Kyushu University [Noriko Isobe (Professor) Faculty of Medical Sciences, Neurological Institute]

Noriko Isobe

Last modified date：2023.11.22

Professor / Department of Neurology / Neurological Institute / Faculty of Medical Sciences

Papers

1.	Takashi Irie, Kanae Matsuda-Ito, Taito Matsuda, Takahiro Masuda, Marco Prinz, Noriko Isobe, Kinichi Nakashima, Lineage tracing identifies in vitro microglia-to-neuron conversion by NeuroD1 expression., Genes to cells : devoted to molecular & cellular mechanisms, 10.1111/gtc.13033, 2023.04, Neuronal regeneration to replenish lost neurons after injury is critical for brain repair. Microglia, brain-resident macrophages that have the propensity to accumulate at the site of injury, can be a potential source for replenishing lost neurons through fate conversion into neurons, induced by forced expression of neuronal lineage-specific transcription factors. However, it has not been strictly demonstrated that microglia, rather than central nervous system-associated macrophages, such as meningeal macrophages, convert into neurons. Here, we show that NeuroD1-transduced microglia can be successfully converted into neurons in vitro using lineage-mapping strategies. We also found that a chemical cocktail treatment further promoted NeuroD1-induced microglia-to-neuron conversion. NeuroD1 with loss-of-function mutation, on the other hand, failed to induce the neuronal conversion. Our results indicate that microglia are indeed reprogrammed into neurons by NeuroD1 with neurogenic transcriptional activity..
2.	David Leppert, Mitsuru Watanabe, Sabine Schaedelin, Fredrik Piehl, Roberto Furlan, Matteo Gastaldi, Jeremy Lambert, Björn Evertsson, Katharina Fink, Takuya Matsushita, Katsuhisa Masaki, Noriko Isobe, Jun-Ichi Kira, Pascal Benkert, Aleksandra Maceski, Eline Willemse, Johanna Oechtering, Annette Orleth, Stephanie Meier, Jens Kuhle, Granulocyte activation markers in cerebrospinal fluid differentiate acute neuromyelitis spectrum disorder from multiple sclerosis., Journal of neurology, neurosurgery, and psychiatry, 10.1136/jnnp-2022-330796, 2023.04, BACKGROUND: Granulocyte invasion into the brain is a pathoanatomical feature differentiating neuromyelitis optica spectrum disorder (NMOSD) from multiple sclerosis (MS). We aimed to determine whether granulocyte activation markers (GAM) in cerebrospinal fluid (CSF) can be used as a biomarker to distinguish NMOSD from MS, and whether levels associate with neurological impairment. METHODS: We quantified CSF levels of five GAM (neutrophil elastase, myeloperoxidase, neutrophil gelatinase-associated lipocalin, matrixmetalloproteinase-8, tissue inhibitor of metalloproteinase-1), as well as a set of inflammatory and tissue-destruction markers, known to be upregulated in NMOSD and MS (neurofilament light chain, glial fibrillary acidic protein, S100B, matrix metalloproteinase-9, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1), in two cohorts of patients with mixed NMOSD and relapsing-remitting multiple sclerosis (RRMS). RESULTS: In acute NMOSD, GAM and adhesion molecules, but not the other markers, were higher than in RRMS and correlated with actual clinical disability scores. Peak GAM levels occurred at the onset of NMOSD attacks, while they were stably low in MS, allowing to differentiate the two diseases for ≤21 days from onset of clinical exacerbation. Composites of GAM provided area under the curve values of 0.90-0.98 (specificity of 0.76-1.0, sensitivity of 0.87-1.0) to differentiate NMOSD from MS, including all anti-aquaporin-4 protein (aAQP4)-antibody-negative patients who were untreated. CONCLUSIONS: GAM composites represent a novel biomarker to reliably differentiate NMOSD from MS, including in aAQP4- NMOSD. The association of GAM with the degree of concurrent neurological impairment provides evidence for their pathogenic role, in turn suggesting them as potential drug targets in acute NMOSD..
3.	Hajime Takeuchi, Katsuhisa Masaki, Hidenori Ogata, Satoshi Nagata, Takafumi Shimogawa, Ryo Yamasaki, Noriko Isobe, Teaching Video NeuroImage: Reversible Parkinsonism Caused by Lumboperitoneal Shunt Overdrainage., Neurology, 10.1212/WNL.0000000000200994, 99, 11, 486-488, 2022.09.
4.	Yuji Nishimura, Katsuhisa Masaki, Dai Matsuse, Hiroo Yamaguchi, Tatsunori Tanaka, Eriko Matsuo, Shotaro Hayashida, Mitsuru Watanabe, Takuya Matsushita, Shoko Sadashima, Naokazu Sasagasako, Ryo Yamasaki, Noriko Isobe, Toru Iwaki, Jun-Ichi Kira, Early and extensive alterations of glial connexins, distal oligodendrogliopathy type demyelination, and nodal/paranodal pathology are characteristic of multiple system atrophy., Brain pathology (Zurich, Switzerland), 10.1111/bpa.13131, e13131, 2022.11, The pathological hallmark of multiple system atrophy (MSA) is aberrant accumulation of phosphorylated α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions (GCIs). Extensive demyelination occurs particularly in the olivopontocerebellar and striatonigral pathways, but its precise mechanism remains elusive. Glial connexins (Cxs), which form gap junction channels between astrocytes and oligodendrocytes, play critical roles in myelin maintenance, and have not been studied in MSA. Therefore, we immunohistochemically investigated glial Cx changes in the cerebellar afferent fibers in 15 autopsied patients with MSA. We classified demyelinating lesions into three stages based on Klüver-Barrera staining: early (Stage I), intermediate (Stage II), and late (Stage III) stages showing subtle, moderate, and severe myelin reduction, respectively. Myelin-associated glycoprotein, but not myelin oligodendrocyte glycoprotein, was preferentially decreased in Stage I, suggesting distal oligodendrogliopathy type demyelination. Accumulation of phosphorylated α-synuclein in oligodendrocytes was frequently seen in Stage I but less frequently observed in Stages II and III. Tubulin polymerization-promoting protein (TPPP/p25α)-positive oligodendrocytes were preserved in Stage I but successively decreased in Stages II and III. Even at Stage I, Cx32 was nearly absent from myelin, despite the relative preservation of other nodal proteins, such as neurofascin, claudin-11/oligodendrocyte-specific protein, and contactin-associated protein 1, which successively decreased in the later stages. Cx32 was re-distributed in the oligodendrocyte cytoplasm and co-localized with GCIs. Cx47 gradually decreased at the oligodendrocyte surface in a stage-dependent manner but was not co-localized with GCIs. Astrocytic Cx43 was down-regulated in Stage I but up-regulated in Stages II and III, reflecting astrogliosis. Cx43/Cx47 gap junctions significantly decreased from Stage I to III. Activated microglia/macrophages and T cells infiltrated in Stage I rather than Stages II and III. Therefore, early and extensive alterations of glial Cxs, particularly Cx32 loss, occur in MSA and may accelerate distal oligodendrogliopathy type demyelination and nodal/paranodal dysfunction through disruption of inter-glial communication..
5.	Yu Hashimoto, Ryo Yamasaki, Senri Ko, Eriko Matsuo, Yuko Kobayakawa, Katsuhisa Masaki, Dai Matsuse, Noriko Isobe, Connexin 30 Deficiency Ameliorates Disease Progression at the Early Phase in a Mouse Model of Amyotrophic Lateral Sclerosis by Suppressing Glial Inflammation., International journal of molecular sciences, 10.3390/ijms232416046, 23, 24, 2022.12, Connexin 30 (Cx30), which forms gap junctions between astrocytes, regulates cell adhesion and migration, and modulates glutamate transport. Cx30 is upregulated on activated astroglia in central nervous system inflammatory lesions, including spinal cord lesions in mutant superoxide dismutase 1 (mSOD1) transgenic amyotrophic lateral sclerosis (ALS) model mice. Here, we investigated the role of Cx30 in mSOD1 mice. Cx30 was highly expressed in the pre-onset stage in mSOD1 mice. mSOD1 mice with knockout (KO) of the Cx30 gene (Cx30KO-mSOD1 mice) showed delayed disease onset and tended to have an extended survival period (log-rank, p = 0.09). At the progressive and end stages of the disease, anterior horn cells were significantly preserved in Cx30KO-mSOD1 mice. In lesions of these mice, glial fibrillary acidic protein/C3-positive inflammatory astroglia were decreased. Additionally, the activation of astrocytes in Cx30KO-mSOD1 mice was reduced compared with mSOD1 mice by gene expression microarray. Furthermore, expression of connexin 43 at the pre-onset stage was downregulated in Cx30KO-mSOD1 mice. These findings suggest that reduced expression of astroglial Cx30 at the early disease stage in ALS model mice protects neurons by attenuating astroglial inflammation..
6.	Takahiko Mukaino, Taira Uehara, Jun Yokohama, Toshiki Okadome, Tomomi Arakawa, Setsu Yokoyama, Ayumi Sakata, Kei-Ichiro Takase, Osamu Togao, Naoki Akamatsu, Hiroshi Shigeto, Noriko Isobe, Jun-Ichi Kira, Atrophy of the hippocampal CA1 subfield relates to long-term forgetting in focal epilepsy., Epilepsia, 10.1111/epi.17378, 63, 10, 2623-2636, 2022.10, OBJECTIVE: The mechanisms underlying accelerated long-term forgetting (ALF) in patients with epilepsy are still under investigation. We examined the contribution of hippocampal subfields and their morphology to long-term memory performance in patients with focal epilepsy. METHODS: We prospectively assessed long-term memory and performed magnetic resonance imaging in 80 patients with focal epilepsy (61 with temporal lobe epilepsy and 19 with extratemporal lobe epilepsy) and 30 healthy controls. The patients also underwent electroencephalography recording. Verbal and visuospatial memory was tested 30 s, 10 min, and 1 week after learning. We assessed the volumes of the whole hippocampus and seven subfields and deformation of the hippocampal shape. The contributions of the hippocampal volumes and shape deformation to long-term forgetting, controlling for confounding factors, including the presence of interictal epileptiform discharges, were assessed by multiple regression analyses. RESULTS: Patients with focal epilepsy had lower intelligence quotients and route recall scores at 10 min than controls. The focal epilepsy group had smaller volumes of both the right and left hippocampal tails than the control group, but there were no statistically significant group differences for the volumes of the whole hippocampus or other hippocampal subfields. Multiple regression analyses showed a significant association between the left CA1 volume and the 1-week story retention (β = 7.76; Bonferroni-corrected p = 0.044), but this was not found for the whole hippocampus or other subfield volumes. Hippocampal shape analyses revealed that atrophy of the superior-lateral, superior-central, and inferior-medial regions of the left hippocampus, corresponding to CA1 and CA2/3, was associated with the verbal retention rate. SIGNIFICANCE: Our results suggest that atrophy of the hippocampal CA1 region and its associated structures disrupts long-term memory consolidation in focal epilepsy. Neuronal cell loss in specific hippocampal subfields could be a key underlying cause of ALF in patients with epilepsy..
7.	Yuko Kobayakawa, Koji Todaka, Yu Hashimoto, Senri Ko, Wataru Shiraishi, Junji Kishimoto, Jun-Ichi Kira, Ryo Yamasaki, Noriko Isobe, A novel quantitative indicator for disease progression rate in amyotrophic lateral sclerosis., Journal of the neurological sciences, 10.1016/j.jns.2022.120389, 442, 120389-120389, 2022.08, OBJECTIVE: The current study sought to develop a new indicator for disease progression rate in amyotrophic lateral sclerosis (ALS). METHODS: We used a nonparametric method to score diverse patterns of decline in the percentage of predicted forced vital capacity (%FVC) in patients with ALS. This involved 6317 longitudinal %FVC data sets from 920 patients in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database volunteered by PRO-ACT Consortium members. To assess the utility of the derived scores as a disease indicator, we examined changes over time, the association with prognosis, and correlation with the Risk Profile of the Treatment Research Initiative to Cure ALS (TRICALS). Our local cohort (n = 92) was used for external validation. RESULTS: We derived scores ranging from 35 to 106 points to construct the FVC Decline Pattern scale (FVC-DiP). Individuals' FVC-DiP scores were determined from a single measurement of %FVC and disease duration at assessment. Although the %FVC declined over the disease course (p
8.	Taiki Fukushima, Shohei Ikeda, Minoru Tomita, Yu Mori, Yuki Fukami, Haruki Koike, Masahisa Katsuno, Hidenori Ogata, Noriko Isobe, Naoki Hattori, A Case of Demyelinating Neuropathy with Markedly Elevated Serum IgG4 Levels and Anti-Contactin 1 IgG4 Antibody., Internal medicine (Tokyo, Japan), 10.2169/internalmedicine.9286-21, 2022.07, We herein report a 77-year-old man with a 4-month history of progressive gait and sensory disturbances of the extremities. A nerve conduction study indicated demyelinating polyneuropathy. Serum IgG4 levels and anti-contactin 1 IgG4 antibodies were markedly increased. The sural nerve biopsy specimen showed IgG4-positive plasma cell infiltration in the epineurium. Treatment with steroids resulted in an amelioration of functional status, improvement of nerve conduction parameters, decreased serum IgG4 levels, and negative conversion of anti-contactin1 antibody. Further studies are needed to clarify the significance of IgG4-positive plasma cell infiltration in anti-contactin 1 antibody-positive neuropathies..
9.	Yuko Ichimiya, Pin Fee Chong, Yuri Sonoda, Vlad Tocan, Mitsuru Watanabe, Hiroyuki Torisu, Ryutaro Kira, Toshiyuki Takahashi, Jun-Ichi Kira, Noriko Isobe, Yasunari Sakai, Shouichi Ohga, Long-lasting pain and somatosensory disturbances in children with myelin oligodendrocyte glycoprotein antibody-associated disease., European journal of pediatrics, 10.1007/s00431-023-04989-z, 2023.04, UNLABELLED: Myelin oligodendrocyte glycoprotein antibody (MOG-Ab) is an autoantibody associated with acquired demyelinating syndrome (ADS) in childhood and adults. The pathogenic roles of MOG-Ab and long-term outcomes of children with MOG-Ab-associated disease (MOGAD) remain elusive. We investigated the clinical features of children with ADS during follow-up in our institute. Clinical data were retrospectively analyzed using medical charts of patients managed in Kyushu University Hospital from January 1st, 2001, to March 31st, 2022. Participants were children of
10.	Eizo Tanaka, Mitsuru Watanabe, Shoko Fukumoto, Katsuhisa Masaki, Ryo Yamasaki, Takuya Matsushita, Noriko Isobe, Effect of smoking on disease activity in multiple sclerosis patients treated with dimethyl fumarate or fingolimod., Multiple sclerosis and related disorders, 10.1016/j.msard.2023.104513, 70, 104513-104513, 2023.01, BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), smoking is a known risk factor for disease susceptibility and disability progression. However, its impact on the efficacy of oral disease-modifying drugs (DMDs) is unclear. Therefore, we initiated a single-center, retrospective, observational study to investigate the relationship between smoking and disease activity in RRMS patients under oral DMDs. METHODS: We retrospectively enrolled RRMS patients who initiated oral DMDs (fingolimod or dimethyl fumarate) at our hospital between January 2012 and December 2019. Clinical data and smoking status at oral DMD initiation were collected up to December 2020. We conducted survival analyses for relapse and any disease activity, defined as relapse or MRI disease activity, among patients with distinct smoking statuses. RESULTS: We enrolled 103 RRMS patients under oral DMDs including 19 (18.4%) current smokers at baseline. Proportions of relapses and any disease activity during follow-up were higher in current smokers (relapse: p = 0.040, any disease activity: p = 0.004) and time from initiating oral DMDs to relapse was shorter in current smokers (log-rank test: p = 0.011; Cox proportional hazard analysis: hazard ratio (HR) 2.72 [95% confidence interval (CI) 1.22-6.09], p = 0.015) than in non-smokers. Time from initiating oral DMDs to any disease activity was also shorter in current smokers (log-rank test: p = 0.016; Cox proportional hazard analysis: HR 2.18 [95% CI 1.14-4.19], p = 0.019) than in non-smokers. The survival curves for relapse and any disease activity were not different between the former smoker and never-smoker groups. Multivariate survival analysis showed current smoking was an independent risk factor for relapse or any disease activity after adjusting for covariates (relapse: HR 2.54 [95% CI 1.06-6.10], p = 0.037; any disease activity: HR 3.47 [95% CI 1.27-9.50], p = 0.015). CONCLUSION: Smoking was a risk factor for disease activity in RRMS patients under oral DMD treatment. RRMS patients should be advised to stop smoking even after the initiation of DMDs..
