Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

Optic chiasm involvement in multiple sclerosis, aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein-associated disease.

BACKGROUND: Optic neuritis (ON) is a common feature of inflammatory demyelinating diseases (IDDs) such as multiple sclerosis (MS), aquaporin 4-antibody neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, the involvement of the optic chiasm (OC) in IDD has not been fully investigated. AIMS: To examine OC differences in non-acute IDD patients with (ON+) and without ON (ON-) using magnetisation transfer ratio (MTR), to compare differences between MS, AQP4 + NMOSD and MOGAD and understand their associations with other neuro-ophthalmological markers. METHODS: Twenty-eight relapsing-remitting multiple sclerosis (RRMS), 24 AQP4 + NMOSD, 28 MOGAD patients and 32 healthy controls (HCs) underwent clinical evaluation, MRI and optical coherence tomography (OCT) scan. Multivariable linear regression models were applied. RESULTS: ON + IDD patients showed lower OC MTR than HCs (28.87 ± 4.58 vs 31.65 ± 4.93; p = 0.004). When compared with HCs, lower OC MTR was found in ON + AQP4 + NMOSD (28.55 ± 4.18 vs 31.65 ± 4.93; p = 0.020) and MOGAD (28.73 ± 4.99 vs 31.65 ± 4.93; p = 0.007) and in ON- AQP4 + NMOSD (28.37 ± 7.27 vs 31.65 ± 4.93; p = 0.035). ON+ RRMS had lower MTR than ON- RRMS (28.87 ± 4.58 vs 30.99 ± 4.76; p = 0.038). Lower OC MTR was associated with higher number of ON (regression coefficient (RC) = -1.15, 95% confidence interval (CI) = -1.819 to -0.490, p = 0.001), worse visual acuity (RC = -0.026, 95% CI = -0.041 to -0.011, p = 0.001) and lower peripapillary retinal nerve fibre layer (pRNFL) thickness (RC = 1.129, 95% CI = 0.199 to 2.059, p = 0.018) when considering the whole IDD group. CONCLUSION: OC microstructural damage indicates prior ON in IDD and is linked to reduced vision and thinner pRNFL.

Brain and spinal cord atrophy in NMOSD and MOGAD: Current evidence and future perspectives.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe form of inflammation of the central nervous system (CNS) including acute myelitis, optic neuritis and brain syndrome. Currently, the classification of NMOSD relies on serologic testing, distinguishing between seropositive or seronegative anti-aquaporin-4 antibody (AQP4) status. However, the situation has recently grown more intricate with the identification of patients exhibiting the NMOSD phenotype and myelin oligodendrocyte glycoprotein antibodies (MOGAD). NMOSD is primarily recognized as a relapsing disorder; MOGAD can manifest with either a monophasic or relapsing course. Significant symptomatic inflammatory CNS injuries with stability in clinical findings outside the acute phase are reported in both diseases. Nevertheless, recent studies have proposed the existence of a subclinical pathological process, revealing longitudinal changes in brain and spinal cord atrophy. Within this context, we summarise key studies investigating brain and spinal cord measurements in adult NMOSD and MOGAD. We also explore their relationship with clinical aspects, highlight differences from multiple sclerosis (MS), and address future challenges. This exploration is crucial for determining the presence of chronic damage processes, enabling the customization of therapeutic interventions irrespective of the acute phase of the disease.

Temporal and topological properties of dynamic networks reflect disability in patients with neuromyelitis optica spectrum disorders.

