Spinal Cord Atrophy in Neuromyelitis Optica Spectrum Disorders Is                    Spatially Related to Cord Lesions and Disability

Abstract Background: Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) autoimmune inflammatory demyelinating diseases characterized by recurrent episodes of acute optic neuritis and transverse myelitis. Aquaporin-4 immunoglobulin G (AQP4-IgG) autoantibodies, which target the water channel aquaporin-4 (AQP4) on astrocytic membrane, are pathogenic in NMOSD. Glutamate excitotoxicity, which is triggered by internalization of AQP4-glutamate transporter complex after AQP4-IgG binding to astrocytes, is involved in early NMOSD pathophysiologies. We studied the effects of memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, on motor impairments and spinal cord pathologies in mice which received human AQP4-IgG. Methods: Purified IgG from AQP4-IgG-seropositive NMOSD patients were passively transferred to adult C57BL/6 mice with disrupted blood-brain barrier. Memantine was administered by oral gavage. Motor impairments of the mice were assessed by beam walking test. Spinal cords of the mice were assessed by immunofluorescence and ELISA. Results: Oral administration of memantine ameliorated the motor impairments induced by AQP4-IgG, no matter the treatment was initiated before (preventive) or after (therapeutic) disease flare. Memantine profoundly reduced AQP4 and astrocyte loss, and attenuated demyelination and axonal loss in the spinal cord of mice which had received AQP4-IgG. The protective effects of memantine were associated with inhibition of apoptosis and suppression of neuroinflammation, with decrease in microglia activation and neutrophil infiltration and reduction of increase in levels of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α). In addition, memantine elevated growth factors including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) in the spinal cord. Conclusions: Our findings support that glutamate excitotoxicity and neuroinflammation plays important roles in complement-independent pathophysiology during early development of NMOSD lesions, and highlight the potential of oral memantine as a therapeutic agent in NMOSD acute attacks.

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Lymphocyte Subsets Are Associated with Disease Status in Neuromyelitis Optica Spectrum Disorders

NeuroImmunoModulation ◽

10.1159/000520745 ◽

2021 ◽

pp. 1-10

Author(s):

Hong Yang ◽

Wei Liu ◽

Yi-Fan Wu ◽

De-Sheng Zhu ◽

Xia-Feng Shen ◽

...

Keyword(s):

Spinal Cord ◽

B Cells ◽

Neuromyelitis Optica ◽

Peripheral Blood ◽

Lymphocyte Subsets ◽

Disease Status ◽

Neuromyelitis Optica Spectrum Disorders ◽

Spinal Cord Lesions ◽

Cross Sectional ◽

Spectrum Disorders

Objective: At present, studies on lymphocytes are mostly conducted on CD19+ B cells and CD27+ B cells in neuromyelitis optica spectrum disorders (NMOSDs), but the exact changes in lymphocyte subsets (CD19+ B cells, CD3+ T cells, CD4+ Th cells, CD8+ Ts cells, the CD4+/CD8+ ratio, and NK [CD56+ CD16] cells) have rarely been studied. This study aimed to assess lymphocyte subset changes in patients with NMOSD. Methods: We performed a cross-sectional study of consecutive patients with acute NMOSD (n = 41), chronic NMOSD (n = 21), and healthy individuals (n = 44). Peripheral blood samples were obtained upon admission, and lymphocyte subsets were analyzed by flow cytometry. Levels of lymphocyte subsets among 3 groups were compared and its correlation with the length of spinal cord lesions was analyzed. Results: The levels of peripheral blood CD19+ B cells were significantly higher in patients with acute and chronic NMOSD than in healthy controls (HCs) (17.91 ± 8.7%, 13.08 ± 7.562%, and 12.48 ± 3.575%, respectively; p < 0.001) and were positively correlated with the length of spinal cord lesions in acute NMOSD (r = 0.433, p < 0.05). The peripheral blood CD4+/CD8+ ratio was significantly lower in patients with acute NMOSD and chronic NMOSD than in HCs (1.497 ± 0.6387, 1.33 ± 0.5574, and 1.753 ± 0.659, respectively; p < 0.05), and the levels of peripheral blood NK (CD56+ CD16) cells were significantly lower in patients with acute and chronic NMOSD than in HCs (13.6 ± 10.13, 11.11 ± 7.057, and 14.7 [interquartile range = 9.28], respectively; p < 0.01). Conclusions: The levels of certain subsets of peripheral blood lymphocytes are associated with disease status in NMOSD.

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Neuromyelitis Optica Spectrum Disorders

Neuroimmunology ◽

10.1093/med/9780190050801.003.0006 ◽

2019 ◽

pp. 109-129

Author(s):

A. Sebastian López-Chiriboga ◽

Brian G. Weinshenker

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Neuromyelitis Optica ◽

Inflammatory Diseases ◽

Treatment Options ◽

Neuromyelitis Optica Spectrum Disorders ◽

Future Prospects ◽

Mortality And Morbidity ◽

The Central Nervous System ◽

Spectrum Disorders

Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory diseases of the central nervous system, traditionally diagnosed in patients with inflammatory attacks restricted to the optic nerves and spinal cord. The chapter considers the epidemiology, pathophysiology and immunopathogenesis of NMOSD. The clinical presentation and radiographic features are reviewed and the prognosis of patients with NMOSD is considered. The mortality and morbidity of untreated NMOSD is much greater than those of MS. Treatment options are summarized and finally future prospects of research are considered.

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