11.	Xu Zhang, Jun-Ichi Kira, Hidenori Ogata, Tomohiro Imamura, Mikio Mitsuishi, Takayuki Fujii, Masaki Kobayashi, Kazuo Kitagawa, Yukihiro Namihira, Yusuke Ohya, Guzailiayi Maimaitijiang, Ryo Yamasaki, Yuko Fukata, Masaki Fukata, Noriko Isobe, Yuri Nakamura, Anti-LGI4 Antibody Is a Novel Juxtaparanodal Autoantibody for Chronic Inflammatory Demyelinating Polyneuropathy., Neurology(R) neuroimmunology & neuroinflammation, 10.1212/NXI.0000000000200081, 10, 2, 2023.03, BACKGROUND AND OBJECTIVES: The objective of this study was to discover novel nodal autoantibodies in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We screened for autoantibodies that bind to mouse sciatic nerves and dorsal root ganglia (DRG) using indirect immunofluorescence (IFA) assays with sera from 113 patients with CIDP seronegative for anti-neurofascin 155 and anticontactin-1 antibodies and 127 controls. Western blotting, IFA assays using HEK293T cells transfected with relevant antigen expression plasmids, and cell-based RNA interference assays were used to identify target antigens. Krox20 and Periaxin expression, both of which independently control peripheral nerve myelination, was assessed by quantitative real-time PCR after application of patient and control sera to Schwann cells. RESULTS: Sera from 4 patients with CIDP, but not control sera, selectively bound to the nodal regions of sciatic nerves and DRG satellite glia (p = 0.048). The main immunoglobulin G (IgG) subtype was IgG4. IgG from these 4 patients stained a 60-kDa band on Western blots of mouse DRG and sciatic nerve lysates. These features indicated leucine-rich repeat LGI family member 4 (LGI4) as a candidate antigen. A commercial anti-LGI4 antibody and IgG from all 4 seropositive patients with CIDP showed the same immunostaining patterns of DRG and cultured rat Schwann cells and bound to the 60-kDa protein in Western blots of LGI4 overexpression lysates. IgG from 3 seropositive patients, but none from controls, bound to cells cotransfected with plasmids containing LGI4 and a disintegrin and metalloprotease domain-containing protein 22 (ADAM22), an LGI4 receptor. In cultured rat Schwann and human melanoma cells constitutively expressing LGI4, LGI4 siRNA effectively downregulated LGI4 and reduced patients' IgG binding compared with scrambled siRNA. Application of serum from a positive patient to Schwann cells expressing ADAM22 significantly reduced the expression of Krox20, but not Periaxin. Anti-LGI4 antibody-positive patients had a relatively old age at onset (mean age 58 years), motor weakness, deep and superficial sensory impairment with Romberg sign, and extremely high levels of CSF protein. Three patients showed subacute CIDP onset resembling Guillain-Barré syndrome. DISCUSSION: IgG4 anti-LGI4 antibodies are found in some elderly patients with CIDP who present subacute sensory impairment and motor weakness and are worth measuring, particularly in patients with symptoms resembling Guillain-Barré syndrome..
12.	Kazunori Iwao, Mitsuru Watanabe, Takahiko Mukaino, Takayuki Fujii, Ryo Yamasaki, Noriko Isobe, A case report of anti-N-methyl-D-aspartate receptor encephalitis with chromosomally integrated human herpesvirus 6, NEUROLOGY AND CLINICAL NEUROSCIENCE, 10.1111/ncn3.12681, 11, 1, 52-54, 2023.01, Chromosomally integrated human herpesvirus 6 (ciHHV6) is a condition where HHV6-DNA is integrated into the host germline genome. ciHHV6 can be misdiagnosed as active HHV6 infection. We report a 30-year-old woman presenting with psychological symptoms without a history of immunodeficiency. She had an ovarian teratoma and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in the cerebrospinal fluid (CSF) with HHV6-DNA in the serum and CSF. The final diagnosis was anti-NMDAR encephalitis and ciHHV6 because laparoscopic oophorectomy and immunotherapy ameliorated her symptoms and HHV6-DNA was detected in her oral mucosa cells. This case suggests the need to assess whether HHV6-DNA is related to infection or ciHHV6 when HHV6-DNA is detected in the CSF of patients with encephalitis..
13.	Jun-ichi Kira, Takuya Matsushita, Noriko Isobe, Takaaki Ishizu, Opticospinal multiple sclerosis in Japanese, NEUROLOGY ASIA, 13, 167-173, 2008.12, Antibodies to aquaporin-4 (AQP4) are found in a number of Japanese opticospinal multiple sclerosis (OSMS) patients. Whether anti-AQP4 antibody-positive and -negative OSMS patients are afflicted with an identical disease remains unknown. To clarify immunological differences between the two groups of patients, we studied serum antibody titres against AQP4 in 191 patients with idiopathic central nervous system demyelinating diseases and clarified any relationships with immunological parameters. The anti-AQP4 antibody positivity rate was higher in patients with OSMS (36.2%), idiopathic recurrent myelitis (23.5%), and recurrent optic neuritis (26.9%) than in conventional MS patients (8.0%), and those with other diseases (0%). Anti-AQP4 antibody titre was significantly higher in patients with SS-A/B antibodies than in those without. Anti-AQP4 antibody-negative OSMS patients showed significantly higher CD4(+)IFN-gamma(+)IL-4(-)T cell percentages and intracellular IFN-gamma/IL-4 ratios than anti-AQP4 antibody-positive patients, anti-AQP4 antibody -negative conventional MS patients, and healthy controls. As well, CD4(+)IFN-gamma(+)IL-4(-)T cell percentages were negatively correlated with anti-AQP4 antibody titres. In CSF, OSMS patients had significantly higher levels of IFN-gamma and granulocyte colony-stimulating factor levels than patients with non-inflammatory neurological diseases and other causes of myelitis. A significant increase of IL-17 compared with non-inflammatory neurological diseases patients was only found in OSMS patients, irrespective of the presence or absence of anti-AQP4 antibody. These findings suggest that high titres of anti-AQP4 antibodies are produced as a result of heightened humoral autoimmunity, and that they are likely to contribute to extensive lesion development through disturbed resolution of vasogenic oedema. Moreover, since intrathecal up-regulation of IL-17 and IFN-gamma is characteristic of OSMS, Th17/Th1 cells may be critical for the initiation of inflammation and the disruption of blood-brain barrier (BBB); rendering anti-AQP4 antibody get across the BBB..
14.	N. Isobe, J. Kira, N. Kawamura, T. Ishizu, K. Arimura, Y. Kawano, Neural damage associated with atopic diathesis A nationwide survey in Japan, NEUROLOGY, 10.1212/WNL.0b013e3181b6bb6b, 73, 10, 790-797, 2009.09, Background: We previously reported the occurrence of myelitis in patients with atopic disorders (atopic myelitis [AM]). To uncover the spectrum of neural damage associated with atopy, we conducted a cross-sectional nationwide survey of AM and atopy-related peripheral neuritis (APN), including Churg-Strauss syndrome (CSS), in individuals with atopic diathesis. Method: Cases with AM diagnosed between 1996 and 2006 and cases with APN between 2000 and 2006 were collected from all over Japan. Detailed data on 109 patients with AM and 133 patients with APN were collated. Results: Patients with APN showed a preponderance of women, higher age at onset, and greater eosinophil counts than patients with AM. Patients with AM most commonly showed cervical cord involvement, whereas patients with APN preferentially exhibited mononeuritis multiplex predominantly affecting the lower limbs. Among patients with AM, motor weakness and muscle atrophy were significantly more frequent in those with bronchial asthma than in those with other atopic disorders. Patients with APN who met the criteria for CSS showed a higher age at onset, higher frequencies of systemic organ involvement, and greater disability than those who did not. Abnormalities suggesting peripheral nervous system involvement were seen in 25.7% of patients with AM, whereas 18.8% of patients with APN had abnormalities indicating CNS involvement. Multiple logistic regression analyses revealed that atopic dermatitis increased the risk of myelitis, whereas high age at onset and bronchial asthma decreased that risk. Conclusions: Atopy-related neural inflammation multifocally affects CNS and peripheral nervous system tissues. Both preceding atopic disorders and age seem to influence the distribution of neural damage. Neurology (R) 2009;73:790-797.
15.	H. Doi, T. Matsushita, N. Isobe, T. Matsuoka, M. Minohara, H. Ochi, J. I. Kira, Hypercomplementemia at relapse in patients with anti-aquaporin-4 antibody, MULTIPLE SCLEROSIS, 10.1177/1352458508099139, 15, 3, 304-310, 2009.03, Objective Because Asian patients with opticospinal multiple sclerosis (OSMS) frequently have anti-aquaporin-4 (AQP4) antibody, complement-mediated disruption of astrocyte foot processes is proposed but not yet proven. We aimed to clarify whether complement consumption occurs at relapse in anti-AQP4 antibody-positive patients. Methods We analyzed serum CH50, C3, C4, and C-reactive protein (CRP) levels and their relation to clinical phases in 118 MS patients with or without anti-AQP4 antibody. Serum CH50 levels were higher in 24 patients with anti-AQP4 antibody than in 39 OSMS and 54 conventional form of MS (CMS) patients without anti-AQP4 antibody at relapse (P(corr) < 0.05) but not in remission. The frequency of hypercomplementemia at relapse was also higher in anti-AQP4 antibody-positive patients than in anti-AQP4 antibody-negative CMS patients (70.4% vs 29.0%, P(corr) < 0.05). C3 and C4 levels did not differ significantly among the three groups at relapse. In patients with anti-AQP4 antibody, the coexistence of hypercomplementemia and high CRP values was more common at relapse than in the remission phase (36.0% vs 10.5%, P < 0.05). In patients with extensive central nervous system lesions, hypercomplementemia was significantly more common in anti-AQP4 antibody-positive patients than anti-AQP4 antibody-negative ones (88.9% vs 16.7%, P < 0.01). We consider that hypercomplementemia in anti-AQP4 antibody-positive patients may reflect a systemic inflammatory reaction at relapse. Multiple Sclerosis 2009; 15: 304-310. http://msj.sagepub.com.
16.	Hikaru Doi, Takuya Matsushita, Noriko Isobe, Takaaki Ishizu, Yasumasa Ohyagi, Jun-ichi Kira, Frequency of Chronic Headaches in Japanese Patients With Multiple Sclerosis: With Special Reference to Opticospinal and Common Forms of Multiple Sclerosis, HEADACHE, 10.1111/j.1526-4610.2009.01427.x, 49, 10, 1513-1520, 2009.11, Background.- Headache is common in Western patients with multiple sclerosis (MS), but its frequency has not been reported in Asian patients. In Asians, the opticospinal form of MS, showing similar characteristics to relapsing neuromyelitis optica in Westerners, is regarded as a different subtype from conventional MS. Objectives.- The aim of this study was to clarify the frequency of primary and chronic secondary headaches in Japanese patients with MS and the factors associated with the emergence of such headaches. Methods.- We investigated 127 consecutive patients with clinically definite MS. Frequencies of primary and chronic secondary headaches were compared according to clinical subtype, administration of interferon beta, and anti-aquaporin-4 antibody status. Results.- The frequency of patients with primary and chronic secondary headaches at the time of interview was 64/127 (50.4%); the frequency of migraine was 26/127 (20.4%) and that of tension-type headache was 38/127 (29.9%). The frequencies of patients with primary and chronic secondary headaches and migraine without aura after the onset of MS were higher in patients undergoing interferon beta therapy than in those not on the therapy (42.4% vs 23.4%, P < .05 and 15.1% vs 4.3%, P = .05, respectively). There were no significant differences in the frequency of primary and chronic secondary headaches based on clinical subtype of MS. However, among patients not receiving interferon beta, the occurrence of migraine with aura after the onset of MS was significantly higher in patients with anti-aquaporin-4 antibody than in patients without the antibody (13.3% vs 0.0%, P < .05). Conclusions.- In Japanese patients with MS, the frequency of primary and chronic secondary headaches, especially migraine, was higher than in the general Japanese population. Administration of interferon beta was related to a higher frequency of primary and chronic secondary headaches, especially migraine without aura, irrespective of clinical subtype of MS..
17.	T. Matsushita, N. Isobe, T. Matsuoka, T. Ishizu, Y. Kawano, T. Yoshiura, Y. Ohyagi, J. Kira, Extensive vasogenic edema of anti-aquaporin-4 antibody-related brain lesions, MULTIPLE SCLEROSIS, 10.1177/1352458509106613, 15, 9, 1113-1117, 2009.09, Objective Using neuroimaging, we analyzed the nature of extensive brain lesions in five anti-aquaporin-4 (AQP4) antibody-positive patients with neuromyelitis optica spectrum disorders. Results Extensive brain lesions involved white matter in three, and basal ganglia and corpus callosum in one each. Four patients showed high diffusivity on apparent diffusion coefficient maps and three demonstrated increased choline/creatine ratios and decreased N-acetyl-aspartate/creatine ratios on (1)H-magnetic resonance spectroscopy. These findings suggested that the lesions were vasogenic edema associated with inflammation. Unusual brain symptoms associated with such lesions included recurrent limbic encephalitis, parkinsonism, and coma. Conclusion Anti-AQP4 antibody is considered to be associated with the neuroimaging appearances of vasogenic edema. Multiple Sclerosis 2009; 15: 1113-1117. http://msj.sagepub.com.
18.	T. Matsushita, T. Matsuoka, N. Isobe, Y. Kawano, M. Minohara, N. Shi, Y. Nishimura, H. Ochi, J. Kira, Association of the HLA-DPB10501 allele with anti-aquaporin-4 antibody positivity in Japanese patients with idiopathic central nervous system demyelinating disorders, TISSUE ANTIGENS, 10.1111/j.1399-0039.2008.01172.x, 73, 2, 171-176, 2009.02, There are two subtypes of multiple sclerosis (MS) in Asians: the opticospinal (OSMS) form that shows a selective involvement of the optic nerve and the spinal cord and the conventional (CMS) form that has disseminated lesions in the central nervous system including the cerebrum, cerebellum and brainstem. Both show distinct human leukocyte antigen (HLA) class II associations. OSMS has similar features to the relapsing form of neuromyelitis optica (NMO) in Western populations. Recently, it was shown that antibodies to aquaporin-4 (AQP4) are specifically detected in NMO patients and in some Japanese patients with OSMS or recurrent optic neuritis or myelitis. To clarify the immunogenetic background of anti-AQP4 antibody production, we studied HLA-DRB1 and -DPB1 gene polymorphisms in anti-AQP4 antibody-positive and -negative patients with idiopathic demyelinating diseases, such as MS, recurrent optic neuritis and recurrent myelitis. The phenotypic frequency of the HLA-DPB10501 allele was significantly increased in anti-AQP4 antibody-positive patients (89.5%, odds ratio = 4.8; 95% confidence interval = 1.6-14.3, n = 38, P(corr) = 0.032) compared with controls (64.0%, n = 125) but not in either anti-AQP4 antibody-negative OSMS (75.0%, n = 32) or CMS (69.2%, n = 52) patients. There was no significant correlation between any HLA-DRB1 allele and the existence of anti-AQP4 antibody. These findings suggest that the emergence of anti-AQP4 antibody is reinforced by the presence of the HLA-DPB1*0501 allele in Japanese..
19.	T. Matsushita, N. Isobe, T. Matsuoka, N. Shi, Y. Kawano, X. M. Wu, T. Yoshiura, Y. Nakao, T. Ishizu, J. I. Kira, Aquaporin-4 autoimmune syndrome and anti-aquaporin-4 antibody-negative opticospinal multiple sclerosis in Japanese, MULTIPLE SCLEROSIS, 10.1177/1352458509104595, 15, 7, 834-847, 2009.07, Background Antibodies to aquaporin-4 (AQP4) are found in a fraction of Japanese opticospinal multiple sclerosis (OSMS) patients. However, it remains unknown whether anti-AQP4 antibody-positive and negative OSMS patients possess an identical disease. Objective The objective of the current study was to clarify immunological differences between the two groups of patients. Methods We studied the serum antibody titers against AQP4 in 191 patients with idiopathic central nervous system demyelinating diseases and clarified their relationships with immunological parameters. Results Anti-AQP4 antibody positivity rate was higher in patients with OSMS (21/58, 36.2%), idiopathic recurrent myelitis (4/17, 23.5%), and recurrent optic neuritis (7/26, 26.9%), than in conventional MS (CMS) patients (6/90, 6.7%) and patients with other diseases (0/87). Anti-AQP4 antibody titer was significantly higher in patients with SS-A/B antibodies than in those without them. Anti-AQP4 antibody-negative OSMS patients showed significantly higher CD4(+) IFN-gamma(+)IL-4(-)T cell percentages and intracellular IFN-gamma/IL-4 ratios than anti-AQP4 antibody-positive patients, anti-AQP4 antibody-negative CMS patients, and healthy controls, and CD4(+)IFN-gamma(+)IL-4(-)T cell percentages were negatively correlated with anti-AQP4 antibody titers. Conclusion Anti-AQP4 antibody-positive patients are immunologically distinct from anti-AQP4 antibody-negative OSMS patients owing to a Th2 shift in the former group in comparison to a Th1 shift in the latter. Multiple Sclerosis 2009; 15: 834-847. http://msj.sagepub.com.
20.	N. Isobe, T. Matsushita, R. Yamasaki, S. V. Ramagopalan, Y. Kawano, Y. Nishimura, G. C. Ebers, J. Kira, Influence of HLA-DRB1 alleles on the susceptibility and resistance to multiple sclerosis in Japanese patients with respect to anti-aquaporin 4 antibody status, MULTIPLE SCLEROSIS, 10.1177/1352458509355067, 16, 2, 147-155, 2010.02, Background: Epistatic interactions between human leukocyte antigen (HLA)-DRB1 alleles alter multiple sclerosis (MS) risk in Caucasians. Such interactions have never been studied in Asian MS patients. Objective: To investigate the influence of HLA-DRB1 alleles, including epistatic interactions at this locus, in Japanese MS patients with and without the anti-aquaporin 4 (AQP4) antibody. Methods: The HLA-DRB1 locus was genotyped in 108 MS patients and 127 healthy controls. MS patients were further classified into two groups according to anti-AQP4 antibody status (27 positive and 81 negative). Results: HLA-DRB109 (adjusted odds ratio (OR) = 0.243, 95% confidence interval (CI) 0.099-0.533) and HLA-DRB101 (adjusted OR = 0.327, 95% CI 0.103-0.873) decreased the incidence of anti-AQP4 antibody-negative MS. By contrast, HLA-DRB112 increased the risk of anti-AQP4 antibody-positive MS (adjusted OR = 3.691, 95% CI 1.233-10.565). Individuals with HLA-DRB109/15 decreased the risk of anti-AQP4 antibody-negative MS (adjusted OR = 0.164, 95% CI 0.026-0.593), while those with HLA-DRB112/15 increased the risk of anti-AQP4 antibody-positive MS (adjusted OR = 10.870, 95% CI 2.004-81.752). Conclusions: The ability of HLA-DRB109 to reduce the risk of anti-AQP4 antibody-negative MS may arise from an interaction with HLA-DRB115. By contrast, HLA-DRB112 increases susceptibility to anti-AQP4 antibody-positive MS, possibly via an interaction with HLA-DRB1*15..
