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White Matter Network Disruption and Cognitive Dysfunction in Neuromyelitis Optica Spectrum Disorder.

ABSTRACT: Background: In neuromyelitis optica spectrum disorder (NMOSD), brain involvement is common and cognitive dysfunction is frequently found. The study investigated alterations of white matter (WM) connectivity using graph theory and correlations with cognitive dysfunction in patients with NMOSD. Methods: We prospectively enrolled patients with NMOSD (N = 14) and age- and sex-matched healthy controls (N = 21). Structural connections between any pair of the 90 cortical and subcortical regions were established using diffusion tensor imaging and graph theory. Network-based statistics was employed to assess differences in WM connectivity between the NMOSD and healthy control groups. We further investigated the relationship between the topological network characteristics and cognitive test performances. Results: WM network analysis showed decreased total strength of brain networks and two disrupted sub-networks in patients with NMOSD. The first featured six hub nodes in the rectus, hippocampus, calcarine, cuneus, and precuneus with the left-sided predominance. The second had six hub nodes in the orbitomiddle frontal, post-central, superior parietal, superior, and middle temporal, and caudate with the right-sided predominance. Compared to healthy controls, NMOSD patients showed poor performance on tests for attention/working memory and processing speed, visuospatial processing, and executive function, which were associated with significant decreases in nodal clustering coefficient, local efficiency, and regional efficiency in the disrupted sub-networks (all p < 0.05). Conclusions: The data show the overall WM disruption and the relationship between poor cognitive function and sub-network alterations identified by the network analysis in NMOSD patients. We suggest that cognitive dysfunction is related to dysconnectivity of WM network including default mode network in NMOSD.

SUBMITTER: Cho EB

PROVIDER: S-EPMC6304415 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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White Matter Network Disruption and Cognitive Dysfunction in Neuromyelitis Optica Spectrum Disorder.

Cho Eun Bin EB Han Cheol E CE Seo Sang Won SW Chin Juhee J Shin Jeong-Hyeon JH Cho Hye-Jin HJ Seok Jin Myoung JM Kim Sung Tae ST Kim Byoung Joon BJ Na Duk L DL Lee Kwang-Ho KH Seong Joon-Kyung JK Min Ju-Hong JH

Frontiers in neurology 20181217

Background: In neuromyelitis optica spectrum disorder (NMOSD), brain involvement is common and cognitive dysfunction is frequently found. The study investigated alterations of white matter (WM) connectivity using graph theory and correlations with cognitive dysfunction in patients with NMOSD. Methods: We prospectively enrolled patients with NMOSD (N = 14) and age- and sex-matched healthy controls (N = 21). Structural connections between any pair of the 90 cortical and ...[more]

PMID: 30619061

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Project description:ObjectivesStudies of longitudinally extensive spinal cord lesions (LESCLs) in neuromyelitis optica (NMO) have focused on gray matter, where the relevant antigen, aquaporin-4 (AQP4), is abundant. Because spinal white matter pathology in NMO is not well characterized, we aimed to clarify spinal white matter pathology of LESCLs in NMO.MethodsWe analyzed 50 spinal cord lesions from eleven autopsied NMO/NMO spectrum disorder (NMOSD) cases. We also evaluated LESCLs with three or fewer spinal cord attacks by 3-tesla MRI in 15 AQP4 antibody-positive NMO/NMOSD patients and in 15 AQP4 antibody-negative multiple sclerosis (MS) patients.ResultsPathological analysis revealed seven cases of AQP4 loss and four predominantly demyelinating cases. Forty-four lesions from AQP4 loss cases involved significantly more frequently posterior columns (PC) and lateral columns (LC) than anterior columns (AC) (59.1%, 63.6%, and 34.1%, respectively). The posterior horn (PH), central portion (CP), and anterior horn (AH) were similarly affected (38.6%, 36.4% and 31.8%, respectively). Isolated perivascular inflammatory lesions with selective loss of astrocyte endfoot proteins, AQP4 and connexin 43, were present only in white matter and were more frequent in PC and LC than in AC (22.7%, 29.5% and 2.3%, Pcorr = 0.020, and Pcorr = 0.004, respectively). MRI indicated LESCLs more frequently affected PC and LC than AC in anti-AQP4 antibody-seropositive NMO/NMOSD (86.7%, 60.0% and 20.0%, Pcorr = 0.005, and Pcorr = 0.043, respectively) and AQP4 antibody-seronegative MS patients (86.7%, 73.3% and 33.3%, Pcorr = 0.063, and Pcorr = 0.043, respectively). PH, CP and AH were involved in 93.3%, 86.7% and 73.3% of seropositive patients, respectively, and in 53.3%, 60.0% and 40.0% of seronegative patients, respectively.ConclusionsNMO frequently and extensively affects spinal white matter in addition to central gray matter, especially in PC and LC, where isolated perivascular lesions with astrocyte endfoot protein loss may emerge. Spinal white matter involvement may also appear in early NMO, similar to cerebral white matter lesions.

Project description:BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system. Although complement-dependent astrocyte damage mediated by anti-aquaporin 4 autoantibody (AQP4-Ab) is well acknowledged to be the core of NMOSD pathogenesis, additional inflammatory cascades may contribute to the establishment of lesion formation. Thus, in this study, we investigated the possible pathogenic role of immune-reactive mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) of NMOSD patients.MethodsUsing quantitative polymerase chain reaction, we measured extracellular mtDNA levels in CSF of NMOSD patients positive for AQP4-Ab. Patients with multiple sclerosis or other neurological diseases were examined as controls. Pre- and post-treatment extracellular mtDNA levels were also compared in the NMOSD group. Extracellular mtDNA release from human astrocytes was analyzed in vitro utilizing NMOSD sera, and interleukin (IL)-1? production was measured in supernatants of mixed glial cells stimulated with DNA fraction of CSF derived from NMOSD patients. Furthermore, specific innate immune pathways mediating the IL-1? production by mtDNA were investigated in peripheral blood mononuclear cells with selective inhibitors of Toll-like receptor 9 (TLR9) and NOD-like receptor protein 3 (NLRP3) inflammasomes.ResultsExtracellular mtDNA level was specifically elevated in acute phase of NMOSD CSF. In vitro studies provided the evidence that mtDNA is released from human astrocytes by NMOSD sera. In addition, DNA fraction isolated from NMOSD CSF promoted secretion of IL-1? from mixed glial cells. Selective inhibition of TLR9 and NLRP3 inflammasomes revealed that mtDNA-mediated IL-1? production depends on specific innate immune pathways.ConclusionExtracellular mtDNA is specifically elevated in the CSF of patients with acute phase NMOSD, and mtDNA released by AQP4-Ab-mediated cellular damage elicits the innate immune cascades via TLR9 and NLRP3 inflammasomes pathways. Our study highlights mtDNA-mediated innate immune pathways as a novel therapeutic target for future treatment of NMOSD patients.

Dataset Information

White Matter Network Disruption and Cognitive Dysfunction in Neuromyelitis Optica Spectrum Disorder.

Publications

White Matter Network Disruption and Cognitive Dysfunction in Neuromyelitis Optica Spectrum Disorder.

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