Approximately 36% of patients with neuromyelitis optica spectrum disorders (NMOSD) suffer from severe visual and motor disability (blindness or light perception or unable to walk) with abnormalities of whole-brain functional networks. However, it remains unclear how whole-brain functional networks and their dynamic properties are related to clinical disability in patients with NMOSD. Our study recruited 30 NMOSD patients (37.70 ± 11.99 years) and 45 healthy controls (HC, 41.84 ± 11.23 years). The independent component analysis, sliding-window approach and graph theory analysis were used to explore the static strength, time-varying and topological properties of large-scale functional networks and their associations with disability in NMOSD. Compared to HC, NMOSD patients showed significant alterations in dynamic networks rather than static networks. Specifically, NMOSD patients showed increased occurrence (fractional occupancy; P < 0.001) and more dwell times of the low-connectivity state (P < 0.001) with fewer transitions (P = 0.028) between states than HC, and higher fractional occupancy, increased dwell times of the low-connectivity state and lower transitions were related to more severe disability. Moreover, NMOSD patients exhibited altered small-worldness, decreased degree centrality and reduced clustering coefficients of hub nodes in dynamic networks, related to clinical disability. NMOSD patients exhibited higher occurrence and more dwell time in low-connectivity states, along with fewer transitions between states and decreased topological organizations, revealing the disrupted communication and coordination among brain networks over time. Our findings could provide new perspective to help us better understand the neuropathological mechanism of the clinical disability in NMOSD.

The critical role of magnetic resonance imaging in the diagnosis of transverse myelitis: a case report.

INTRODUCTION: Transverse Myelitis is a rare inflammatory disorder of the spinal cord, characterized by the inflammation of the myelin sheath covering nerve fibers. Although rare, Transverse Myelitis holds significant clinical importance due to its potential life-altering consequences. The case report provides insight into the clinical presentation of Transverse Myelitis and the importance of Magnetic Resonance Imaging in confirming Transverse Myelitis. CASE PRESENTATION: A 27-year-old Nigerian female presented to a hospital facility after 2 months onset of paraplegia, urinary, and fecal incontinence. She was diagnosed with Acute Transverse Myelitis with Magnetic Resonance Imaging, a lacking imaging modality in Nigeria. On presentation, it was important to rule out spinal cord compression, a close differential to her presentation. Despite her late arrival at the facility, early diagnosis and prompt initiation of treatment with high-dose intravenous steroids and physiotherapy improved her quality of life. DISCUSSION: This case report reveals the poor health-seeking behavior in developing countries and the need for imaging modalities like Magnetic Resonance Imaging for improved diagnoses of rare neurological conditions such as Transverse Myelitis. The lack of healthcare infrastructure has led to clinical misdiagnosis, patient mismanagement, and underrepresentation of data in the country, underscoring the critical role of diagnostic tools for improved patient care pre-treatment and post-treatment. Additionally, follow-up of these patients is important to prevent the long-term sequelae of Transverse Myelitis like Neuromyelitis Optica or Multiple Sclerosis.

T1 hypointense brain lesions in NMOSD and its relevance with disability: a single institution cross-sectional study.

BACKGROUND: T1 hypointense lesions are considered a surrogate marker of tissue destruction. Although there is a shortage of evidence about T1 hypointense brain lesions, black holes, in patients with Neuromyelitis Optica Spectrum Disorder (NMOSD), the clinical significance of these lesions is not well determined. OBJECTIVES: The impact of T1 hypointense brain lesions on the clinical status and the disability level of patients with NMOSD was sought in this study. METHODS: A total of 83 patients with the final diagnosis of NMOSD were recruited. Aquaporin-4 measures were collected. The expanded disability status scale (EDSS) and MRI studies were also extracted. T1 hypointense and T2/FLAIR hyperintense lesions were investigated. The correlation of MRI findings, AQP-4, and EDSS was assessed. RESULTS: T1 hypointense brain lesions were detected in 22 patients. Mean ± SD EDSS was 3.7 ± 1.5 and significantly higher in patients with brain T1 hypointense lesions than those without them (p-value = 0.01). Noticeably, patients with more than four T1 hypointense lesions had EDSS scores ≥ 4. The presence of T2/FLAIR hyperintense brain lesions correlated with EDSS (3.6 ± 1.6 vs 2.3 ± 1.7; p-value = 0.01). EDSS was similar between those with and without positive AQP-4 (2.7 ± 1.6 vs. 3.2 ± 1.7; p-value = 0.17). Also, positive AQP-4 was not more prevalent in patients with T1 hypointense brain lesions than those without them (50.9 vs 45.4%; p-value = 0.8). CONCLUSION: We demonstrated that the presence of the brain T1-hypointense lesions corresponds to a higher disability level in NMOSD.