21.	T. Matsushita, N. Isobe, M. Kawajiri, M. Mogi, K. Tsukuda, M. Horiuchi, Y. Ohyagi, J. Kira, CSF angiotensin II and angiotensin-converting enzyme levels in anti-aquaporin-4 autoimmunity, JOURNAL OF THE NEUROLOGICAL SCIENCES, 10.1016/j.jns.2010.05.014, 295, 1-2, 41-45, 2010.08, Background: Anti-aquaporin-4 (AQP4) antibody targets perivascular astrocyte foot processes, which contain abundant angiotensinogen, a precursor of angiotensin II, angiotensin-converting enzyme (ACE) and ACE2. Objective: To disclose any abnormality in the intrathecal angiotensin II metabolic pathway in Japanese patients with neuromyelitis optica (NMO) or NMO spectrum disorders (NMOs) and positive for anti-AQP4 antibody. Methods: We measured CSF angiotensin II, ACE and ACE2 levels in 15 anti-AQP4 antibody-positive patients with NMO or NMOs, 21 anti-AQP4 antibody-negative multiple sclerosis (MS) patients, 32 patients with other neurological diseases (OND) and 24 non-neurologic controls, using established ELISAs. Results: CSF angiotensin II levels were lower in patients with NMO/NMOs (2.01 +/- 1.82 pg/ml) and those with MS (3.15 +/- 1.67 pg/ml) than in the OND (5.41 +/- 2.34 pg/ml) and control groups (6.71 +/- 2.65 pg/ml) (P-corr<0.005). The difference in CSF angiotensin II levels between NMO/NMOs and MS patients was nearly significant (P-uncorr=0.052). In NMO/NMOs and MS patients, angiotensin II levels were negatively correlated with CSF/serum albumin ratio (P<0.05). ACE levels in CSF were lower in patients with NMO/NMOs (34.3 +/- 5.61 ng/ml) than in MS patients (42.5 +/- 8.19 ng/ml, P-corr=0.035) and controls (44.7 +/- 4.02 ng/ml, P-corr<0.0003) while ACE2 levels were lower in NMO/NMOs (1.13 +/- 0.49 ng/ml) and MS (1.75 +/- 0.86 ng/ml) patients than in controls (2.76 +/- 0.23 ng/ml, P-corr<0.001 for both). Conclusion: CSF angiotensin II, ACE, and ACE2 levels are decreased in NMO/NMOs patients with anti-AQP4 antibody, reflecting severe destruction of perivascular astrocytes. (C) 2010 Elsevier B.V. All rights reserved..
22.	Tomomi Yonekawa, Takuya Matsushita, Motozumi Minohara, Noriko Isobe, Katsuhisa Masaki, Satoshi Yoshimura, Yasuharu Nishimura, Jun-ichi Kira, T cell reactivities to myelin protein-derived peptides in neuromyelitis optica patients with anti-aquaporin-4 antibody, NEUROLOGY ASIA, 16, 2, 139-142, 2011.06, We previously reported the establishment of major myelin protein-derived T cell lines from 11 patients with multiple sclerosis. In the present study, we determined anti-aquaporin-4 (AQP4) antibody status in these patients and classified them into five patients with anti-AQP4 antibody who met the criteria for neuromyelitis optica (NMO) or NMO spectrum disorders, and six patients without anti-AQP4 antibody who fulfilled the revised McDonald criteria for multiple sclerosis. T cell lines reactive to myelin oligodendrocyte glycoprotein, proteolipid protein and myelin basic protein were detected in 5/5, 3/5 and 3/5 of the anti-AQP4 antibody-positive patients, respectively, and in 5/6, 4/6 and 4/6 of the anti-AQP4 antibody-negative ones, respectively. T cell lines from most of these patients showed inter-or intra-molecular epitope spreading, irrespective of anti-AQP4 antibody status. These findings suggest that T cells are stimulated in vivo against major myelin proteins in anti-AQP4 antibody-positive patients with NMO/NMO spectrum disorders..
23.	Hikaru Doi, Takuya Matsushita, Noriko Isobe, Takahisa Tateishi, Jun-ichi Kira, Analysis of cerebrospinal fluid cytokines and growth factors in multiple sclerosis patients with and without chronic headaches, NEUROLOGY ASIA, 16, 1, 65-70, 2011.03, Background: We previously reported that, in Japanese patients with multiple sclerosis (MS), the frequency of chronic headaches was significantly higher after administration of interferon beta (IFN beta). However, the mechanisms underlying IFN beta-related chronic headaches were unknown. Objective: To clarify the mechanisms underlying IFN beta-induced chronic headaches in MS patients by analyzing cytokine levels in cerebrospinal fluid (CSF). Methods: We measured the levels of 27 CSF cytokines and growth factors using a fluorescent bead-based immunoassay, during a headache-free period, in 34 MS patients enrolled in our previous survey on chronic headaches. Results: There were no significant differences in CSF cytokine levels between the 21 MS patients with chronic headaches and the 13 without chronic headaches. Among the 14 patients receiving IFN beta therapy, the 5 patients with chronic headaches showed significantly lower levels of interleukin (IL) 15, IL17 and chemokine (C-C motif) ligand 2 (CCL2) (also known as monocyte chemoattractant protein 1; MCP1) compared with the 9 patients without chronic headaches (P < 0.05). Conclusions: The present survey revealed that in MS, chronic headache sufferers on IFN beta therapy had decreased levels of IL15, IL17 and CCL2 in CSF. This suggests that chronic headaches may tend to develop in good responders to IFN beta..
24.	Yuji Kawano, Takuya Matsushita, Yi Wen Cui, Noriko Isobe, Satoshi Yoshimura, Tomomi Yonekawa, Katsuhisa Masaki, Ryo Yamasaki, Hiroyuki Murai, Jun-Ichi Kira, Protein kinase C-η polymorphism rs2230500 does not confer disease susceptibility to multiple sclerosis or neuromyelitis optica, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12056, 4, 3, 283-287, 2013.12, Objectives To determine whether the non-synonymous 1425G/A polymorphism (rs2230500), an Asian-specific single nucleotide polymorphism that increases the kinase activity and affects the function of immune cells, of the protein kinase C-η gene (PRKCH) confers the risk of developing idiopathic demyelinating diseases of the central nervous system in a Japanese population. Methods Blood samples were collected from 96 multiple sclerosis (MS) patients, 52 neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) patients and 151 healthy controls. The polymorphism rs2230500 was genotyped by sequencing. Results No significant association was observed between the PRKCH rs2230500 polymorphism and the risk of either MS or NMO/NMOSD. Clinical characteristics were also unaffected by the rs2230500 status. Conclusions Although the possibility that PRKCH has some effect on MS and NMO/NMOSD risk cannot be completely excluded because of the small study sample size, the polymorphism rs2230500 did not appear to confer disease susceptibility to MS or NMO/NMOSD in this Japanese population. © 2013 Japanese Society for Neuroimmunology..
25.	Jian Huang, Noriko Isobe, Takuya Matsushita, Satoshi Yoshimura, Shinya Sato, Tomomi Yonekawa, Ryo Yamasaki, Hiroyuki Murai, Jun-Ichi Kira, Distinct genetic profiles between Japanese multiple sclerosis patients with and without Barkhof brain lesions, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12017, 4, 2, 173-180, 2013.08, Objectives The frequency of brain lesions that fulfil the Barkhof criteria (Barkhof brain lesions) is low in Asian patients with multiple sclerosis (MS). Several genes are associated with MS in the Japanese, but their influence on brain lesion development is unknown. Here, we clarified the genetic profiles of Barkhof brain lesion-positive and -negative MS in the Japanese. Methods We genotyped the HLA-DRB1 and -DPB1 alleles, the NOTCH4 missense mutation rs422951, and the IL-7RA single nucleotide polymorphism rs6897932 in 123 non-neuromyelitis optica/neuromyelitis optica spectrum disorder MS patients and 367 healthy controls by annealing of sequence-specific oligonucleotide probes to polymerase chain reaction-amplified genomic DNA (for the HLA alleles), DNA sequencing (for rs422951), and real-time polymerase chain reaction using TaqMan genotyping assays (for rs6897932). Results Compared with the healthy controls, the frequency of DRB10405 was significantly higher in the Barkhof brain lesion-negative group, that of DPB10301 was significantly higher in the Barkhof brain lesion-positive group, and those of DRB10901 and DPB10401 were significantly lower in the Barkhof brain lesion-positive group. The frequency of NOTCH4 rs422951 G allele carriers was significantly lower in both groups compared with the healthy controls, whereas the frequency of the IL-7RA rs6897932 CC genotype was significantly higher in the Barkhof brain lesion-positive group. Haplotype analyses identified one susceptibility and three resistance haplotypes for Barkhof brain lesion-positive MS, and two susceptibility and three resistance haplotypes for Barkhof brain lesion-negative MS. Conclusions The genetic profiles of Japanese MS patients are distinct according to the presence or absence of Barkhof brain lesions. © 2013 Japanese Society for Neuroimmunology..
26.	Yi Wen Cui, Yuji Kawano, Nan Shi, Katsuhisa Masaki, Noriko Isobe, Tomomi Yonekawa, Takuya Matsushita, Takahisa Tateishi, Ryo Yamasaki, Hiroyuki Murai, Jun-Ichi Kira, Alterations in chemokine receptor expressions on peripheral blood monocytes in multiple sclerosis and neuromyelitis optica, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12039, 4, 2, 201-205, 2013.08, Objectives Human peripheral blood monocytes comprise three different subtypes: CD14+CD16- (classical type), CD14lowCD16+ (non-classical type) and CD14+CD16+ (intermediate type). These subsets are known to have different functions, but little is known about their roles in multiple sclerosis (MS), especially for maintaining remission. We aimed to clarify the alterations in monocyte subsets in patients with MS and neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) in the remission phase. Methods Blood samples were collected from 19 MS patients and 10 NMO/NMOSD patients in the remission phase, and 42 healthy controls (HC). The surface expressions of CCR2, CX3CR1, CD64 (FcγR1) and CD62L were analyzed in the monocyte subsets by flow cytometry. Results CCR2 expression was significantly decreased in classical monocytes from MS patients, regardless of interferon-β (IFN-β) treatment, but not in those from NMO/NMOSD patients. CX3CR1 expression was also decreased in all monocyte subsets from MS patients receiving IFN-β, whereas CX3CR1 expression in classical monocytes was only decreased in NMO/NMOSD patients receiving prednisolone. In NMO/NMOSD patients on prednisolone, the percentages of CD14+CD16+ intermediate monocytes, CD14lowCD16+ non-classical monocytes and CD64+CD14+CD16+ monocytes among total monocytes were significantly lower than in HC. CD62L expression on the monocyte subsets showed no significant differences among the patients and HC. Conclusions Our findings suggest that alterations in chemokine receptor expressions on peripheral blood monocytes can occur in MS and NMO/NMOSD during the remission phase. Down-modulation of CCR2 in MS, and CX3CR1 in MS and NMO/NMOSD could partly contribute to sustained remission by preventing monocyte infiltration into the central nervous system. © 2013 Japanese Society for Neuroimmunology..
27.	Noriko Isobe, Tomomi Yonekawa, Takuya Matsushita, Yuji Kawano, Katsuhisa Masaki, Satoshi Yoshimura, Hiroyuki Murai, Ryo Yamasaki, Jun-Ichi Kira, Distinct features of immunoglobulin G2 aquaporin-4 antibody carriers with neuromyelitis optica, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12179, 6, 2, 154-158, 2015.05, Objective Neuromyelitis optica (NMO) is an inflammatory disease in which NMO-immunoglobulin G (IgG) targeting aquaporin-4 (AQP4) is specifically detected. Although the main subclass of AQP4 antibody was reported to be in the IgG1 subclass, other subclasses have also been described, including IgG2 AQP4 antibody, as a second common subclass. NMO patients were analyzed to clarify the clinical features of NMO patients with IgG2 AQP4 antibody. Methods Serum samples from 58 NMO patients, who met the revised 2006 criteria for NMO, were analyzed for AQP4 antibody subclass expression using an established flow cytometric assay, and clinical features were compared according to the main AQP4 antibody subclasses. Results A total of 50 patients (86.2%) had IgG1 AQP4 antibodies, while eight (13.8%) expressed IgG2 AQP4 antibody as the main subclass. Those eight individuals exhibited younger age of onset (P = 0.0089), lower AQP4 antibody titers (P = 0.0024) and a more common fulfillment of Barkhof's criteria (P = 0.0466) than patients with IgG1 AQP4 antibody expression. Conclusions Results from the present study suggest that the characteristics of individuals with IgG2 AQP4 antibody as a main subclass are more similar to multiple sclerosis and somewhat distinct from NMO patients with IgG1 AQP4 antibody..
28.	基礎疾患なく雷鳴頭痛とposterior reversible encephalopathy syndrome(PRES)を発症し、経過中可逆性の脳血管攣縮をみとめた1例症例は56歳女性である。雷鳴頭痛を主訴に当院へ救急搬送されるも、頭部CT、髄液検査で異常なく帰宅した。しかし数日後、ふたたび雷鳴頭痛が出現し当院へ搬送され、来院時左下肢の痙攣をみとめた。MRIにて両側後頭葉を中心にADC値上昇をともなうT2延長領域をみとめ、posterior reversible encephalopathy syndrome(PRES)と診断した。高血圧や免疫抑制剤の使用歴はなかった。MRAにて両側後大脳動脈を中心に脳血管攣縮をみとめたため、Ca拮抗薬を投与し、約2週間でMRI所見と共にMRA所見も改善し、ほぼ後遺症なく回復した。雷鳴頭痛およびPRESの発症に、脳血管攣縮が強く関与していることが示唆された。(著者抄録).
29.	Jun-Ichi Kira, Noriko Isobe, Yuji Kawano, Manabu Osoegawa, Yasumasa Ohyagi, Futoshi Mihara, Hiroyuki Murai, Atopic myelitis with focal amyotrophy: a possible link to Hopkins syndrome., Journal of the neurological sciences, 10.1016/j.jns.2008.01.009, 269, 1-2, 143-51, 2008.06, Among 22 consecutive patients with myelitis, of unknown etiology, and atopic diathesis (atopic myelitis) who from April 2002 to March 2006 had been studied in our clinic, 5 (23%) showed focal amyotrophy in one or two limbs. These 5 patients were subjected to combined clinical, electrophysiological, neuroimaging and immunological studies. Ages were 18 to 58-years-old (average 39). Four showed amyotrophy of unilateral or bilateral upper limbs while one showed amyotrophy in both thighs. All patients showed on-going denervation potentials in the affected muscles, while motor conduction study including F wave was normal except for in one patient who showed prolonged F wave latency in one nerve. Two had localized high signal intensity lesions involving anterior horns on spinal cord MRI and three showed abnormalities suggesting pyramidal tract involvement on motor evoked potentials. All had a present and/or past history of atopic disorders and specific IgE against common environmental allergens, such as mite antigens and cedar pollens, and four showed mild eosinophilia, all of which were compatible with atopic myelitis. When clinical and laboratory findings were compared between atopic myelitis with (n=5) or without focal amyotrophy (n=17), the former showed a significantly higher frequency of present and past history of asthma (80% vs. 24%, p=0.0393) and tended to have higher EDSS scores (3.8+/-1.6 vs. 3.1+/-1.4). Two patients showed mild to moderate improvements after immunotherapies such as methylprednisolone pulse therapy or plasma exchange, while two recovered with low dose corticosteroids and one without treatment had a gradually progressive course. Although atopic myelitis preferentially involves the posterior column of the cervical spinal cord, it is possible that anterior horn cells are affected in some cases of atopic myelitis, especially in patients with asthma. This suggests a possible link between atopic myelitis and Hopkins syndrome (asthmatic amyotrophy)..
30.	Noriko Kuroki, Yasumasa Ohyagi, Yuji Kawano, Takashi Yoshiura, Takayuki Taniwaki, Jun-ichi Kira, Acute onset facial numbness., Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 15, 9, 1049, 1077, 2008.09.
