髄液サイトカインプロファイルによる多巣性運動ニューロパチーと進行性筋萎縮症の鑑別

Objective: We aimed to compare the cytokine and chemokine profiles of patients with multifocal motor neuropathy (MMN) with those of patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) to investigate immunologic differences in the CNS. Methods: CSF from 12 patients with MMN, 8 with PMA, 26 with sporadic ALS, and 10 with other noninflammatory neurologic disorders was analyzed for 27 cytokines and chemokines using the multiplex bead array assay. Cytokine titers of the 4 groups were compared, and correlations between the titers of relevant cytokines and clinical parameters were evaluated. Results: There were no obvious intrathecal changes except for interleukin (IL)-1 receptor antagonist in patients with MMN. In contrast, IL-4, IL-7, IL-17, eotaxin/CCL11, fibroblast growth factor- 2 (FGF-2), granulocyte colony-stimulating factor (G-CSF), and platelet-derived growth factor BB titers were significantly elevated in patients with PMA and ALS; of these, FGF-2 and G-CSF titers were elevated compared with those in patients with MMN. IL-4 and IL-10 titers were high in patients with ALS, particularly patients with possible ALS presenting with a slowly progressive course or mild symptoms. Conclusions: The CSF cytokine profile of patients with MMN is distinct from that of patients with PMA and ALS. The similarity of the cytokine profiles between patients with PMA and ALS suggests that PMA shares common immunologic features with ALS in the CNS, even without clinical evidence of upper motor neuron involvement

実験的アレルギー性神経炎モデルの治療におけるCOX-2阻害剤の作用機序

京都大学0048新制・課程博士博士(医学)甲第8226号医博第2182号新制||医||729(附属図書館)UT51-2000-F130京都大学大学院医学研究科脳統御医科学系専攻(主査)教授 湊 長博, 教授 武藤 誠, 教授 柴崎 浩学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Cerebrospinal fluid mitochondrial DNA in neuromyelitis optica spectrum disorder

Abstract Background Neuromyelitis 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. Methods Using 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)-1β 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-1β 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. Results Extracellular 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-1β from mixed glial cells. Selective inhibition of TLR9 and NLRP3 inflammasomes revealed that mtDNA-mediated IL-1β production depends on specific innate immune pathways. Conclusion Extracellular 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

Apathy/depression, but not subjective fatigue, is related with cognitive dysfunction in patients with multiple sclerosis

BACKGROUND: Cognitive impairment could affect quality of life for patients with multiple sclerosis (MS), and cognitive function may be correlated with several factors such as depression and fatigue. This study aimed to evaluate cognitive function in Japanese patients with MS and the association between cognitive function and apathy, fatigue, and depression. METHODS: The Brief Repeatable Battery of Neuropsychological tests (BRB-N) was performed in 184 Japanese patients with MS and 163 healthy controls matched for age, gender, and education. The Apathy Scale (AS), Fatigue Questionnaire (FQ), and Beck Depression Inventory Second Edition (BDI-II) were used to evaluate apathy, fatigue, and depression, respectively. Student’s t-test was used to compare MS patients and healthy controls. Correlations between two factors were assessed using the Pearson correlation test, and multiple regression analysis was used to evaluate how much each factor affected the BRB-N score. RESULTS: In all BRB-N tests, patients with MS scored significantly lower than controls, and the effect size of symbol digit modalities test was the highest among the 9 tests of the BRB-N. Patients with MS had higher AS (p < 0.001), FQ (p < 0.0001), and BDI-II (p < 0.0001) scores than controls. In patients with MS, scores on most of the BRB-N tests correlated with scores on the AS and BDI-II; however, there was little correlation between scores on the BRB-N tests and those on the FQ. CONCLUSIONS: Cognitive function was impaired, particularly information-processing speed, and decreased cognitive function was correlated with apathy and depression in Japanese patients with MS. Despite the association between cognitive variables and depression/apathy, cognitive function was impaired beyond the effect of depression and apathy. However, subjective fatigue is not related with cognitive impairment. Taken together, this suggests that different therapeutic approaches are needed to improve subjective fatigue and cognition, and thereby quality of life, in patients with MS

Additional file 2: of Cerebrospinal fluid mitochondrial DNA in neuromyelitis optica spectrum disorder

Table S1. Clinical and CSF characteristics of patients with similar CSF counts. Table S2. Clinical and CSF characteristics of patients enrolled in the experiments utilizing DNA fractions from CSF. (PDF 56 kb