M-DDC: MRI based demyelinative diseases classification with U-Net segmentation and convolutional network.

Childhood demyelinative diseases classification (DDC) with brain magnetic resonance imaging (MRI) is crucial to clinical diagnosis. But few attentions have been paid to DDC in the past. How to accurately differentiate pediatric-onset neuromyelitis optica spectrum disorder (NMOSD) from acute disseminated encephalomyelitis (ADEM) based on MRI is challenging in DDC. In this paper, a novel architecture M-DDC based on joint U-Net segmentation network and deep convolutional network is developed. The U-Net segmentation can provide pixel-level structure information, that helps the lesion areas location and size estimation. The classification branch in DDC can detect the regions of interest inside MRIs, including the white matter regions where lesions appear. The performance of the proposed method is evaluated on MRIs of 201 subjects recorded from the Children's Hospital of Zhejiang University School of Medicine. The comparisons show that the proposed DDC achieves the highest accuracy of 99.19% and dice of 71.1% for ADEM and NMOSD classification and segmentation, respectively.

Interferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (Th17) and antibody responses to the water channel protein, aquaporin 4 (AQP4), and associated with astrocytopathy, demyelination and axonal loss. Knowledge about disease pathogenesis is limited and the search for new therapies impeded by the absence of a reliable animal model. In our work, we determined that NMOSD is characterized by decreased IFN-γ receptor signalling and that IFN-γ depletion in AQP4201-220-immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD. Pathologically, the disease causes autoimmune astrocytic and CNS injury secondary to cellular and humoral inflammation. Immunologically, the absence of IFN-γ allows for increased expression of IL-6 in B cells and activation of Th17 cells, and generation of a robust autoimmune inflammatory response. Consistent with NMOSD, the experimental disease is exacerbated by administration of IFN-ß, whereas repletion of IFN-γ, as well as therapeutic targeting of IL-17A, IL-6R and B cells, ameliorates it. We also demonstrate that immune tolerization with AQP4201-220-coupled poly(lactic-co-glycolic acid) nanoparticles could both prevent and effectively treat the disease. Our findings enhance the understanding of NMOSD pathogenesis and provide a platform for the development of immune tolerance-based therapies, avoiding the limitations of the current immunosuppressive therapies.

Bruton's tyrosine kinase-bearing B cells and microglia in neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte-microglia interaction, which both contribute to evolution of NMOSD lesions. MAIN BODY: Through transcriptomic and flow cytometry analyses, we found that Bruton's tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes-microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes. CONCLUSIONS: Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target.

Understanding the Pathophysiology and Magnetic Resonance Imaging of Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders.

Magnetic resonance imaging (MRI) has been extensively applied in the study of multiple sclerosis (MS), substantially contributing to diagnosis, differential diagnosis, and disease monitoring. MRI studies have significantly contributed to the understanding of MS through the characterization of typical radiological features and their clinical or prognostic implications using conventional MRI pulse sequences and further with the application of advanced imaging techniques sensitive to microstructural damage. Interpretation of results has often been validated by MRI-pathology studies. However, the application of MRI techniques in the study of neuromyelitis optica spectrum disorders (NMOSD) remains an emerging field, and MRI studies have focused on radiological correlates of NMOSD and its pathophysiology to aid in diagnosis, improve monitoring, and identify relevant prognostic factors. In this review, we discuss the main contributions of MRI to the understanding of MS and NMOSD, focusing on the most novel discoveries to clarify differences in the pathophysiology of focal inflammation initiation and perpetuation, involvement of normal-appearing tissue, potential entry routes of pathogenic elements into the CNS, and existence of primary or secondary mechanisms of neurodegeneration.