31.	Akihiro Watanabe, Takuya Matsushita, Hikaru Doi, Takashi Matsuoka, Hiroshi Shigeto, Noriko Isobe, Yuji Kawano, Shozo Tobimatsu, Jun-ichi Kira, Multimodality-evoked potential study of anti-aquaporin-4 antibody-positive and -negative multiple sclerosis patients., Journal of the neurological sciences, 10.1016/j.jns.2009.02.371, 281, 1-2, 34-40, 2009.06, Neuromyelitis optica (NMO) is claimed to be a distinct disease entity from multiple sclerosis (MS) because of its strong association with NMO-IgG/anti-AQP4 antibody; however, the in vivo role of the antibody remains unknown. Therefore, we aimed to clarify whether the presence of anti-AQP4 antibody is associated with any abnormalities in multimodality-evoked potentials in 111 patients with relapsing-remitting or relapsing-progressive MS, including the opticospinal form of MS, 18 of whom were seropositive for anti-AQP4 antibody. More patients with anti-AQP4 antibody showed a lack of the P100 component on visual-evoked potentials (VEPs) than those without the antibody (11/17, 64.7% vs. 20/84, 23.8%, p=0.003), whereas the frequency of delayed P100 latency was significantly higher in the latter group than in the former (1/17, 5.9% vs. 28/84, 33.3%, p=0.021). The frequencies of non-responses and delayed central sensory conduction times in median and posterior tibial nerve somatosensory-evoked potentials (SEPs) were not significantly different between anti-AQP4 antibody-positive and -negative patients. In terms of upper and lower limb motor-evoked potentials (MEPs), the frequencies of non-responses and delayed central motor conduction times did not differ significantly based on the presence or absence of anti-AQP4 antibody. The frequency of optic nerve lesions on MRI was significantly higher in anti-AQP4 antibody-positive patients than in anti-AQP4 antibody-negative patients (p=0.0137). Multiple logistic analyses revealed that anti-AQP4 antibody positivity (OR=8.406, p=0.02) and unevoked VEP responses (OR=35.432, p
32.	Wei Li, Motozumi Minohara, Hua Piao, Takuya Matsushita, Katsuhisa Masaki, Takeshi Matsuoka, Noriko Isobe, Jen Jen Su, Yasumasa Ohyagi, Jun-ichi Kira, Association of anti-Helicobacter pylori neutrophil-activating protein antibody response with anti-aquaporin-4 autoimmunity in Japanese patients with multiple sclerosis and neuromyelitis optica., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458509348961, 15, 12, 1411-21, 2009.12, There are two distinct subtypes of multiple sclerosis (MS) in Asians: opticospinal (OSMS) and conventional (CMS). OSMS has similar features to neuromyelitis optica (NMO) and half of OSMS patients have the NMO-Immunoglobulin G (IgG)/ anti-aquaporin-4 (AQP4) antibody. We reported that Helicobacter pylori (H. pylori) infection was significantly less common in CMS patients than controls. To reveal the immune responses to the H. pylori neutrophil-activating protein (HP-NAP) in Japanese MS patients, according to anti-AQP4 antibody status, sera from 162 MS patients, 37 patients with other inflammatory neurological diseases (OIND), and 85 healthy subjects were assayed for anti-H. pylori antibodies, anti-HP-NAP antibodies, and myeloperoxidase (MPO) by enzyme immunoassays. H. pylori seropositivity rates were significantly higher in anti-AQP4 antibody-positive MS/NMO (AQP4 + /MS) patients (19/27, 70.4%) than anti-AQP4 antibody-negative CMS (AQP4 - /CMS) patients (22/83, 26.5%). Among H. pylori-infected individuals, the anti-HP-NAP antibody was significantly more common in AQP4 + /MS and AQP4 - /OSMS patients than healthy subjects (36.8%, 34.6% versus 2.8%). Among the AQP4 + /MS patients, a significant positive correlation between anti-HP-NAP antibody levels and the final Kurtzke's Expanded Disability Status Scale scores was found, and MPO levels were higher in anti-HP-NAP antibody-positive patients than anti-HP-NAP antibody-negative ones. Therefore, HP-NAP may be associated with the pathology of anti-AQP4 antibody-related neural damage in MS/NMO patients..
33.	特発性血小板減少性紫斑病に関連した多発単神経障害の1例症例は78歳男性。某年7月、左前腕に紫斑が出現。血小板数1.1万/μl、血小板関連自己抗体陽性であり、特発性血小板減少性紫斑病と診断された。翌月初旬より左手指および左下腿の脱力と異常感覚、両下腿外側の異常感覚が出現した。来院時所見では、左尺骨神経領域の感覚障害と筋力低下、両側浅腓骨神経領域の感覚障害、左前脛骨筋の筋力低下をみとめ多発単神経障害の病像を呈していた。ステロイド治療による血小板数の増加とともに脱力、感覚障害も改善した。特発性血小板減少性紫斑病に関連した多発単神経障害と考えられ、免疫学的機序による障害が推察された。(著者抄録).
34.	Takuya Matsushita, Noriko Isobe, Hua Piao, Takeshi Matsuoka, Takaaki Ishizu, Hikaru Doi, Katsuhisa Masaki, Takashi Yoshiura, Ryo Yamasaki, Yasumasa Ohyagi, Jun-Ichi Kira, Reappraisal of brain MRI features in patients with multiple sclerosis and neuromyelitis optica according to anti-aquaporin-4 antibody status., Journal of the neurological sciences, 10.1016/j.jns.2010.01.009, 291, 1-2, 37-43, 2010.04, Brain lesions are not uncommon in neuromyelitis optica (NMO) patients with anti-aquaporin-4 (AQP4) antibody; however, the appearance of these lesions is said to be different from that of those in Western patients with multiple sclerosis (MS). To clarify the similarities and dissimilarities of brain lesions in anti-AQP4 antibody-positive and -negative MS and NMO patients, we examined the presence of anti-AQP4 antibody in the sera of 148 consecutive patients fulfilling Poser's criteria for clinically definite MS, of whom 38 also met the revised NMO criteria, using an immunofluorescence method, and analyzed brain lesions by magnetic resonance imaging (MRI). Brain lesions fulfilling the Barkhof criteria were significantly more common in 121 patients without anti-AQP4 antibody than in 27 patients with anti-AQP4 antibody (57.0% vs. 33.3%, P=0.033), while the frequency of those that met the Paty criteria was not different between the two groups (74.4% vs. 73.5%). Ovoid lesions were detected more commonly in patients without anti-AQP4 antibody than in those with the antibody (72.3% vs. 48.2%, P=0.022). The anti-AQP4 antibody-positive patients had significantly more atypical brain lesions, such as extensive brain lesions, than the anti-AQP4 antibody-negative ones (18.5% vs. 1.7%, P=0.0023). Thus, although MS-like brain lesions are more common in anti-AQP4 antibody-negative patients than anti-AQP4 antibody-positive patients, approximately 30 to 50% of patients with anti-AQP4 antibody harbour brain MRI lesions indistinguishable from those present in typical MS patients, such as periventricular ovoid lesions, suggesting the existence of considerable overlap in brain MRI features between anti-AQP4 antibody-positive and -negative Asian patients. In the present study, NMO patients with brain lesions showed a significantly higher annualized relapse rate (P(corr)=0.017) and higher frequency of anti-AQP4 antibody (P(corr)
35.	Non-NMO MSとNMOにおけるHLA-DRB1アリル間のepistatic interaction解析.
36.	Non-NMO MSとNMOにおけるHLA-DRB1アリル間のepistatic interaction解析.
37.	Takahisa Tateishi, Ryo Yamasaki, Masahito Tanaka, Takuya Matsushita, Hitoshi Kikuchi, Noriko Isobe, Yasumasa Ohyagi, Jun-ichi Kira, CSF chemokine alterations related to the clinical course of amyotrophic lateral sclerosis., Journal of neuroimmunology, 10.1016/j.jneuroim.2010.03.004, 222, 1-2, 76-81, 2010.05, We measured the levels of 27 cytokines/chemokines and growth factors in cerebrospinal fluid (CSF) from 42 patients with sporadic amyotrophic lateral sclerosis (ALS), 12 patients with lower motor neuron disease (LMND), and 34 control patients with non-inflammatory neurological diseases (OND), using a multiplexed fluorescent bead-based immunoassay. Among cytokines/chemokines elevated in ALS, CCL2 and CXCL8 levels were negatively correlated with the revised ALS functional rating scale (ALSFRS-R) score, while CCL4 showed a positive correlation with ALSFRS-R score. CCL4 and CXCL10 showed negative correlations with disease progression rate. These chemokine alterations are assumed to somehow correlate with the clinical course of ALS..
38.	Satoshi Yoshimura, Hirofumi Ochi, Noriko Isobe, Takuya Matsushita, Kyoko Motomura, Takeshi Matsuoka, Motozumi Minohara, Jun-ichi Kira, Altered production of brain-derived neurotrophic factor by peripheral blood immune cells in multiple sclerosis., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458510375706, 16, 10, 1178-88, 2010.10, BACKGROUND: Within multiple sclerosis lesions, brain-derived neurotrophic factor is detected in neurons and immunocytes. OBJECTIVE: To clarify brain-derived neurotrophic factor production by peripheral blood immunocytes and its relationship with clinical parameters in multiple sclerosis. METHODS: Serum brain-derived neurotrophic factor levels were measured by conventional enzyme-linked immunosorbent assay while brain-derived neurotrophic factor production by immunocytes was determined by an in situ enzyme-linked immunosorbent assay in 74 multiple sclerosis patients, 32 healthy controls, and 86 patients with other neurological diseases. The tyrosine kinase receptor TrkB expression level in peripheral blood mononuclear cells was measured by real-time polymerase chain reaction. RESULTS: Multiple sclerosis patients showed significantly higher serum brain-derived neurotrophic factor levels than healthy controls and patients with other neurological diseases. Multiple sclerosis patients with high brain-derived neurotrophic factor levels were younger, and showed fewer relapse numbers than those with low brain-derived neurotrophic factor levels. Brain-derived neurotrophic factor production by T cells increased with age in healthy controls, but not in multiple sclerosis patients. Interferon beta induced a significant increase in serum brain-derived neurotrophic factor levels. Brain-derived neurotrophic factor production from T cells and TrkB expression levels in peripheral blood mononuclear cells were significantly enhanced in interferon beta-treated multiple sclerosis patients compared with untreated ones. CONCLUSIONS: A high brain-derived neurotrophic factor level is related to early mild disease in young multiple sclerosis patients. Interferon beta potentiates brain-derived neurotrophic factor production and brain-derived neurotrophic factor receptor expression in peripheral blood mononuclear cells, which may act beneficially..
39.	Koji Shinoda, Takuya Matsushita, Konosuke Furuta, Noriko Isobe, Tomomi Yonekawa, Yasumasa Ohyagi, Jun-ichi Kira, Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome in a patient with neuromyelitis optica spectrum disorder and anti-aquaporin-4 antibody., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458510391690, 17, 7, 885-7, 2011.07, This report describes, for the first time, an occurrence of wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) in a 19-year-old female with neuromyelitis optica (NMO) spectrum disorder, who had anti-aquaporin-4 (AQP4) antibody. A high signal intensity lesion on T2-weighted MRI was detected in the midbrain tegmentum adjacent to the aqueduct, and presumably involved the medial longitudinal fasciculus bilaterally at the caudal levels. Plasma exchange resolved both WEBINO syndrome and the midbrain lesion. Although WEBINO syndrome is occasionally reported in multiple sclerosis patients, diagnosis of NMO should not be excluded in patients with WEBINO syndrome, because AQP4 is expressed abundantly around the periaqueductal region..
40.	Satoshi Yoshimura, Noriko Isobe, Takuya Matsushita, Tomomi Yonekawa, Katsuhisa Masaki, Jun-ichi Kira, Common and Distinct Associations of HLA-DRB1 and-DPB1 Alleles with Neuromyelitis Optica and Multiple Sclerosis in Japanese, ANNALS OF NEUROLOGY, 70, S45-S46, 2011.10.
41.	Hiroyuki Murai, Natsumi Yamashita, Makoto Watanabe, Yoshiko Nomura, Masakatsu Motomura, Hiroaki Yoshikawa, Yosikazu Nakamura, Naoki Kawaguchi, Hiroshi Onodera, Shigeru Araga, Noriko Isobe, Masaki Nagai, Jun-ichi Kira, Characteristics of myasthenia gravis according to onset-age: Japanese nationwide survey., Journal of the neurological sciences, 10.1016/j.jns.2011.03.004, 305, 1-2, 97-102, 2011.06, OBJECTIVE: To clarify the prevalence and clinical characteristics of myasthenia gravis (MG) in Japan. METHODS: We performed a nationwide epidemiological survey of MG in Japan. The clinical features were compared among five groups of patients, divided according to onset age. A generalized additive model (GAM) was used to assess the linearity of these relationships. RESULTS: A total of 8542 patients were reported, and detailed data were analyzed for 3141 patients. The estimated number of MG patients in Japan was 15,100, giving a prevalence of 11.8 per 100,000. Elderly-onset MG (≥ 65 years) accounted for 7.3% in 1987 (adjusted for population in 2005), but this had increased to 16.8% in 2006. Infantile-onset MG (0-4 years) accounted for 10.1% in 1987, and was still as high as 7.0% in 2006. The rate of ocular MG was highest (80.6%) in infantile-onset and lowest (26.4%) in early-onset disease, but the rate rose again in the late-onset group. GAM analysis of the ocular form showed a U-shaped curve, with a dip in the 20s. Anti-acetylcholine receptor antibodies were positive in only 50% of infantile-onset, but nearly 90% of elderly-onset patients. GAM analyses assessing the concurrence of thymoma and hyperplasia both showed reversed U-shapes, with peaks in the 50s and 20s-40s, respectively. CONCLUSIONS: Persistent high incidence of infantile-onset disease and clinical heterogeneity according to onset age are characteristic features of MG in Japan..
42.	Noriko Isobe, Tomomi Yonekawa, Takuya Matsushita, Yuji Kawano, Katsuhisa Masaki, Satoshi Yoshimura, Jakub Fichna, Shu Chen, Jadwiga Furmaniak, Bernard Rees Smith, Jun-ichi Kira, Quantitative assays for anti-aquaporin-4 antibody with subclass analysis in neuromyelitis optica., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458512443917, 18, 11, 1541-51, 2012.11, BACKGROUND: To clarify the clinical relevance of anti-aquaporin-4 (anti-AQP4) antibody titers and immunoglobulin (IgG) subclass. METHODS: Using a bridging enzyme-linked immunosorbent assay (ELISA), a flow cytometric assay (FCMA) and an immunofluorescence assay (IFA) for anti-AQP4 antibodies, sera from 142 patients with multiple sclerosis (MS) as defined by the McDonald criteria (2005), 29 with neuromyelitis optica (NMO) who fulfilled the 1999 criteria, 19 with recurrent and/or longitudinally extensive myelitis (RM/LM), 86 with other non-inflammatory neurological diseases (OND) and 28 healthy controls (HC) were studied. RESULTS: Anti-AQP4 antibody positivity rates by IFA, FCMA, and ELISA were 41.4%, 51.7% and 48.3%, respectively, in NMO (1999) patients, and 0% in the OND and HC groups. Twenty-six MS patients (18.3%) were positive for the antibody; 17 met the 2006 NMO criteria, including positivity for anti-AQP4 antibody, and five had longitudinally extensive myelitis (LM). Among the cases with anti-AQP4 antibody detected by FCMA, IgG1, 2, 3, and 4 anti-AQP4 antibodies were found in 97.8%, 37.0%, 6.5% and 6.5% respectively. There was no association of either antibody positivity or level of anti-AQP4 antibody IgG subclasses with clinical parameters after adjustment of p values for multiple comparisons. CONCLUSIONS: FCMA and bridging ELISA are useful for detecting and quantifying anti-AQP4 antibodies..
43.	Shinya Sato, Noriko Isobe, Satoshi Yoshimura, Yuji Kanamori, Katsuhisa Masaki, Takuya Matsushita, Jun-Ichi Kira, HLA-DPB10201 is associated with susceptibility to atopic myelitis in Japanese., Journal of neuroimmunology, 10.1016/j.jneuroim.2012.07.007, 251, 1-2, 110-3, 2012.10, To determine the relationship between susceptibility to atopic myelitis (AM) and polymorphisms of the human leukocyte antigen (HLA)-DPB1 and -DRB1 alleles, we compared each phenotype frequency between 55 AM patients and 367 unrelated healthy controls in Japan. The HLA-DPB10201 allele was significantly more frequent in AM patients than in healthy controls (54.5% vs. 31.9%, corrected P value=0.0150, odds ratio=2.564, 95% confidence interval=1.444-4.554). Our result suggests that the immunogenetic background of AM differs from that of other CNS autoimmune diseases, such as multiple sclerosis and neuromyelitis optica, which show distinct HLA class II associations..
44.	Noriko Isobe, Yuji Kanamori, Tomomi Yonekawa, Takuya Matsushita, Hiroshi Shigeto, Nobutoshi Kawamura, Jun-ichi Kira, First diagnostic criteria for atopic myelitis with special reference to discrimination from myelitis-onset multiple sclerosis., Journal of the neurological sciences, 10.1016/j.jns.2012.02.007, 316, 1-2, 30-5, 2012.05, OBJECTIVE: To establish the first evidence-based diagnostic criteria for atopic myelitis (AM) enabling it to be discriminated from myelitis-onset multiple sclerosis (MS), which is a difficult differential diagnosis. METHODS: Sixty-nine consecutive AM patients examined from 1996 to 2010 at Kyushu University hospital, who fulfilled the empirical definition of AM (2003), and 51 myelitis-onset MS patients in whom allergen-specific IgE was measured, were enrolled. The first available brain MRI findings were compared between the two. Then, we compared the clinical and laboratory features between the 16 AM cases who did not meet the Barkhof brain MRI criteria for MS after more than 5 years follow-up and 51 myelitis-onset MS cases. Based on the discriminative findings, we established diagnostic criteria for AM and calculated the sensitivity and specificity. RESULTS: AM patients had a significantly lower frequency of Barkhof brain lesions on baseline MRI than myelitis-onset MS patients. AM patients had a significantly higher frequency of present and/or past history of atopic disease and hyperIgEemia, and higher cerebrospinal fluid levels of interleukin 9 and CCL11/eotaxin, but a lower frequency of oligoclonal IgG bands than myelitis-onset MS patients. Our proposed diagnostic criteria for AM demonstrated 93.3% sensitivity and 93.3% specificity for AM against myelitis-onset MS, with 82.4% positive predictive value and 97.7% negative predictive value. CONCLUSION: Our first evidence-based criteria for AM show high sensitivity and specificity, and would be useful clinically..
