between MRI visits in patients with disease-related attacks in both groups. Regional SC MRI measures are pertinent for monitoring disease-related cord pathology in AQP4-IgG + NMOSD and MOGAD.</p

Image_1_Regional spinal cord volumes and pain profiles in AQP4-IgG + NMOSD and MOGAD.TIFF

ObjectiveAquaporin-4-antibody-seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorder (MOGAD) are relapsing neuroinflammatory diseases, frequently leading to chronic pain. In both diseases, the spinal cord (SC) is often affected by myelitis attacks. We hypothesized that regional SC volumes differ between AQP4-IgG + NMOSD and MOGAD and that pain intensity is associated with lower SC volumes. To evaluate changes in the SC white matter (WM), gray matter (GM), and pain intensity in patients with recent relapses (myelitis or optic neuritis), we further profiled phenotypes in a case series with longitudinal imaging and clinical data.MethodsCross-sectional data from 36 participants were analyzed in this retrospective study, including 20 AQP4-IgG + NMOSD and 16 MOGAD patients. Pain assessment was performed in all patients by the Brief Pain Inventory and painDETECT questionnaires. Segmentation of SC WM, GM, cervical cord volumes (combined volume of WM + GM) was performed at the C2/C3 cervical level. WM% and GM% were calculated using the cervical cord volume as a whole per patient. The presence of pain, pain severity, and clinical disability was evaluated and tested for associations with SC segmentations. Additionally, longitudinal data were deeply profiled in a case series of four patients with attacks between two MRI visits within one year.ResultsIn AQP4-IgG + NMOSD, cervical cord volume was associated with mean pain severity within 24 h (β = −0.62, p = 0.009) and with daily life pain interference (β = −0.56, p = 0.010). Cross-sectional analysis showed no statistically significant SC volume differences between AQP4-IgG + NMOSD and MOGAD. However, in AQP4-IgG + NMOSD, SC WM% tended to be lower with increasing time from the last attack (β = −0.41, p = 0.096). This tendency was not observed in MOGAD. Our case series including two AQP4-IgG + NMOSD patients revealed SC GM% increased by roughly 2% with either a myelitis or optic neuritis attack between visits. Meanwhile, GM% decreased by 1–2% in two MOGAD patients with a myelitis attack between MRI visits.ConclusionIn AQP4-IgG + NMOSD, lower cervical cord volume was associated with increased pain. Furthermore, cord GM changes were detected between MRI visits in patients with disease-related attacks in both groups. Regional SC MRI measures are pertinent for monitoring disease-related cord pathology in AQP4-IgG + NMOSD and MOGAD.</p

sj-jpg-2-mso-10.1177_20552173231226107 - Supplemental material for Superficial white matter integrity in neuromyelitis optica spectrum disorder and multiple sclerosis

Supplemental material, sj-jpg-2-mso-10.1177_20552173231226107 for Superficial white matter integrity in neuromyelitis optica spectrum disorder and multiple sclerosis by Darko Komnenić, Owen Robert Phillips, Shantanu H Joshi, Claudia Chien, Tanja Schmitz-Hübsch, Susanna Asseyer, Friedemann Paul and Carsten Finke in Multiple Sclerosis Journal – Experimental, Translational and Clinical</p

sj-docx-1-mso-10.1177_20552173231226107 - Supplemental material for Superficial white matter integrity in neuromyelitis optica spectrum disorder and multiple sclerosis

Supplemental material, sj-docx-1-mso-10.1177_20552173231226107 for Superficial white matter integrity in neuromyelitis optica spectrum disorder and multiple sclerosis by Darko Komnenić, Owen Robert Phillips, Shantanu H Joshi, Claudia Chien, Tanja Schmitz-Hübsch, Susanna Asseyer, Friedemann Paul and Carsten Finke in Multiple Sclerosis Journal – Experimental, Translational and Clinical</p

Pathways validation for canonical pathway.

Complex diseases such as Multiple Sclerosis (MS) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to the full organism. In fact, any phenotype for an organism is dictated by the interplay among these scales. We conducted a multilayer network analysis and deep phenotyping with multi-omics data (genomics, phosphoproteomics and cytomics), brain and retinal imaging, and clinical data, obtained from a multicenter prospective cohort of 328 patients and 90 healthy controls. Multilayer networks were constructed using mutual information for topological analysis, and Boolean simulations were constructed using Pearson correlation to identified paths within and among all layers. The path more commonly found from the Boolean simulations connects protein MK03, with total T cells, the thickness of the retinal nerve fiber layer (RNFL), and the walking speed. This path contains nodes involved in protein phosphorylation, glial cell differentiation, and regulation of stress-activated MAPK cascade, among others. Specific paths identified were subsequently analyzed by flow cytometry at the single-cell level. Combinations of several proteins (GSK3AB, HSBP1 or RS6) and immune cells (Th17, Th1 non-classic, CD8, CD8 Treg, CD56 neg, and B memory) were part of the paths explaining the clinical phenotype. The advantage of the path identified from the Boolean simulations is that it connects information about these known biological pathways with the layers at higher scales (retina damage and disability). Overall, the identified paths provide a means to connect the molecular aspects of MS with the overall phenotype.</div

Building multilayer networks using multi-omics, imaging, and clinical data.