Cortical ischemic lesions from atrial myxoma as a mimic of disease activity in an RRMS antiCD20-treated patient.

Cortical lesions (CLs) detected with double inversion recovery (DIR) magnetic resonance imaging (MRI) are very helpful in differentiating multiple sclerosis (MS) from other neuroinflammatory diseases of the central nervous system (CNS), that is, neuromyelitis optica spectrum disorders (NMOSDs). Furthermore, CLs are closely related to motor and cognitive impairment. We report a case of a 48-year-old female MS patient who developed several CLs during anti-CD20 therapy. Some CLs disappeared during follow-up MRIs. In the suspicion of a treatment failure, the screening for the autologous hematopoietic stem cell transplant (AHSCT) was performed with the evidence of an atrial myxoma. In MS patients with new CLs, a comorbid ischemic pathology should be considered and carefully investigated.

[Correlation of cognitive function with intracranial lesions and the degree of depression and anxiety in patients with neuromyelitis optica spectrum disorders].

Objective: To investigate the correlation of cognitive dysfunction with intracranial lesions and symptoms of depression and anxiety in patients with neuromyelitis optica spectrum disorders (NMOSD). Methods: Thirty-one NMOSD patients (7/24 males/females) were enrolled in the Department of Neurology of the Sixth Medical Center of the PLA General Hospital from August 2019 to August 2022. The average age was 42±13 years, and the average education level was 12 (9, 12) years. There were 30 healthy controls, 11/19 males/females, with an average age of 47±9 years and an average education of 12 (9, 15) years. The general clinical data and imaging data were collected, and the subjects were assessed on their cognition, anxiety and depression using the assessment scale approved at home and abroad. A cross-sectional study was conducted on them. The t-test or Wilcoxon test was used for inter-group comparison, and Pearson test or Spearman test was used to explore the correlation between the cognition of NMOSD patients and their intracranial lesions, depression and anxiety. Results: Compared with the healthy control group, NMOSD patients had significantly lower scores on MoCA (Z=-3.10,P=0.002), CRAVLT-N7 (Z=-5.12, P<0.001), CRAVLT-N8 (t=-4.40, P<0.001), ROCF-R (t=-3.10,P<0.01), ROCF-C (Z=-2.72,P<0.01), PASAT-3 (Z=-2.71,P<0.01), PASAT-2 (Z=-3.14,P<0.01), and CWT-A (Z=-3.10,P<0.01)scales. Frontal lobe lesions were negatively correlated with PASAT-2 (r=-0.448, P=0.012) scores, temporal lobe lesions were negatively correlated with CRAVLT-N9 (r=-0.564, P=0.001), and parietal lobe lesions were negatively correlated with MoCA (r=-0.374, P=0.038), PASAT-3 (r=-0.426, P=0.017), and PASAT-2 (r=-0.459, P=0.009) scores; The scores of MoCA (r=-0.392, P=0.029), CRAVLT-N6 (r=-0.396, P=0.028), CRAVLT-N7 (r=-0.415, P=0.020), CRAVLT-N8 (r=-0.406, P=0.023), PASAT-3 (r=-0.537, P=0.002) and PASAT-2 (r=-0.495, P=0.005) scales were negatively correlated with the scores of HAMD assessment, and the scores of PASAT-3 (r=-0.499, P=0.004) and PASAT-2 (r=-0.452, P=0.011) were negatively correlated with the scores of HAMA. Conclusions: The cognitive function of patients with NMOSD is significantly reduced, involving multiple cognitive domains. The cognitive function is affected by the distribution of intracranial lesions and the degree of depression and anxiety.