45.	Katsuhisa Masaki, Satoshi O Suzuki, Takuya Matsushita, Tomomi Yonekawa, Takeshi Matsuoka, Noriko Isobe, Kyoko Motomura, Xiao-Mu Wu, Takeshi Tabira, Toru Iwaki, Jun-ichi Kira, Extensive loss of connexins in Baló's disease: evidence for an auto-antibody-independent astrocytopathy via impaired astrocyte-oligodendrocyte/myelin interaction., Acta neuropathologica, 10.1007/s00401-012-0972-x, 123, 6, 887-900, 2012.06, Extensive aquaporin-4 (AQP4) loss without perivascular deposition of either activated complement or immunoglobulins is a characteristic of Baló's disease. Our aim in this study was to investigate the relationship between astrocytopathy and demyelination in Baló's disease, focusing on connexins (Cx), which form gap junctions among glial cells and myelin. Autopsied specimens from four cases that provided seven actively demyelinating concentric lesions infiltrated with numerous CD68(+) macrophages were immunohistochemically examined for the astrocyte markers glial fibrillary acidic protein (GFAP), AQP4, Cx43, Cx30 and megalencephalic leukoencephalopathy with subcortical cyst 1 (MLC1). Specimens were also stained for oligodendrocyte/myelin markers, namely Cx32, Cx47, myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein (OSP) and Nogo-A. Serum samples from six patients that had undergone magnetic resonance imaging, confirming a diagnosis of Baló's disease, were assayed for the presence of anti-Cx43, -Cx32 and -AQP4 antibodies. Despite the presence of numerous GFAP- and MLC1-positive astrocytes, there was a marked decrease in the levels of Cx43, Cx32 and Cx47. At the leading edges, Cx43 and AQP4 were mostly absent despite positive GFAP, MLC1, Cx32, Cx47, MOG, MAG, and OSP immunoreactivity. Of the six Baló's disease patients, none were positive for anti-Cxs or -AQP4 antibodies. Baló's disease is characterized by extensive loss of Cxs and AQP4, and a lack of auto-antibodies to Cxs and AQP4. Loss of Cx43 and AQP4 in the presence of other oligodendrocyte/myelin proteins at the leading edges suggests the possibility that auto-antibody-independent astrocytopathy may contribute to disease pathology via the disruption of astrocyte-oligodendrocyte/myelin interactions..
46.	Satoshi Yoshimura, Tomomi Yonekawa, Noriko Isobe, Katsuhisa Masaki, Shinya Satou, Takuya Matsushita, Jun-ichi Kira, Distinct Genetic and Infectious Profiles between Multiple Sclerosis and Neuromyelitis Optica in Japanese Patients, NEUROLOGY, 78, 2012.04.
47.	Riwanti Estiasari, Takuya Matsushita, Katsuhisa Masaki, Takuya Akiyama, Tomomi Yonekawa, Noriko Isobe, Jun-ichi Kira, Comparison of clinical, immunological and neuroimaging features between anti-aquaporin-4 antibody-positive and antibody-negative Sjogren's syndrome patients with central nervous system manifestations., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458511431727, 18, 6, 807-16, 2012.06, BACKGROUND AND OBJECTIVE: The objective of this study is to clarify clinical, immunological, and neuroimaging features in anti-aquaporin-4 (AQP4) antibody-positive and antibody-negative Sjögren's syndrome (SS) patients with central nervous system (CNS) involvement. METHODS: Medical records and MRI scans were retrospectively analyzed in 22 consecutive SS patients with CNS manifestations. RESULTS: Seven (31.8%) patients were positive for anti-AQP4 antibodies. The frequency of visual impairment was higher in anti-AQP4 antibody-positive patients than in antibody-negative patients (71.4% vs. 0.0%, p = 0.0008). Brain MRI showed that discrete lesions were more commonly found in the cerebrum, brainstem, and optic nerve in anti-AQP4 antibody-positive patients than in antibody-negative patients (p = 0.002, p = 0.006, and p = 0.004, respectively), while spinal cord MRI showed that posterior column lesions in the cervical spinal cord were more frequent in anti-AQP4 antibody-positive patients than in antibody-negative patients (71.4% vs. 14.3%, p = 0.01). SS-A antibody titers were higher in anti-AQP4 antibody-positive patients than in antibody-negative patients (p = 0.012) and were also higher in patients with longitudinally extensive spinal cord lesions (LESCLs) than in those without LESCLs (p = 0.019). CONCLUSIONS: In SS, the presence of anti-AQP4 antibodies is associated with involvement of the optic nerve, cerebrum and brainstem, and with cervical posterior column lesions in the spinal cord..
48.	Gulibahaer Ainiding, Ken-ichiro Yamashita, Takako Torii, Konosuke Furuta, Noriko Isobe, Takuya Matsushita, Katsuhisa Masaki, Shoji Matsumoto, Jun-ichi Kira, Clinical disability progression and platelet GP IIb/IIIa values in patients with atopic myelitis., Journal of neuroimmunology, 10.1016/j.jneuroim.2012.03.009, 246, 1-2, 108-12, 2012.05, We aimed to clarify the disability progression and platelet aggregative function in atopic myelitis (AM). Seventeen AM patients and 35 healthy controls were subjected to clinico-allergological evaluations and glycoprotein IIb/IIIa (GP IIb/IIIa) measurements using a VerifyNow assay system. In AM patients, the disease duration had significant positive correlations with the Kurtzke Expanded Disability Status Scale scores and Sensory Functional Scale scores. The GP IIb/IIIa values were significantly higher in AM patients than in controls as well as in females compared with males. AM is essentially a progressive disease affecting the sensory system, and involves an increased platelet aggregative function..
49.	Noriko Isobe, Pierre-Antoine Gourraud, Hanne F Harbo, Stacy J Caillier, Adam Santaniello, Pouya Khankhanian, Martin Maiers, Stephen Spellman, Nezih Cereb, SooYoung Yang, Marcelo J Pando, Laura Piccio, Anne H Cross, Philip L De Jager, Bruce A C Cree, Stephen L Hauser, Jorge R Oksenberg, Genetic risk variants in African Americans with multiple sclerosis., Neurology, 10.1212/WNL.0b013e31829bfe2f, 81, 3, 219-27, 2013.07, OBJECTIVES: To assess the association of established multiple sclerosis (MS) risk variants in 3,254 African Americans (1,162 cases and 2,092 controls). METHODS: Human leukocyte antigen (HLA)-DRB1, HLA-DQB1, and HLA-A alleles were typed by molecular techniques. Single nucleotide polymorphism (SNP) genotyping was conducted for 76 MS-associated SNPs and 52 ancestry informative marker SNPs selected throughout the genome. Self-declared ancestry was refined by principal component analysis of the ancestry informative marker SNPs. An ancestry-adjusted multivariate model was applied to assess genetic associations. RESULTS: The following major histocompatibility complex risk alleles were replicated: HLA-DRB115:01 (odds ratio [OR] = 2.02 [95% confidence interval: 1.54-2.63], p = 2.50e-07), HLA-DRB103:01 (OR = 1.58 [1.29-1.94], p = 1.11e-05), as well as HLA-DRB104:05 (OR = 2.35 [1.26-4.37], p = 0.007) and the African-specific risk allele of HLA-DRB115:03 (OR = 1.26 [1.05-1.51], p = 0.012). The protective association of HLA-A*02:01 was confirmed (OR = 0.72 [0.55-0.93], p = 0.013). None of the HLA-DQB1 alleles were associated with MS. Using a significance threshold of p
50.	Satoshi Yoshimura, Noriko Isobe, Takuya Matsushita, Tomomi Yonekawa, Katsuhisa Masaki, Shinya Sato, Yuji Kawano, Jun-ichi Kira, Distinct genetic and infectious profiles in Japanese neuromyelitis optica patients according to anti-aquaporin 4 antibody status., Journal of neurology, neurosurgery, and psychiatry, 10.1136/jnnp-2012-302925, 84, 1, 29-34, 2013.01, OBJECTIVE: To clarify whether genetic and common infectious backgrounds are distinct, according to anti-aquaporin 4 (AQP4) antibody status in Japanese patients with neuromyelitis optica (NMO). METHODS: We analysed human leucocyte antigen (HLA)-DRB1 and HLA-DPB1 alleles, and IgG antibodies against Helicobacter pylori, Chlamydia pneumoniae, varicella zoster virus and Epstein-Barr virus nuclear antigen (EBNA) in 116 patients with NMO, including 39 patients with neuromyelitis optica spectrum disorder (NMOSD), 145 multiple sclerosis (MS) patients and 367 unrelated healthy controls. 77 NMO/NMOSD patients were seropositive for AQP4 antibody while 39 were seronegative. RESULTS: Compared with healthy controls, NMO/NMOSD patients showed a significantly lower frequency of DRB10901 and significantly higher frequencies of DRB11602 and DPB10501, which conferred susceptibility to anti-AQP4 antibody positive NMO/NMOSD, but not antibody negative NMO/NMOSD. DRB10901 was a common protective allele, irrespective of the presence or absence of anti-AQP4 antibody. Anti-H pylori and anti-C pneumoniae antibodies were more commonly detected in anti-AQP4 antibody positive NMO/NMOSD patients than healthy controls. Antibody negative NMO/NMOSD patients did not differ from healthy controls regarding the presence of these antibodies. The presence or absence of antibodies against varicella zoster virus and EBNA did not vary among the groups. The frequencies of antibodies against these four pathogens were not significantly different between MS patients and healthy controls. CONCLUSIONS: Our results suggest that HLA-DRB11602 and DPB10501 alleles and H pylori and Chlamydia pneumonia infection are risk factors only for anti-AQP4 antibody positive NMO/NMOSD but not for anti-AQP4 antibody negative NMO/NMOSD..
51.	Noriko Isobe, Tomomi Yonekawa, Takuya Matsushita, Katsuhisa Masaki, Satoshi Yoshimura, Jakub Fichna, Shu Chen, Jadwiga Furmaniak, Bernard Rees Smith, Jun-Ichi Kira, Clinical relevance of serum aquaporin-4 antibody levels in neuromyelitis optica., Neurochemical research, 10.1007/s11064-013-1009-0, 38, 5, 997-1001, 2013.05, Neuromyelitis optica (NMO) is an inflammatory disease that selectively affects the optic nerves and spinal cord. The discovery of NMO-IgG targeting aquaporin-4 (AQP4) in NMO patients suggested that NMO is a distinct entity, with a fundamentally different etiology from that of multiple sclerosis (MS). Although NMO usually leads to grave disability because of the more severe tissue destruction compared with classical MS, there have been several reports describing a benign form of NMO over a long disease term. NMO-IgG/AQP4 antibodies show high specificity but medium sensitivity for NMO, while the clinical relevance of AQP4 antibody titers remains to be determined. We aimed to clarify the clinical relevance of AQP4 antibody levels determined by a bridging enzyme-linked immunosorbent assay in 38 patients with NMO or NMO spectrum disorder. The AQP4 antibody levels were higher in patients with optic neuritis (ON) than in those without ON (p = 0.0164). Among the 12 patients examined in a longitudinal study, four showed an increase in the ELISA values during some relapses, and eight showed no clear correlation between the ELISA values and relapse. Of the four patients who demonstrated a steady rise in the antibody levels over time, two patients had no concomitant relapses, despite elevation of the AQP4 antibody levels. We conclude that high AQP4 antibody levels are associated with the occurrence of ON, but that the antibody levels themselves are not closely correlated with the onset of relapse..
52.	Jian Huang, Satoshi Yoshimura, Noriko Isobe, Takuya Matsushita, Tomomi Yonekawa, Shinya Sato, Ryo Yamasaki, Jun-ichi Kira, A NOTCH4 missense mutation confers resistance to multiple sclerosis in Japanese., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458513482512, 19, 13, 1696-703, 2013.11, BACKGROUND: The G allele of NOTCH4 rs422951 is protective against demyelinating disease in Japanese. OBJECTIVES: The purpose of this study was to assess the relation of the G allele to neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) and multiple sclerosis (MS) and the interaction between the G allele and HLA-DRB1 alleles, and to clarify any association of the G allele with clinical features. METHODS: DNA sequencing was used to genotype 106 NMO/NMOSD patients, 118 MS patients and 152 healthy controls (HCs) for rs422951. RESULTS: G allele frequency in MS patients, but not that in NMO/NMOSD patients, was lower than that in HCs (8.9% vs 21.7%, p
53.	Hanne F Harbo, Noriko Isobe, Pål Berg-Hansen, Steffan D Bos, Stacy J Caillier, Marte W Gustavsen, Inger-Lise Mero, Elisabeth Gulowsen Celius, Stephen L Hauser, Jorge R Oksenberg, Pierre-Antoine Gourraud, Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458513506503, 20, 6, 660-8, 2014.05, BACKGROUND: Many genetic risk variants are now well established in multiple sclerosis (MS), but the impact on clinical phenotypes is unclear. OBJECTIVE: To investigate the impact of established MS genetic risk variants on MS phenotypes, in well-characterized MS cohorts. METHODS: Norwegian MS patients (n = 639) and healthy controls (n = 530) were successfully genotyped for 61 established MS-associated single nucleotide polymorphisms (SNPs). Data including and excluding Major Histocompatibility Complex (MHC) markers were summed to a MS Genetic Burden (MSGB) score. Study replication was performed in a cohort of white American MS patients (n = 1997) and controls (n = 708). RESULTS: The total human leukocyte antigen (HLA) and the non-HLA MSGB scores were significantly higher in MS patients than in controls, in both cohorts (P
54.	Gulibahaer Ainiding, Yuji Kawano, Shinya Sato, Noriko Isobe, Takuya Matsushita, Satoshi Yoshimura, Tomomi Yonekawa, Ryo Yamasaki, Hiroyuki Murai, Jun-ichi Kira, Interleukin 2 receptor α chain gene polymorphisms and risks of multiple sclerosis and neuromyelitis optica in southern Japanese., Journal of the neurological sciences, 10.1016/j.jns.2013.11.037, 337, 1-2, 147-50, 2014.02, BACKGROUND: Interleukin 2 receptor α subunit (IL2RA) is a genetic risk for multiple sclerosis (MS) in Caucasians. However, the association between MS and IL2RA in Japanese idiopathic demyelinating diseases of the central nervous system has not been examined. OBJECTIVE: To determine whether IL2RA gene polymorphisms confer risks of developing MS or neuromyelitis optica (NMO) in a Japanese population. METHODS: DNA samples were obtained from 115 MS patients, 75 NMO/NMO spectrum disorder (NMOSD) patients, and 238 healthy controls. The single nucleotide polymorphisms (SNPs) rs2104286, rs12722489, and rs7090512 were genotyped by real-time PCR using TaqMan SNP genotyping assays. RESULTS: No significant associations of the three IL2RA SNPs with the development of the diseases were observed. In MS patients only, the annualized relapse rates were significantly higher for the rs2104286-TT genotype than for the non-TT (CT+CC) genotype and for the rs12722489-CC genotype than for the non-CC genotype in females (p = 0.0138 for both), but not in males. CONCLUSIONS: Although the possibility that IL2RA is a risk factor for MS development was not confirmed in this Japanese population, IL2RA gene polymorphisms were able to modify the disease activity in female MS patients, but had no influence on either susceptibility or disease phenotype in NMO/NMOSD patients..
55.	Tomomi Yonekawa, Hiroyuki Murai, Satoshi Utsuki, Takuya Matsushita, Katsuhisa Masaki, Noriko Isobe, Ryo Yamasaki, Mari Yoshida, Susumu Kusunoki, Kiyomi Sakata, Kiyotaka Fujii, Jun-ichi Kira, A nationwide survey of hypertrophic pachymeningitis in Japan., Journal of neurology, neurosurgery, and psychiatry, 10.1136/jnnp-2013-306410, 85, 7, 732-9, 2014.07, OBJECTIVES: To clarify the prevalence, frequent causes and distinct features of hypertrophic pachymeningitis (HP) according to background conditions in a nationwide survey in Japan. METHODS: The study began with a preliminary survey to determine the approximate number of HP patients diagnosed from 1 January 2005 to 31 December 2009, and was followed by a questionnaire survey for clinical and laboratory findings. HP was defined as a condition with thickening of the cranial or spinal dura mater with inflammation, evidenced by MRI or histology. RESULTS: Crude HP prevalence was 0.949/100 000 population. The mean age at onset was 58.3±15.8 years. Among 159 cases for whom detailed data were collated, antineutrophil cytoplasmic antibody (ANCA)-related HP was found in 54 cases (34.0%) and IgG4/multifocal fibrosclerosis (MFS)-related HP in 14 cases (8.8%). Seventy cases (44.0%) were classified as 'idiopathic' and 21 (13.2%) as 'others'. ANCA-related HP cases showed a female preponderance, a higher age of onset, and higher frequencies of otological symptoms and elevated systemic inflammatory biomarkers, but lower frequencies of diplopia compared with idiopathic HP. IgG4/MFS-related HP cases showed a marked male predominance; all had cranial HP while none had isolated spinal HP or decreased sensation. CONCLUSIONS: HP is not extremely rare. ANCA-related HP is the most frequent form, followed by IgG4/MFS-related HP. Both forms have unique features, which may help to differentiate background causes..