(a) Illustration of network construction. The data from each layer is taken from the cohorts and used to create networks, where the nodes are the elements in the dataset (genomics (SNPs), phosphoproteomics, cytomics, CNS tissue imaging, and clinical data), and the edges correspond to the mutual information between element pairs across all subjects. Once individual networks are created, they are linked together, again using mutual information, following a hierarchy that connects each layer successively, starting with genomics and working up to the phenotypic (clinical) layer. (b-f) Topology of individual layer networks from the experimental data. In each of the networks, the degree of each node is color-coded, with higher degrees in darker colors. The edge weights are coded in gray scale in a similar manner, with a darker edge representing a higher weight, and thus a higher correlation between nodes. The genomics network was enriched with the previous knowledge on regulatory networks (f) and included the MS genetic burden scores (g). In the combined five-layer network, the layers are connected using the hierarchy described above, with genomics at the bottom and clinical phenotype at the top. These networks are meant to show the nodes that are more highly correlated with other nodes in the network. They provide the base to examine the topological structure of the overall multilayer network. High resolution network representations for single-layer networks are available at Github link https://keithtopher.github.io/single_networks/#/ and for multilayer networks at https://keithtopher.github.io/combo_networks/#/. Icons used in the figure are open source from onlinewebfonts.com, flaticon.com and icons8.com.</p

Sys4MS cohort: Clinical and imaging variables of MS patients and healthy controls.

Disability scales are shown as the mean ± SD, except for the EDSS which is displayed as the median (range).</p

Overlap between the paths identified in the single-cell analysis and the paths identified in the UNIPROT database.

Overlap between the paths identified in the single-cell analysis and the paths identified in the UNIPROT database.</p

Network permutation for negative controls of paths.

The five-layer network built using Pearson correlation is used as the base network. For each of the 100 repetitions, the network was permuted by swapping the edges between pairs of nodes. In permutation 1, the edge between B and C was swapped with the edge between D and E. In the permutation 2, the edge between A and E was swapped with the edge between B and C. In permutation 3, first the edge swap from the top network was applied, followed by the edge swap from the middle network. In each case, the edge swap can only be done if it does not result in two edges between the same pair of nodes. Making the permutation in this way keeps the original degree distribution of the network. The weights for each of the edges are permuted as well. This edge swapping technique is applied 10 times for each edge in the original network. After they are permuted, the top paths for each network are identified in the same manner as before. There are three possibilities for considering whether the paths from the original network appear in the paths from the permuted networks. In permutation 1, the path exists in the permuted network and furthermore was identified as a top path. In permutation 2, the original path does exist in the permuted network but was not identified as a top path. In permutation 3, the original path doesn’t exist in the permuted network at all.</p

Linear regressions for GSK3AB node.

Complex diseases such as Multiple Sclerosis (MS) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to the full organism. In fact, any phenotype for an organism is dictated by the interplay among these scales. We conducted a multilayer network analysis and deep phenotyping with multi-omics data (genomics, phosphoproteomics and cytomics), brain and retinal imaging, and clinical data, obtained from a multicenter prospective cohort of 328 patients and 90 healthy controls. Multilayer networks were constructed using mutual information for topological analysis, and Boolean simulations were constructed using Pearson correlation to identified paths within and among all layers. The path more commonly found from the Boolean simulations connects protein MK03, with total T cells, the thickness of the retinal nerve fiber layer (RNFL), and the walking speed. This path contains nodes involved in protein phosphorylation, glial cell differentiation, and regulation of stress-activated MAPK cascade, among others. Specific paths identified were subsequently analyzed by flow cytometry at the single-cell level. Combinations of several proteins (GSK3AB, HSBP1 or RS6) and immune cells (Th17, Th1 non-classic, CD8, CD8 Treg, CD56 neg, and B memory) were part of the paths explaining the clinical phenotype. The advantage of the path identified from the Boolean simulations is that it connects information about these known biological pathways with the layers at higher scales (retina damage and disability). Overall, the identified paths provide a means to connect the molecular aspects of MS with the overall phenotype.</div