Pearls & Oy-sters: Syndrome of Inappropriate Antidiuretic Hormone Secretion Presenting as Neuromyelitis Optica Spectrum Disorder Flare.

While it was previously believed that neuromyelitis optic spectrum disorder (NMOSD) mostly affected the optic nerves and the spinal cord, it is increasingly recognized that NMOSD can involve any area of the CNS where aquaporin-4 is highly expressed. These other areas can include the hypothalamus and the circumventricular organs that surround the third and fourth ventricles, serving as osmoregulators. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the most common causes of hyponatremia and has been associated with NMOSD due to these lesions. In this report, we present a case of a patient with known NMOSD, who presented with dizziness, fatigue, and generalized weakness and whose workup revealed hyponatremia in the setting of SIADH and hypothalamic demyelinating lesions. This case illustrates an atypical presentation of NMOSD and the importance of looking for syndromes, such as SIADH. This can guide diagnostic testing, such as getting thin MRI cuts through the hypothalamus and brainstem, as well as advanced management techniques such as immunotherapy.

Evaluation of microvascular changes in the retina and choriocapillaris in primary glaucoma and neuromyelitis optica spectrum disorder with optical coherence tomography angiography.

BACKGROUND: To assess quantitatively the microvascular changes in the retina and choroid of healthy eyes, eyes of subjects with primary angle-closure glaucoma (PACG), primary open-angle glaucoma (POAG) and neuromyelitis optica spectrum disorder (NMOSD) using optical coherence tomography angiography (OCTA). METHODS: A series of healthy individuals and subjects with PACG, POAG and NMOSD were recruited in this cross-sectional study. OCTA was performed to capture the optic nerve head and macula images and the vessel density (VD) and retinal nerve fiber layer (RNFL) thickness were quantified. The choriocapillary flow density (CFD) was calculated as the percentage of flow area to the whole selected area. RESULTS: A total of 68 PACG subjects, 25 POAG subjects, 51 NMOSD subjects and 37 healthy controls were enrolled. Significant decreases in peripapillary VD and RNFL thickness were observed in PACG (p < 0.001) and POAG (p < 0.001) eyes and also in NMOSD subjects with an optic neuritis history (p < 0.001) compared with healthy controls. Unaffected eyes in PACG and POAG subjects had lower baseline peripapillary VD than healthy controls (p = 0.002 and p = 0.011, respectively). PACG eyes showed a lower baseline CFD than POAG (p = 0.0027) and the CFD in early and advanced PACG eyes showed a significantly much more decrease than POAG (p = 0.002 and p < 0.001, respectively). CONCLUSIONS: The peripapillary vessel density and RNFL thickness was reduced in glaucomatous and NMOSD eyes compared with healthy controls. PACG eyes showed a lower CFD than POAG and the distinct peripapillary and choriocapillaris microvasculature changes may be correlated to different PACG and POAG pathogenesis.

Genetic Basis of Inflammatory Demyelinating Diseases of the Central Nervous System: Multiple Sclerosis and Neuromyelitis Optica Spectrum.

Demyelinating diseases alter myelin or the coating surrounding most nerve fibers in the central and peripheral nervous systems. The grouping of human central nervous system demyelinating disorders today includes multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) as distinct disease categories. Each disease is caused by a complex combination of genetic and environmental variables, many involving an autoimmune response. Even though these conditions are fundamentally similar, research into genetic factors, their unique clinical manifestations, and lesion pathology has helped with differential diagnosis and disease pathogenesis knowledge. This review aims to synthesize the genetic approaches that explain the differential susceptibility between these diseases, explore the overlapping clinical features, and pathological findings, discuss existing and emerging hypotheses on the etiology of demyelination, and assess recent pathogenicity studies and their implications for human demyelination. This review presents critical information from previous studies on the disease, which asks several questions to understand the gaps in research in this field.