56.	Wataru Shiraishi, Shintaro Hayashi, Takashi Kamada, Noriko Isobe, Ryo Yamasaki, Hiroyuki Murai, Yasumasa Ohyagi, Jun-ichi Kira, A case of neuromyelitis optica harboring both anti-aquaporin-4 antibodies and a pathogenic mitochondrial DNA mutation for Leber's hereditary optic neuropathy., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458513513057, 20, 2, 258-60, 2014.02, We report the first case of definite neuromyelitis optica (NMO) with a pathogenic mitochondrial DNA (mtDNA) mutation for Leber's hereditary optic neuropathy (LHON) (G11778A point mutation). A 36-year-old Japanese woman had experienced recurrent neurological symptoms originating from involvements of the optic nerves and spinal cord. She finally lost her bilateral vision, and spastic paraparesis and sensory disturbances below the T6 level remained despite intensive immunotherapies. Brain and spinal magnetic resonance imaging (MRI) revealed T2-high-intensity lesions in the optic nerves and thoracic spinal cord, but no lesions in the brain. A blood examination revealed positivity for both anti-aquaproin-4 antibodies and an LHON mtDNA mutation..
57.	西郷和真, 吉村怜, 泉川友美, 松下拓也, 磯部紀子, 小池敏靖, 宮本勝一, 平野牧人, 田原康玄, 三木哲郎, 北川裕之, 吉良潤一, 楠進, 多発性硬化症の進行はChGn-1多型と関連する(Progression of multiple sclerosis is associated with ChGn-1 polymorphism), 臨床神経学, 55, Suppl., S322-S322, 2015.12.
58.	Dorothee Nickles, Lohith Madireddy, Nihar Patel, Noriko Isobe, Bruce L Miller, Sergio E Baranzini, Joel H Kramer, Jorge R Oksenberg, Whole genome sequences of 2 octogenarians with sustained cognitive abilities., Neurobiology of aging, 10.1016/j.neurobiolaging.2014.11.003, 36, 3, 1435-8, 2015.03, Although numerous genetic variants affecting aging and mortality have been identified, for example, apolipoprotein E ε4, the genetic component influencing cognitive aging has not been fully defined yet. A better knowledge of the genetics of aging will prove helpful in understanding the underlying biological processes. Here, we describe the whole genome sequences of 2 female octogenarians. We provide the repertoire of genomic variants that the 2 octogenarians have in common. We also describe the overlap with the previously reported genomes of 2 supercentenarians—individuals aged ≥110 years. We assessed the genetic disease propensities of the octogenarians and non-aged control genomes and could not find support for the hypothesis that long-lived healthy individuals might exhibit greater genetic fitness than the general population. Furthermore, there is no evidence for an accumulation of previously described variants promoting longevity in the 2 octogenarians. These findings suggest that genetic fitness, as currently defined, is not the sole factor enabling an increased life span. We identified a number of healthy-cognitive-aging candidate genetic loci awaiting confirmation in larger studies..
59.	Masaaki Niino, Shinya Sato, Toshiyuki Fukazawa, Satoshi Yoshimura, Shin Hisahara, Takuya Matsushita, Noriko Isobe, Kazuto Yoshida, Hideki Houzen, Yusei Miyazaki, Shun Shimohama, Seiji Kikuchi, Jun-ichi Kira, Latitude and HLA-DRB1 alleles independently affect the emergence of cerebrospinal fluid IgG abnormality in multiple sclerosis., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458514560924, 21, 9, 1112-20, 2015.08, BACKGROUND: It is unclear whether the prevalence of oligoclonal IgG bands (OCBs) in multiple sclerosis (MS) is different between northern and southern regions of Asia. OBJECTIVE: This study aimed to compare the prevalence of OCBs and positive cerebrospinal fluid (CSF) findings between northern and southern regions of Japan and to investigate the association of these CSF findings with HLA-DRB1 alleles. METHODS: The study included 180 MS patients from Hokkaido (northern Japan) and 184 patients from Kyushu (southern Japan). The IgG index was defined as increased if it was >0.658. Presence of CSF OCBs and/or increased IgG index was defined as positive CSF findings. RESULTS: Positive CSF findings and OCB positivity were significantly higher in MS patients from Hokkaido than in those from Kyushu (p
60.	Shinya Sato, Ken Yamamoto, Takuya Matsushita, Noriko Isobe, Yuji Kawano, Kyoko Iinuma, Masaaki Niino, Toshiyuki Fukazawa, Yuri Nakamura, Mitsuru Watanabe, Tomomi Yonekawa, Katsuhisa Masaki, Satoshi Yoshimura, Hiroyuki Murai, Ryo Yamasaki, Jun-Ichi Kira, Copy number variations in multiple sclerosis and neuromyelitis optica., Annals of neurology, 10.1002/ana.24511, 78, 5, 762-74, 2015.11, OBJECTIVE: To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. METHODS: Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. RESULTS: A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti-aquaporin-4 antibody or had significantly lower titers than those without CNV. INTERPRETATION: Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility..
61.	Noriko Isobe, Lohith Madireddy, Pouya Khankhanian, Takuya Matsushita, Stacy J Caillier, Jayaji M Moré, Pierre-Antoine Gourraud, Jacob L McCauley, Ashley H Beecham, Laura Piccio, Joseph Herbert, Omar Khan, Jeffrey Cohen, Lael Stone, Adam Santaniello, Bruce A C Cree, Suna Onengut-Gumuscu, Stephen S Rich, Stephen L Hauser, Stephen Sawcer, Jorge R Oksenberg, An ImmunoChip study of multiple sclerosis risk in African Americans., Brain : a journal of neurology, 10.1093/brain/awv078, 138, Pt 6, 1518-30, 2015.06, The aims of this study were: (i) to determine to what degree multiple sclerosis-associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. Using the ImmunoChip custom array we genotyped 803 African American cases with multiple sclerosis and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. Of the 110 non-major histocompatibility complex multiple sclerosis-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P
62.	Alessandro Didonna, Noriko Isobe, Stacy J Caillier, Kathy H Li, Alma L Burlingame, Stephen L Hauser, Sergio E Baranzini, Nikolaos A Patsopoulos, Jorge R Oksenberg, A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome., Human molecular genetics, 10.1093/hmg/ddv412, 24, 24, 7151-8, 2015.12, Despite recent progress in the characterization of genetic loci associated with multiple sclerosis (MS) risk, the ubiquitous linkage disequilibrium operating across the genome has stalled efforts to distinguish causative variants from proxy single-nucleotide polymorphisms (SNPs). Here, we have identified through fine mapping and meta-analysis EVI5 as the most plausible disease risk gene within the 1p22.1 locus. We further show that an exonic SNP associated with risk induces changes in superficial hydrophobicity patterns of the coiled-coil domain of EVI5, which, in turns, affects the EVI5 interactome. Immunoprecipitation of wild-type and mutated EVI5 followed by mass spectrometry generated a roster of disease-specific interactors functionally linked to lipid metabolism. Among the exclusive binding partners of the risk variant, we describe the novel interaction with sphingosine 1-phosphate lyase (SGPL1)-a key enzyme for the creation of the sphingosine-1 phosphate gradient, which is relevant to the pathogenic process and therapeutic management of MS..
63.	Yuri Nakamura, Takuya Matsushita, Shinya Sato, Masaaki Niino, Toshiyuki Fukazawa, Satoshi Yoshimura, Shin Hisahara, Noriko Isobe, Shun Shimohama, Mitsuru Watanabe, Kazuto Yoshida, Hideki Houzen, Yusei Miyazaki, Ryo Yamasaki, Seiji Kikuchi, Jun-Ichi Kira, Latitude and HLA-DRB104:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study., Journal of neuroinflammation, 10.1186/s12974-016-0695-3, 13, 1, 239-239, 2016.09, BACKGROUND: Higher latitude and human leukocyte antigen (HLA)-DRB104:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown. We aimed to clarify the effects of latitude and the HLA-DRB1 and HLA-DPB1 genes on disease severity in Japanese patients with MS. METHODS: We enrolled 247 MS patients and 159 healthy controls (HCs) from the northernmost main island of Japan, Hokkaido Island (42-45° north), and 187 MS patients and 235 HCs from the southern half (33-35° north) of the Japanese archipelago (33-45° north). We genotyped HLA-DRB1 and HLA-DPB1 alleles, compared demographic features, and analyzed factors contributing to differences in clinical and laboratory findings between MS patients from southern and northern Japan. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Kurtzke's Expanded Disability Status Scale score according to disease duration, was used to estimate disease severity. RESULTS: The HLA-DRB104:05 and DRB115:01 alleles conferred susceptibility to MS in our Japanese population (p (corr) = 0.0004 and p (corr) = 0.0019, respectively). Southern patients had higher MSSS scores than northern patients (p = 0.003). Northern patients had higher frequencies of brain lesions meeting the Barkhof criteria (Barkhof brain lesions) and cerebrospinal fluid (CSF) IgG abnormalities than southern patients (p = 0.0012 and p
64.	Noriko Isobe, Jorge R Oksenberg, Roland G Henry, HLA Genetic Risk Burden in Multiple Sclerosis-Reply., JAMA neurology, 10.1001/jamaneurol.2016.4326, 73, 12, 1501-1502, 2016.12.
65.	Noriko Isobe, Anisha Keshavan, Pierre-Antoine Gourraud, Alyssa H Zhu, Esha Datta, Regina Schlaeger, Stacy J Caillier, Adam Santaniello, Antoine Lizée, Daniel S Himmelstein, Sergio E Baranzini, Jill Hollenbach, Bruce A C Cree, Stephen L Hauser, Jorge R Oksenberg, Roland G Henry, Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis., JAMA neurology, 10.1001/jamaneurol.2016.0980, 73, 7, 795-802, 2016.07, IMPORTANCE: Although multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive. OBJECTIVES: To investigate whether MS risk-associated HLA alleles also affect disease phenotypes. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, case-control study comprising 652 patients with MS who had comprehensive phenotypic information and 455 individuals of European origin serving as controls was conducted at a single academic research site. Patients evaluated at the Multiple Sclerosis Center at University of California, San Francisco between July 2004 and September 2005 were invited to participate. Spinal cord imaging in the data set was acquired between July 2013 and March 2014; analysis was performed between December 2014 and December 2015. MAIN OUTCOMES AND MEASURES: Cumulative HLA genetic burden (HLAGB) calculated using the most updated MS-associated HLA alleles vs clinical and magnetic resonance imaging outcomes, including age at onset, disease severity, conversion time from clinically isolated syndrome to clinically definite MS, fractions of cortical and subcortical gray matter and cerebral white matter, brain lesion volume, spinal cord gray and white matter areas, upper cervical cord area, and the ratio of gray matter to the upper cervical cord area. Multivariate modeling was applied separately for each sex data set. RESULTS: Of the 652 patients with MS, 586 had no missing genetic data and were included in the HLAGB analysis. In these 586 patients (404 women [68.9%]; mean [SD] age at disease onset, 33.6 [9.4] years), HLAGB was higher than in controls (median [IQR], 0.7 [0-1.4] and 0 [-0.3 to 0.5], respectively; P = 1.8 × 10-27). A total of 619 (95.8%) had relapsing-onset MS and 27 (4.2%) had progressive-onset MS. No significant difference was observed between relapsing-onset MS and primary progressive MS. A higher HLAGB was associated with younger age at onset and the atrophy of subcortical gray matter fraction in women with relapsing-onset MS (standard β = -1.20 × 10-1; P = 1.7 × 10-2 and standard β = -1.67 × 10-1; P = 2.3 × 10-4, respectively), which were driven mainly by the HLA-DRB115:01 haplotype. In addition, we observed the distinct role of the HLA-A24:02-B07:02-DRB115:01 haplotype among the other common DRB115:01 haplotypes and a nominally protective effect of HLA-B44:02 to the subcortical gray atrophy (standard β = -1.28 × 10-1; P = 5.1 × 10-3 and standard β = 9.52 × 10-2; P = 3.6 × 10-2, respectively). CONCLUSIONS AND RELEVANCE: We confirm and extend previous observations linking HLA MS susceptibility alleles with disease progression and specific clinical and magnetic resonance imaging phenotypic traits..
66.	Mitsuru Watanabe, Wataru Shiraishi, Ryo Yamasaki, Noriko Isobe, Motohiro Sawatsubashi, Ryuji Yasumatsu, Takashi Nakagawa, Jun-Ichi Kira, Oral phase dysphagia in facial onset sensory and motor neuronopathy., Brain and behavior, 10.1002/brb3.999, 8, 6, e00999, 2018.06, INTRODUCTION: Facial onset motor and sensory neuronopathy (FOSMN) is a rare disease whose cardinal features are initial asymmetrical facial sensory deficits followed by bulbar symptoms and spreading of sensory and motor deficits from face to scalp, neck, upper trunk, and upper extremities in a rostral-caudal direction. Although bulbar involvement is frequently observed in FOSMN, dysphagia in these patients has not been fully described. In this study, we aimed to characterize dysphagia as a prognostic factor in FOSMN by investigating our institutional case series. METHODS: We retrospectively reviewed the medical records, including swallowing function tests, of six patients with FOSMN (three men and three women) who were thoroughly examined at Kyushu University Hospital between 1 January 2005 and 30 November 2017. RESULTS: Average age at onset was 58.5 years; average disease duration was 5.7 years. All patients developed bulbar dysfunction and dysphagia (at an average of 1.8 and 2.6 years from onset, respectively), resulting in choking episodes in three patients, percutaneous endoscopic gastrostomy placement in three, and recurrent aspiration pneumonia in one. Four of five patients evaluated with videofluoroscopic swallowing studies had poor oral retention, leading to bolus flowing into the pharynx before swallowing; the fifth patient showed poor lingual transfer. Fiberoptic endoscopic evaluation of swallowing revealed leakage of blue-dyed water from the mouth to the pharynx in three patients because of poor oral retention, but only mild pharyngeal phase dysphagia in all four cases evaluated. CONCLUSIONS: Oral phase dysphagia predominates in the early stage of FOSMN..
67.	Facial onset sensory and motor neuronopathy症候群は早期からoral phase dysphagiaを呈する.
68.	Guzailiayi Maimaitijiang, Koji Shinoda, Yuri Nakamura, Katsuhisa Masaki, Takuya Matsushita, Noriko Isobe, Ryo Yamasaki, Yasunobu Yoshikai, Jun-ichi Kira, Association of Decreased Percentage of Vδ2+Vγ9+ γδ T Cells With Disease Severity in Multiple Sclerosis, Frontiers in Immunology, 10.3389/fimmu.2018.00748, 9, 2018.04, We recently reported that deletion-type copy number variations of the T cell receptor (TCR)gamma, alpha, and delta genes greatly enhanced susceptibility to multiple sclerosis (MS). However, the effect of abnormal TCR gamma delta gene rearrangement on MS pathogenesis remains unknown. In the present study, we aimed to clarify gamma delta TCR repertoire alterations and their relationship to clinical and immunological parameters in MS patients by comprehensive flow cytometric immunophenotyping. Peripheral blood mononuclear cells obtained from 30 untreated MS patients in remission and 23 age- and sex-matched healthy controls (HCs) were stained for surface markers and intracellular cytokines after stimulation with phorbol 12-myristate 13-acetate and ionomycin, and analyzed by flow cytometry. MS patients showed significantly decreased percentages of V delta 2(+) and V delta 2(+) V gamma 9(+) cells in gamma delta T cells (p(corr) = 0.0297 and p(corr) = 0.0288, respectively) and elevated V delta 1/ V delta 2 ratios compared with HCs (p = 0.0033). The percentages of interferon (IFN)-gamma V+delta 2(+) and interleukin (IL)-17A(+)IFN-gamma(+) V delta 2(+) cells in gamma delta T cells, as well as IFN-gamma(+) cells in V delta 2(+) gamma delta T cells, were significantly lower in MS patients than in HCs (p(corr)
69.	Ester Canto, Noriko Isobe, Alessandro Didonna, Stephen L Hauser, Jorge R Oksenberg, Aberrant STAT phosphorylation signaling in peripheral blood mononuclear cells from multiple sclerosis patients., Journal of neuroinflammation, 10.1186/s12974-018-1105-9, 15, 1, 72-72, 2018.03, BACKGROUND: Multiple sclerosis (MS) is characterized by increased activation of peripheral blood mononuclear cells (PBMCs), linked to perturbations in the phosphorylation of signaling proteins. METHODS: We developed a phosphoflow cytometry protocol to assess the levels of 11 phosphorylated nuclear proteins at baseline conditions and after cell activation in distinct PBMC populations from 41 treatment-naïve relapsing-remitting (RR) MS subjects and 37 healthy controls, and in a second cohort of 9 untreated RRMS patients and 10 secondary progressive (SP) MS patients. Levels of HLA-ABC, HLA-E, and HLA-DR were also assessed. Phosphorylation levels of selected proteins were also assessed in mouse splenocytes isolated from myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE). RESULTS: Modest differences were observed at baseline between patients and controls, with general lower phosphorylation levels in cells from affected individuals. Conversely, a dramatic increase in phosphorylated p38MAPK and STAT proteins was observed across all cell types in MS patients compared to controls after in vitro activation. A similar phosphorylation profile was observed in mouse lymphocytes primed in vivo with MOG. Furthermore, levels of all p-STAT proteins were found directly correlated with HLA expression in monocytes. Levels of phosphorylated proteins did not differ between relapsing-remitting and secondary progressive MS patients either in baseline conditions or after stimulation. Lastly, phosphorylation levels appear to be independent of the genotype. CONCLUSION: The response to IFN-α through STAT proteins signaling is strongly dysregulated in MS patients irrespective of disease stage. These findings suggest that the aberrant activation of this pathway could lead to changes in the expression of HLA molecules in antigen presenting cells, which are known to play important roles in the regulation of the immune response in health and disease..
