Yuyi You1, Ling Zhu2, Ting Zhang2, Ting Shen3, Ariadna Fontes4, Con Yiannikas4, John Parratt4, Joshua Barton5, Angela Schulz3, Vivek Gupta3, Michael H Barnett6, Clare L Fraser2, Mark Gillies2, Stuart L Graham7, Alexander Klistorner8. 1. Save Sight Institute, The University of Sydney, NSW, Australia; Department of Health and Medical Sciences, Macquarie University, NSW, Australia. Electronic address: yuyi.you@gmail.com. 2. Save Sight Institute, The University of Sydney, NSW, Australia. 3. Department of Health and Medical Sciences, Macquarie University, NSW, Australia. 4. Department of Neurology, Royal North Shore Hospital, NSW, Australia. 5. Brain and Mind Centre, The University of Sydney, NSW, Australia. 6. Brain and Mind Centre, The University of Sydney, NSW, Australia; Sydney Neuroimaging Analysis Centre, NSW, Australia. 7. Save Sight Institute, The University of Sydney, NSW, Australia; Department of Health and Medical Sciences, Macquarie University, NSW, Australia. 8. Save Sight Institute, The University of Sydney, NSW, Australia; Department of Health and Medical Sciences, Macquarie University, NSW, Australia; Sydney Neuroimaging Analysis Centre, NSW, Australia.
Abstract
PURPOSE: To compare functional and structural changes in the retina in patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). DESIGN: Cross-sectional study; biochemical study of human retinas. PARTICIPANTS: A total of 181 participants, including 22 consecutive patients (44 eyes) with NMOSD, 131 patients (262 eyes) with multiple sclerosis (MS), and 28 normal subjects (56 eyes). In addition, 8 eyeballs from healthy donors were used for biochemical analysis. METHODS: Full-field electroretinography (ERG) and spectral-domain OCT were performed in all the subjects. Topography of AQP4 expression and Müller glial distribution were analyzed using Western blotting and immunohistochemistry. MAIN OUTCOME MEASURES: Full-field ERG parameters, including amplitudes and peak times. Tissue volume of each of the retinal layers at the fovea by OCT segmentation. Levels of AQP4 expression at different retinal regions. RESULTS: The b-wave amplitude was significantly reduced in patients with AQP4-IgG+ NMOSD in scotopic ERGs (compared with AQP4-IgG- subjects, patients with MS, and normal controls) but not in photopic ERGs. Further analysis showed that this b-wave change was mainly caused by reduction of the slow PII component, suggesting specific Müller cell dysfunction. We also found thinning of specific retinal layers at the fovea in patients with AQP4-IgG+ NMOSD, in the Henle fiber outer nuclear layer (HFONL) and the inner segment (IS) layer, but not in the inner nuclear layer (INL), outer plexiform layer (OPL), or outer segment (OS) layer. Furthermore, there was a significant association between foveal HFONL-IS complex thinning and scotopic b-wave amplitude reduction (P = 0.005∼0.01, fixed-effects model). Western blotting demonstrated that Müller cell-specific AQP4 was expressed at a higher level at the fovea than the peripheral retina. Immunohistochemical studies revealed that the specific foveal thinning reflected the topography of AQP4 expression and Müller glial distribution in the human macula. CONCLUSIONS: This study provides in vivo structural and functional evidence of Müller glial dysfunction in eyes of patients with AQP4-IgG+ NMOSD. Topography of retinal structural change is supported by distribution of Müller cells and patterns of AQP4 expression. The study suggests that visual electrophysiology and retinal imaging could be useful biomarkers to assess the potential retinal astrocytopathy in NMOSD.
PURPOSE: To compare functional and structural changes in the retina in patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). DESIGN: Cross-sectional study; biochemical study of human retinas. PARTICIPANTS: A total of 181 participants, including 22 consecutive patients (44 eyes) with NMOSD, 131 patients (262 eyes) with multiple sclerosis (MS), and 28 normal subjects (56 eyes). In addition, 8 eyeballs from healthy donors were used for biochemical analysis. METHODS: Full-field electroretinography (ERG) and spectral-domain OCT were performed in all the subjects. Topography of AQP4 expression and Müller glial distribution were analyzed using Western blotting and immunohistochemistry. MAIN OUTCOME MEASURES: Full-field ERG parameters, including amplitudes and peak times. Tissue volume of each of the retinal layers at the fovea by OCT segmentation. Levels of AQP4 expression at different retinal regions. RESULTS: The b-wave amplitude was significantly reduced in patients with AQP4-IgG+ NMOSD in scotopic ERGs (compared with AQP4-IgG- subjects, patients with MS, and normal controls) but not in photopic ERGs. Further analysis showed that this b-wave change was mainly caused by reduction of the slow PII component, suggesting specific Müller cell dysfunction. We also found thinning of specific retinal layers at the fovea in patients with AQP4-IgG+ NMOSD, in the Henle fiber outer nuclear layer (HFONL) and the inner segment (IS) layer, but not in the inner nuclear layer (INL), outer plexiform layer (OPL), or outer segment (OS) layer. Furthermore, there was a significant association between foveal HFONL-IS complex thinning and scotopic b-wave amplitude reduction (P = 0.005∼0.01, fixed-effects model). Western blotting demonstrated that Müller cell-specific AQP4 was expressed at a higher level at the fovea than the peripheral retina. Immunohistochemical studies revealed that the specific foveal thinning reflected the topography of AQP4 expression and Müller glial distribution in the human macula. CONCLUSIONS: This study provides in vivo structural and functional evidence of Müller glial dysfunction in eyes of patients with AQP4-IgG+ NMOSD. Topography of retinal structural change is supported by distribution of Müller cells and patterns of AQP4 expression. The study suggests that visual electrophysiology and retinal imaging could be useful biomarkers to assess the potential retinal astrocytopathy in NMOSD.
Authors: Alexander U Brandt; Hanna G Zimmermann; Norman K Gigengack; Frederike C Oertel; Seyedamirhosein Motamedi; Charlotte Bereuter; Ankelien Duchow; Rebekka Rust; Judith Bellmann-Strobl; Klemens Ruprecht; Tanja Schmitz-Hübsch; Friedemann Paul Journal: Sci Rep Date: 2022-10-20 Impact factor: 4.996
Authors: Angeliki G Filippatou; Eleni S Vasileiou; Yufan He; Kathryn C Fitzgerald; Grigorios Kalaitzidis; Jeffrey Lambe; Maureen A Mealy; Michael Levy; Yihao Liu; Jerry L Prince; Ellen M Mowry; Shiv Saidha; Peter A Calabresi; Elias S Sotirchos Journal: J Neuroophthalmol Date: 2021-05-17 Impact factor: 4.415
Authors: Ting Shen; Vivek Gupta; Con Yiannikas; Alexander Klistorner; Stuart L Graham; Yuyi You Journal: Front Neurosci Date: 2019-11-19 Impact factor: 4.677