Inhibition of complement C3 signaling ameliorates locomotor and visual dysfunction in autoimmune inflammatory diseases.

Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by transverse myelitis and optic neuritis. The pathogenic serum IgG antibody against the aquaporin-4 (AQP4) on astrocytes triggers the activation of the complement cascade, causing astrocyte injury, followed by oligodendrocyte injury, demyelination, and neuronal loss. Complement C3 is positioned as a central player that relays upstream initiation signals to activate downstream effectors, potentially stimulating and amplifying host immune and inflammatory responses. However, whether targeting the inhibition of C3 signaling could ameliorate tissue injury, locomotor defects, and visual impairments in NMO remains to be investigated. In this study, using the targeted C3 inhibitor CR2-Crry led to a significant decrease in complement deposition and demyelination in both slice cultures and focal intracerebral injection models. Moreover, the treatment downregulated the expression of inflammatory cytokines and improved motor dysfunction in a systemic NMO mouse model. Similarly, employing serotype 2/9 adeno-associated virus (AAV2/9) to induce permanent expression of CR2-Crry resulted in a reduction in visual dysfunction by attenuating NMO-like lesions. Our findings reveal the therapeutic value of inhibiting the complement C3 signaling pathway in NMO.

Personalized estimates of morphometric similarity in multiple sclerosis and neuromyelitis optica spectrum disorders.

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.

Deviation From Normative Whole Brain and Deep Gray Matter Growth in Children With MOGAD, MS, and Monophasic Seronegative Demyelination.

BACKGROUND AND OBJECTIVES: Pediatric-acquired demyelination of the CNS associated with antibodies directed against myelin oligodendrocyte glycoprotein (MOG; MOG antibody-associated disease [MOGAD]) occurs as a monophasic or relapsing disease and with variable but often extensive T2 lesions in the brain. The impact of MOGAD on brain growth during maturation is unknown. We quantified the effect of pediatric MOGAD on brain growth trajectories and compared this with the growth trajectories of age-matched and sex-matched healthy children and children with multiple sclerosis (MS, a chronic relapsing disease known to lead to failure of normal brain growth and to loss of brain volume) and monophasic seronegative demyelination. METHODS: We included children enrolled at incident attack in the prospective longitudinal Canadian Pediatric Demyelinating Disease Study who were recruited at the 3 largest enrollment sites, underwent research brain MRI scans, and were tested for serum MOG-IgG. Children seropositive for MOG-IgG were diagnosed with MOGAD. MS was diagnosed per the 2017 McDonald criteria. Monophasic seronegative demyelination was confirmed in children with no clinical or MRI evidence of recurrent demyelination and negative results for MOG-IgG and aquaporin-4-IgG. Whole and regional brain volumes were computed through symmetric nonlinear registration to templates. We computed age-normalized and sex-normalized z scores for brain volume using a normative dataset of 813 brain MRI scans obtained from typically developing children and used mixed-effect models to assess potential deviation from brain growth trajectories. RESULTS: We assessed brain volumes of 46 children with MOGAD, 26 with MS, and 51 with monophasic seronegative demyelinating syndrome. Children with MOGAD exhibited delayed (p < 0.001) age-expected and sex-expected growth of thalamus, caudate, and globus pallidus, normalized for the whole brain volume. Divergence from expected growth was particularly pronounced in the first year postonset and was detected even in children with monophasic MOGAD. Thalamic volume abnormalities were less pronounced in children with MOGAD compared with those in children with MS. DISCUSSION: The onset of MOGAD during childhood adversely affects the expected trajectory of growth of deep gray matter structures, with accelerated changes in the months after an acute attack. Further studies are required to better determine the relative impact of monophasic vs relapsing MOGAD and whether relapsing MOGAD with attacks isolated to the optic nerves or spinal cord affects brain volume over time.

Cerebellar connectome alterations and associated genetic signatures in multiple sclerosis and neuromyelitis optica spectrum disorder.

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.