70.	Yuri Nakamura, Laura Gaetano, Takuya Matsushita, Altermatt Anna, Till Sprenger, Ernst-Wilhelm Radue, Jens Wuerfel, Lorena Bauer, Michael Amann, Koji Shinoda, Noriko Isobe, Ryo Yamasaki, Takahiko Saida, Ludwig Kappos, Jun-Ichi Kira, A comparison of brain magnetic resonance imaging lesions in multiple sclerosis by race with reference to disability progression., Journal of neuroinflammation, 10.1186/s12974-018-1295-1, 15, 1, 255-255, 2018.09, BACKGROUND: We compared the magnetic resonance imaging (MRI) features between Japanese and Caucasian patients with multiple sclerosis (MS), and identified the relationships between MRI features and disability. METHODS: From the baseline data of phase II fingolimod trials, 95 Japanese and 246 Caucasian relapsing-remitting MS patients were enrolled. The number, volume, and distribution of brain MRI lesions were evaluated using T2-weighted (T2W) images. Cross-sectional total normalized brain volume (NBV), normalized cortical gray matter volume, normalized deep gray matter volume (NDGMV), normalized white matter volume (NWMV), and normalized thalamic volume were measured. RESULTS: Japanese patients had significantly lower Expanded Disability Status Scale (EDSS) scores than Caucasian patients (mean 2.0 vs. 2.3, p = 0.008), despite a similar disease duration. Japanese patients showed a trend towards fewer T2W-lesions (median 50 vs. 65, p = 0.08) and significantly lower frequencies of cerebellar and parietal lobe lesions (p = 0.02 for both) than Caucasian patients. There were no differences in T2W-lesion volume between races, whereas Japanese patients had a significantly larger T2W-lesion volume per lesion compared with Caucasian patients (median 140 mm3 vs. 85 mm3, p
71.	Alessandro Didonna, Ester Cantó, Hengameh Shams, Noriko Isobe, Chao Zhao, Stacy J Caillier, Carlo Condello, Hana Yamate-Morgan, Seema K Tiwari-Woodruff, Mohammad R K Mofrad, Stephen L Hauser, Jorge R Oksenberg, Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation., Journal of autoimmunity, 10.1016/j.jaut.2019.04.003, 101, 56-69, 2019.07, The molecular events underlying the transition from initial inflammatory flares to the progressive phase of multiple sclerosis (MS) remain poorly understood. Here, we report that the microtubule-associated protein (MAP) Tau exerts a gender-specific protective function on disease progression in the MS model experimental autoimmune encephalomyelitis (EAE). A detailed investigation of the autoimmune response in Tau-deficient mice excluded a strong immunoregulatory role for Tau, suggesting that its beneficial effects are presumably exerted within the central nervous system (CNS). Spinal cord transcriptomic data show increased synaptic dysfunctions and alterations in the NF-kB activation pathway upon EAE in Tau-deficient mice as compared to wildtype animals. We also performed the first comprehensive characterization of Tau post-translational modifications (PTMs) in the nervous system upon EAE. We report that the methylation levels of the conserved lysine residue K306 are significantly decreased in the chronic phase of the disease. By combining biochemical assays and molecular dynamics (MD) simulations, we demonstrate that methylation at K306 decreases the affinity of Tau for the microtubule network. Thus, the down-regulation of this PTM might represent a homeostatic response to enhance axonal stability against an autoimmune CNS insult. The results, altogether, position Tau as key mediator between the inflammatory processes and neurodegeneration that seems to unify many CNS diseases..
72.	Mitsuru Watanabe, Yuri Nakamura, Zuzanna Michalak, Noriko Isobe, Christian Barro, David Leppert, Takuya Matsushita, Fumie Hayashi, Ryo Yamasaki, Jens Kuhle, Jun-Ichi Kira, Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD., Neurology, 10.1212/WNL.0000000000008160, 93, 13, e1299-e1311, 2019.09, OBJECTIVE: To test the hypothesis that serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), which are an intermediate astrocyte and neuron filaments, respectively, are clinically useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorders (NMOSD). METHODS: Levels of GFAP and NfL in serum (sGFAP and sNfL, respectively) and in CSF samples were measured in healthy controls (HCs) (n = 49; 49 serum samples), patients with NMOSD (n = 33; 42 CSF and 102 serum samples), and patients with multiple sclerosis (MS) (n = 49; 53 CSF and 91 serum samples) by ultrasensitive single-molecule array assays. Association of sGFAP and sNfL levels with clinical parameters was determined. RESULTS: For both GFAP and NfL, CSF and serum levels were strongly correlated. Both were higher in the serum of patients with NMOSD than in HCs (both p
73.	Masakazu Kawajiri, Junpei Koge, Tetsuya Hashimoto, Takeshi Yamada, Noriko Isobe, Jun-Ichi Kira, Recurrent rhombencephalomyelitis associated with allergen immunotherapy by mite antigen sublingual tablets., eNeurologicalSci, 10.1016/j.ensci.2019.100190, 15, 100190-100190, 2019.06.
74.	Toshikazu Baba, Koji Shinoda, Mitsuru Watanabe, Shoko Sadashima, Dai Matsuse, Noriko Isobe, Ryo Yamasaki, Kimihiko Kaneko, Toshiyuki Takahashi, Toru Iwaki, Jun-Ichi Kira, MOG antibody disease manifesting as progressive cognitive deterioration and behavioral changes with primary central nervous system vasculitis., Multiple sclerosis and related disorders, 10.1016/j.msard.2019.01.053, 30, 48-50, 2019.05, We report a 60-year-old male with anti-myelin oligodendrocyte glycoprotein (MOG) antibody who developed progressive cognitive deterioration and behavioral changes, with no other focal signs, over 9 months. MRI showed numerous T2-hyperintense lesions with partial contrast enhancement in white and grey matter of cerebrum, cerebellum and spinal cord. A brain biopsy revealed perivascular inflammatory cell infiltration, disturbed vascular continuity and no demyelination, indicative of a lymphocytic pattern of primary CNS vasculitis (PCNSV). Contrast enhancement disappeared after immunotherapy; however, cognitive impairment was not improved. Neurologists should note that MOG antibody disease can present as immunotherapy-resistant progressive cognitive impairment with PCNSV-like histopathology..
75.	Guzailiayi Maimaitijiang, Mitsuru Watanabe, Koji Shinoda, Noriko Isobe, Yuri Nakamura, Katsuhisa Masaki, Takuya Matsushita, Yasunobu Yoshikai, Jun-Ichi Kira, Long-term use of interferon-β in multiple sclerosis increases Vδ1-Vδ2-Vγ9- γδ T cells that are associated with a better outcome., Journal of neuroinflammation, 10.1186/s12974-019-1574-5, 16, 1, 179-179, 2019.09, BACKGROUND: We previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies (untreated MS) and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells. Interferon-β (IFN-β) is one of the first-line disease-modifying drugs for MS. However, no previous studies have reported changes in γδ T cell subsets under IFN-β treatment. Therefore, we aimed to clarify the effects of the long-term usage of IFN-β on γδ T cell subsets in MS patients. METHODS: Comprehensive flow cytometric immunophenotyping was performed in 35 untreated MS and 21 MS patients on IFN-β for more than 2 years (IFN-β-treated MS) including eight super-responders fulfilling no evidence of disease activity criteria, and 44 healthy controls (HCs). RESULTS: The percentages of Vδ2+Vγ9+ cells in γδ T cells were significantly lower in untreated and IFN-β-treated MS patients than in HCs. By contrast, the percentages of Vδ1-Vδ2-Vγ9- cells in γδ T cells were markedly higher in IFN-β-treated MS patients than in HCs and untreated MS patients (both p
76.	Noriko Isobe, Link between HLA alleles and anti-NMDAR encephalitis., Journal of neurology, neurosurgery, and psychiatry, 10.1136/jnnp-2018-319925, 90, 6, 626-626, 2019.06.
77.	Hidenori Ogata, Xu Zhang, Ryo Yamasaki, Takayuki Fujii, Akira Machida, Nobutoshi Morimoto, Kenichi Kaida, Teruaki Masuda, Yukio Ando, Motoi Kuwahara, Susumu Kusunoki, Yuri Nakamura, Takuya Matsushita, Noriko Isobe, Jun-Ichi Kira, Intrathecal cytokine profile in neuropathy with anti-neurofascin 155 antibody., Annals of clinical and translational neurology, 10.1002/acn3.50931, 6, 11, 2304-2316, 2019.11, OBJECTIVE: To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti-neurofascin 155 (NF155) antibodies (NF155+ CIDP) or those lacking anti-NF155 antibodies (NF155- CIDP). METHODS: Twenty-eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155+ CIDP, 36 with NF155- CIDP, and 28 with non-inflammatory neurological disease (NIND). RESULTS: CSF CXCL8/IL-8, IL-13, TNF-α, CCL11/eotaxin, CCL2/MCP-1, and IFN-γ were significantly higher, while IL-1β, IL-1ra, and G-CSF were lower, in NF155+ CIDP than in NIND. Compared with NF155- CIDP, CXCL8/IL-8 and IL-13 were significantly higher, and IL-1β, IL-1ra, and IL-6 were lower, in NF155+ CIDP. CXCL8/IL-8, IL-13, CCL11/eotaxin, CXCL10/IP-10, CCL3/MIP-1α, CCL4/MIP-1β, and TNF-α levels were positively correlated with markedly elevated CSF protein, while IL-13, CCL11/eotaxin, and IL-17 levels were positively correlated with increased CSF cell counts. IL-13, CXCL8/IL-8, CCL4/MIP-1β, CCL3/MIP-1α, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155+ CIDP patients examined longitudinally. By contrast, NF155- CIDP had significantly increased IFN-γ compared with NIND, and exhibited positive correlations of IFN-γ, CXCL10/IP-10, and CXCL8/IL-8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155+ and NF155- CIDP were separable, and that IL-4, IL-10, and IL-13 were the three most significant discriminators. INTERPRETATION: Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155+ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti-NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155+ CIDP..
78.	Yuri Mizuno, Koji Shinoda, Mitsuru Watanabe, Hidenori Ogata, Noriko Isobe, Takuya Matsushita, Ryo Yamasaki, Kimihiro Tanaka, Haruki Koike, Masahisa Katsuno, Jun-Ichi Kira, Intractable axonal neuropathy with multifocal peripheral nerve swelling in neuromyelitis optica spectrum disorders: A case report., Multiple sclerosis and related disorders, 10.1016/j.msard.2019.06.033, 35, 16-18, 2019.10, We report a patient with neuromyelitis optica spectrum disorders (NMOSD) with anti-aquaporin 4 (AQP4) antibodies, who developed intractable axonal neuropathy presenting with multifocal peripheral nerve swelling by magnetic resonance (MR) neurography. A 52-year-old woman with a 12-year history of polymyositis and rheumatoid arthritis had been treated with prednisolone, tacrolimus, and abatacept (CTLA-4-Ig). She developed progressive numbness and tingling sensations in the distal parts of all limbs at the age of 50 years, followed by weakness of both upper limbs 6 months later. Neurological examination revealed severe muscle weakness and atrophy of the right upper limb with proximal dominance, diffuse moderate weakness of the left upper limb, severe sensory impairment of all modalities of four limbs in glove and stocking distribution, wide-based gait with positive Romberg's sign, and absence of all tendon reflexes. She was diagnosed with NMOSD due to positive serum anti-AQP4 antibodies and a longitudinally extensive cervical spinal cord lesion on MR images. Intravenous methylprednisolone pulse therapy, plasma exchange and intravenous immunoglobulin administration were performed, which improved the spinal cord lesion on MRI, but did not ameliorate her symptoms. Notably, she also had axonal neuropathy characterized by asymmetrical, multifocal swelling of peripheral nerves by MR neurography. Histopathological examination of the biopsied sural nerve revealed axonal degeneration and endoneurial edema but no inflammatory cell infiltration. Although she was treated with intravenous methylprednisolone, intravenous immunoglobulin, oral prednisolone, tacrolimus and tocilizumab, her symptoms gradually progressed. Neurologists should be aware of co-existing intractable axonal neuropathy in NMOSD cases presenting as immunotherapy-resistant sensorimotor disturbances..
79.	Jun-Ichi Kira, Noriko Isobe, Helicobacter pylori infection and demyelinating disease of the central nervous system., Journal of neuroimmunology, 10.1016/j.jneuroim.2018.06.017, 329, 14-19, 2019.04, Helicobacter pylori (H. pylori) colonize >50% of the entire human population. Generally, H. pylori infect the human stomach in infancy when parietal cells secreting gastric acids, which reduce the survival of H. pylori, are not well matured. Once acquired, the bacterium persists for life. Thus, H. pylori infection reflects sanitary conditions during childhood. >10 studies performed in various Eastern and Western countries as well as two meta-analyses collectively indicated the H. pylori infection rate is significantly lower in patients with multiple sclerosis (MS) than in healthy controls. Thus, the bacterium might be a protective factor for MS, especially in low prevalence countries and younger generations that grew up in the low prevalence era. The protective effects of H. pylori might be explained by the hygiene hypothesis-encountering generic infection early in life facilitates development of the immunoregulatory system, which suppresses overactivity of autoimmune T cells later in life. However, no influence of common childhood infections on MS risk was reported by large MS cohort studies. Direct attenuation of autoreactive Th1 and Th17 cells by H. pylori infection was found in experimental autoimmune encephalomyelitis, an animal model of MS. These observations may underscore the direct protective effects of H. pylori on MS rather than generic infection in childhood. By contrast, several studies reported that H. pylori infection rates are significantly higher in anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD) than in healthy controls. H. pylori strongly activate Th17 cells via the induction of IL-23, resulting in neutrophil mobilization and activation. H. pylori neutrophil-activating protein (NAP) is a major proinflammatory protein responsible for the pathology of H. pylori-related gastric inflammatory diseases. Anti-H. pylori-NAP antibody levels were positively correlated with final EDSS scores and myeloperoxidase levels in anti-AQP4 antibody-positive NMOSD patients. Given that spinal cord lesions of NMOSD are heavily infiltrated with myeloperoxidase-positive neutrophils, H. pylori-NAP, which can be absorbed and presented to the host immune system, may exacerbate NMOSD. Thus, H. pylori infection and its proinflammatory proteins, such as NAP, may contribute to the pathology of anti-AQP4 antibody-related neural damage, by activating neutrophils. It is interesting that two representative demyelinating diseases of the central nervous system are differentially modulated by chronic H. pylori infection. The direct effects of H. pylori infection on MS and NMOSD warrant future studies..
80.	Ban-Yu Saitoh, Ryo Yamasaki, Akio Hiwatashi, Takuya Matsushita, Shintaro Hayashi, Yoshihiro Mitsunaga, Yasuhiro Maeda, Noriko Isobe, Kunihiro Yoshida, Shu-Ichi Ikeda, Jun-Ichi Kira, Discriminative clinical and neuroimaging features of motor-predominant hereditary diffuse leukoencephalopathy with axonal spheroids and primary progressive multiple sclerosis: A preliminary cross-sectional study., Multiple sclerosis and related disorders, 10.1016/j.msard.2019.03.008, 31, 22-31, 2019.06, BACKGROUND: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal-dominant white matter disease, typically characterized by juvenile cognitive decline and frontoparietal white matter lesions. A portion of HDLS patients exhibit preferential motor dysfunctions as their initial symptoms, mimicking multiple sclerosis (MS). However, there is no study comparing this phenotype of HDLS and primary progressive multiple sclerosis (PPMS), which greatly resemble each other. This is the first preliminary study to clarify the clinical and neuroimaging features of motor-predominant HDLS, and compare it with PPMS, using cases whose colony stimulating factor 1 receptor (CSF1R) were sequenced. METHODS: Clinical and radiological data from Japanese patients at the Department of Neurology, Kyushu University Hospital, Fukuoka, Japan, were evaluated retrospectively and cross-sectionally. Twenty-nine brain and 18 spinal cord magnetic resonance imaging (MRI) scans from four motor-predominant HDLS patients with CSF1R mutations and 15 PPMS patients without CSF1R mutations, were evaluated using an HDLS MRI scoring system. RESULTS: Two patients with HDLS were initially diagnosed with MS and received immunotherapy. Clinically, motor-predominant HDLS and PPMS patients resembled each other in onset age and disability. However, motor-predominant HDLS patients had a significantly higher frequency of frontal release signs, lower positivity rates of oligoclonal IgG bands (OCB), and lower IgG index values. Total HDLS MRI scores, total white matter lesions (WMLs), and brain atrophy were similar between the diseases. However, motor-predominant HDLS patients had more marked atrophy of the corpus callosum (CC) body, more WMLs in the deep and subcortical regions of the frontoparietal lobes, fewer WMLs in the occipitotemporal periventricular regions, and more restricted diffusivity lesions on MRI than PPMS patients. There was a stronger association between disease duration and CC index in HDLS, suggesting more rapid progression compared with PPMS. CONCLUSIONS: Motor-predominant HDLS has characteristic frequent frontal release signs, normal findings for OCB and the IgG index, severe CC body atrophy, abundant deep and subcortical WMLs in the frontoparietal lobes, subtle occipitotemporal lobe periventricular WMLs, and more restricted diffusivity lesions on MRI. Although the present study was limited by the small number of HDLS cases, we propose that immunotherapy should be avoided in such cases..
81.	Xu Zhang, Takayuki Fujii, Hidenori Ogata, Ryo Yamasaki, Katsuhisa Masaki, Yiwen Cui, Takuya Matsushita, Noriko Isobe, Jun-Ichi Kira, Cerebrospinal fluid cytokine/chemokine/growth factor profiles in idiopathic hypertrophic pachymeningitis., Journal of neuroimmunology, 10.1016/j.jneuroim.2019.01.010, 330, 38-43, 2019.05, Hypertrophic pachymeningitis (HP) is a rare neurologic disease causing inflammatory fibrous thickening of the brain and spinal dura mater. We investigated the cerebrospinal fluid cytokine profile of HP by measuring 28 cytokines/chemokines/growth factors with a multiplexed fluorescent immunoassay in 8 patients with HP (6 idiopathic, 1 IgG4-related, 1 anti-neutrophil cytoplasmic antibody-related), and 11 with other non-inflammatory neurologic diseases (OND). Interleukin (IL)-4, IL-5, IL-9, IL-10, TNF-α, and CXCL8/IL-8 levels were significantly higher in idiopathic HP (IHP) than OND. Cluster analyses disclosed two major clusters: one mainly consisted of IHP and the other of OND, suggesting a unique cytokine profile in IHP..
82.	Epidemiology of multiple sclerosis and neuromyelitis optica.
83.	Hidenori Ogata, Noriko Isobe, Xu Zhang, Ryo Yamasaki, Takayuki Fujii, Akira Machida, Nobutoshi Morimoto, Kenichi Kaida, Teruaki Masuda, Yukio Ando, Motoi Kuwahara, Susumu Kusunoki, Yuri Nakamura, Takuya Matsushita, Jun-Ichi Kira, Unique HLA haplotype associations in IgG4 anti-neurofascin 155 antibody-positive chronic inflammatory demyelinating polyneuropathy., Journal of neuroimmunology, 10.1016/j.jneuroim.2019.577139, 339, 577139-577139, 2020.02, To clarify the immunogenetic background of patients with immunoglobulin G (IgG)4 anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP), we genotyped the extended human leukocyte antigen (HLA) haplotypes in 22 Japanese patients with this disorder and compared them with those of healthy Japanese controls. All IgG4 anti-NF155 antibody-positive CIDP patients exclusively carried either HLA-DRB115:01-DRB501:01-DQA101:02-DQB106:02 or -(A24:02)-B52:01-C12:02-DRB115:02-DRB501:02-DQA101:03-DQB106:01, resulting in significantly increased HLA-DRB115, -DRB115:01, -DQB106:01/06:02, -DQB106:02, and -DRB115:01-DQB1*06:02 frequencies compared with healthy Japanese controls. These findings indicate the involvement of specific HLA class II molecules in the pathomechanisms of IgG4 anti-NF155 antibody-positive CIDP..
84.	Mitsuru Watanabe, Yuri Nakamura, Noriko Isobe, Masami Tanaka, Ayako Sakoda, Fumie Hayashi, Yuji Kawano, Ryo Yamasaki, Takuya Matsushita, Jun-Ichi Kira, Two susceptible HLA-DRB1 alleles for multiple sclerosis differentially regulate anti-JC virus antibody serostatus along with fingolimod., Journal of neuroinflammation, 10.1186/s12974-020-01865-7, 17, 1, 206-206, 2020.07, BACKGROUND: Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) is a rare but serious complication of some disease-modifying drugs used to treat multiple sclerosis (MS). Japanese MS patients treated with fingolimod were reported to be 10 times more likely to develop PML than equivalent patients in other countries. The strongest susceptibility human leukocyte antigen (HLA) class II alleles for MS are distinct between races (DRB115:01 for Caucasians and DRB104:05 and DRB115:01 for Japanese); therefore, we investigated whether HLA class II alleles modulate anti-JCV antibody serostatus in Japanese MS patients with and without fingolimod. METHODS: We enrolled 128 Japanese patients with MS, in whom 64 (50%) were under fingolimod treatment at sampling, and examined the relationship between HLA class II alleles and anti-JCV antibody serostatus. Serum anti-JCV antibody positivity and index were measured using a second-generation two-step assay and HLA-DRB1 and -DPB1 alleles were genotyped. RESULTS: HLA-DRB115 carriers had a lower frequency of anti-JCV antibody positivity (57% vs 78%, p = 0.015), and lower antibody index (median 0.42 vs 1.97, p = 0.037) than non-carriers. Among patients without HLA-DRB115, DRB104 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB104:02 carriers had a higher anti-JCV antibody index than non-carriers (3.20 vs 1.34, p = 0.008) although anti-JCV antibody-positivity rates did not differ. Patients treated with fingolimod had a higher antibody index than other patients (1.46 vs 0.64, p = 0.039) and treatment period had a positive correlation with antibody index (p = 0.018). Multivariate logistic regression analysis revealed that age was positively associated, and HLA-DRB115 was negatively associated with anti-JCV antibody positivity (odds ratio [OR] = 1.06, p = 0.006, and OR = 0.37, p = 0.028, respectively). Excluding HLA-DRB115-carriers, DRB104 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023). CONCLUSIONS: HLA-DRB115 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB115, DRB1*04 carriers are associated with a high antibody positive rate in Japanese, suggesting the effects of two susceptible HLA-DRB1 alleles on anti-JCV antibody serostatus differ..
85.	Nathan Nakatsuka, Nick Patterson, Nikolaos A Patsopoulos, Nicolas Altemose, Arti Tandon, Ashley H Beecham, Jacob L McCauley, Noriko Isobe, Stephen Hauser, Philip L De Jager, David A Hafler, Jorge R Oksenberg, David Reich, Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans., Scientific reports, 10.1038/s41598-020-74035-7, 10, 1, 16902-16902, 2020.10, Epidemiological studies have suggested differences in the rate of multiple sclerosis (MS) in individuals of European ancestry compared to African ancestry, motivating genetic scans to identify variants that could contribute to such patterns. In a whole-genome scan in 899 African-American cases and 1155 African-American controls, we confirm that African-Americans who inherit segments of the genome of European ancestry at a chromosome 1 locus are at increased risk for MS [logarithm of odds (LOD) = 9.8], although the signal weakens when adding an additional 406 cases, reflecting heterogeneity in the two sets of cases [logarithm of odds (LOD) = 2.7]. The association in the 899 individuals can be fully explained by two variants previously associated with MS in European ancestry individuals. These variants tag a MS susceptibility haplotype associated with decreased CD58 gene expression (odds ratio of 1.37; frequency of 84% in Europeans and 22% in West Africans for the tagging variant) as well as another haplotype near the FCRL3 gene (odds ratio of 1.07; frequency of 49% in Europeans and 8% in West Africans). Controlling for all other genetic and environmental factors, the two variants predict a 1.44-fold higher rate of MS in European-Americans compared to African-Americans..
86.	Shoko Fukumoto, Yuri Nakamura, Mitsuru Watanabe, Noriko Isobe, Takuya Matsushita, Ayako Sakoda, Akio Hiwatashi, Koji Shinoda, Ryo Yamasaki, Akira Tsujino, Jun-Ichi Kira, Risk HLA-DRB1 alleles differentially influence brain and lesion volumes in Japanese patients with multiple sclerosis., Journal of the neurological sciences, 10.1016/j.jns.2020.116768, 413, 116768-116768, 2020.06, BACKGROUND: The effects of distinct HLA alleles on the brain and lesion volumes remain to be established, particularly in non-Caucasian populations. Two distinct susceptibility alleles, DRB115:01 and DRB104:05, are prevalent in the Japanese population; we therefore aimed to clarify the effects of HLA-DRB1 alleles on brain and lesion volumes in multiple sclerosis (MS). METHODS: A total of 66 patients with MS (50 relapsing remitting, 16 progressive) underwent brain MRI volumetry measuring fluid-attenuated inversion recovery (FLAIR) and T1 lesion volumes, and normalized whole-brain (NWBV), white matter (NWMV), gray matter (NGMV), cortical gray matter (NCGMV), deep gray matter (NDGMV) and thalamus (NTV) volumes, and HLA-DRB1 genotyping. RESULTS: Carriers of HLA-DRB115:01(+)04:05(-) and HLA-DRB115:01(-)04:05(+) comprised 25.8% and 31.8% of patients, respectively. HLA-DRB115:01 carriers showed negative correlations between disease duration and NWBV (rs = -0.484, p = .036), NWMV (rs = -0.593, p = .008), and NTV (rs = -0.572, p = .011), and positive correlations between disease duration and FLAIR (rs = 0.539, p = .017) and T1 lesion volumes (rs = 0.545, p = .016). By contrast, no significant correlation of any MRI parameters with disease duration was found in HLA-DRB104:05 carriers. HLA-DRB115:01 carriers had a significantly faster reduction in NWBV and NWMV by disease duration and smaller NDGMV than DRB115:01 non-carriers, whereas HLA-DRB104:05 carriers had a significantly slower increase in FLAIR and T1 lesion volumes than HLA-DRB104:05 non-carriers. CONCLUSIONS: Our study suggests that distinct HLA-DRB1 alleles could differentially influence brain and lesion volumes over the disease course of MS..
87.	Takayuki Fujii, Ryo Yamasaki, Yukino Miyachi, Kyoko Iinuma, Yu Hashimoto, Noriko Isobe, Takuya Matsushita, Jun-Ichi Kira, Painful trigeminal neuropathy associated with anti-Plexin D1 antibody., Neurology(R) neuroimmunology & neuroinflammation, 10.1212/NXI.0000000000000819, 7, 5, 2020.09, OBJECTIVE: To determine whether anti-Plexin D1 antibody (Plexin D1-immunoglobulin G [IgG]), which is associated with limb and trunk neuropathic pain (NP) and binds to pain-conducting small unmyelinated dorsal root ganglion (DRG) neurons, exists in patients with idiopathic painful trigeminal neuropathy (IPTN) and whether Plexin D1-IgG binds to trigeminal ganglion (TG) neurons. METHODS: We enrolled 21 consecutive patients with IPTN and 35 age- and sex-matched controls without NP (25 healthy persons and 10 with neurodegenerative diseases). We measured serum Plexin D1-IgG using a mouse DRG tissue-based indirect immunofluorescence assay (IFA) and by Western blotting (WB) using a recombinant human Plexin D1 (rhPlexin D1) accompanied by immunoadsorption tests with rhPlexin D1. The reactivity of Plexin D1-IgG toward mouse TG, brain, heart, and kidney was assessed by tissue-based IFAs. RESULTS: Serum Plexin D1-IgG was detected more frequently in IPTN than in controls by both IFA and WB (14.3% vs 0%, p = 0.048). Three Plexin D1-IgG-positive patients also had limb or trunk NP and commonly showed tongue pain. In tissue-based IFAs, IgG from 2 Plexin D1-IgG-positive patients immunostained small TG neurons, which was prevented by preincubation with rhPlexin D1. Moreover, Plexin D1-IgG immunostaining mostly colocalized with isolectin B4-positive pain-conducting unmyelinated TG neurons. IFAs of other tissues with the same IgG revealed weak immunoreactivity only in endothelial cells, which was prevented by preincubation with rhPlexin D1. CONCLUSIONS: Plexin D1-IgG, which binds to pain-conducting small TG neurons in addition to DRG neurons, can be present in IPTN as well as limb and trunk NP..
88.	Hidenori Ogata, Xu Zhang, Saeko Inamizu, Ken-Ichiro Yamashita, Ryo Yamasaki, Takuya Matsushita, Noriko Isobe, Akio Hiwatashi, Shozo Tobimatsu, Jun-Ichi Kira, Optic, trigeminal, and facial neuropathy related to anti-neurofascin 155 antibody., Annals of clinical and translational neurology, 10.1002/acn3.51220, 7, 11, 2297-2309, 2020.11, OBJECTIVE: To characterize the frequency and patterns of optic, trigeminal, and facial nerve involvement by neuroimaging and electrophysiology in IgG4 anti-neurofascin 155 antibody-positive (NF155+ ) chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Thirteen IgG4 NF155+ CIDP patients with mean onset age of 34 years (11 men) were subjected to neurological examination, blink reflex, and visual-evoked potential (VEP) testing, and axial and/or coronal T2-weighted head magnetic resonance imaging (MRI). RESULTS: Among 13 patients, facial sensory impairment, facial weakness, and apparent visual impairment were observed in three (23.1%), two (15.4%), and two (15.4%) patients, respectively. All 12 patients tested had blink reflex abnormalities: absent and/or delayed R1 in 11 (91.7%), and absent and/or delayed R2 in 10 (83.3%). R1 latencies had strong positive correlations with serum anti-NF155 antibody levels (r = 0.9, P ≤ 0.0001 on both sides) and distal and F wave latencies of the median and ulnar nerves. Absent and/or prolonged VEPs were observed in 10/13 (76.9%) patients and 17/26 (65.4%) eyes. On MRI, hypertrophy, and high signal intensity of trigeminal nerves were detected in 9/13 (69.2%) and 10/13 (76.9%) patients, respectively, whereas optic nerves were normal in all patients. The intra-orbital trigeminal nerve width on coronal sections showed a significant positive correlation with disease duration. INTERPRETATION: Subclinical demyelination frequently occurs in the optic, trigeminal, and facial nerves in IgG4 NF155+ CIDP, suggesting that both central and peripheral myelin structures of the cranial nerves are involved in this condition, whereas nerve hypertrophy only develops in myelinated peripheral nerve fibers..
89.	Yinan Zhao, Ryo Yamasaki, Hiroo Yamaguchi, Satoshi Nagata, Hayato Une, Yiwen Cui, Katsuhisa Masaki, Yuko Nakamuta, Kyoko Iinuma, Mitsuru Watanabe, Takuya Matsushita, Noriko Isobe, Jun-Ichi Kira, Oligodendroglial connexin 47 regulates neuroinflammation upon autoimmune demyelination in a novel mouse model of multiple sclerosis., Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1901294117, 117, 4, 2160-2169, 2020.01, In multiple sclerosis plaques, oligodendroglial connexin (Cx) 47 constituting main gap junction channels with astroglial Cx43 is persistently lost. As mice with Cx47 single knockout exhibit no demyelination, the roles of Cx47 remain undefined. We aimed to clarify the effects of oligodendroglia-specific Cx47 inducible conditional knockout (icKO) on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein peptide (MOG35-55) in PLP/CreERT;Cx47fl/fl mice at 14 d after tamoxifen injection. Cx47 icKO mice demonstrated exacerbation of acute and chronic relapsing EAE with more pronounced demyelination than Cx47 flox (fl)/fl littermates. CD3+ T cells more abundantly infiltrated the spinal cord in Cx47 icKO than in Cx47 fl/fl mice throughout the acute to chronic phases. CXCR3-CCR6+CD4+ and IL17+IFNγ-CD4+ helper T (Th) 17 cells isolated from spinal cord and brain tissues were significantly increased in Cx47 icKO mice compared with Cx47 fl/fl mice, while MOG35-55-specific proliferation and proinflammatory cytokine production of splenocytes were unaltered. Microarray analysis of isolated microglia revealed stronger microglial activation toward proinflammatory and injury-response phenotypes with increased expressions of chemokines that can attract Th17 cells, including Ccl2, Ccl3, Ccl4, Ccl7, and Ccl8, in Cx47 icKO mice compared with Cx47 fl/fl mice. In Cx47 icKO mice, NOS2+ and MHC class II+ microglia were more enriched immunohistochemically, and A1-specific astroglial gene expressions and astroglia immunostained for C3, a representative A1 astrocyte marker, were significantly increased at the acute phase, compared with Cx47 fl/fl mice. These findings suggest that oligodendroglia-specific Cx47 ablation induces severe inflammation upon autoimmune demyelination, underscoring a critical role for Cx47 in regulating neuroinflammation..
90.	Takuya Matsushita, Katsuhisa Masaki, Noriko Isobe, Shinya Sato, Ken Yamamoto, Yuri Nakamura, Mitsuru Watanabe, Toshihiko Suenaga, Jun-Ichi Kira, Genetic factors for susceptibility to and manifestations of neuromyelitis optica., Annals of clinical and translational neurology, 10.1002/acn3.51147, 7, 11, 2082-2093, 2020.11, OBJECTIVE: To identify genetic factors associated with susceptibility to and clinical features of neuromyelitis optica spectrum disorders (NMOSD). METHODS: Genome-wide single nucleotide polymorphism (SNP) genotyping was conducted in 211 Japanese patients with NMOSD fulfilling the 2006 criteria with or without anti-aquaporin-4 (AQP4) antibody and 1,919 Japanese healthy controls (HCs). HLA-DRB1 and HLA-DPB1 alleles were genotyped in 184 NMOSD cases and 317 HCs. Multiple sclerosis (MS) risk alleles outside the major histocompatibility complex (MHC) region were tested in NMOSD and MS genetic burden (MSGB) scores were compared between HCs and NMOSD. RESULTS: A SNP (rs1964995) in the MHC region was associated with NMOSD susceptibility (odds ratio (OR) = 2.33, P = 4.07 × 10-11 ). HLA-DRB108:02 (OR = 2.86, P = 3.03 × 10-4 ) and HLA-DRB116:02 (OR = 8.39, P = 1.92 × 10-3 ) were risk alleles for NMOSD susceptibility whereas HLA-DRB1*09:01 was protective (OR = 0.27, P = 1.06 × 10-5 ). Three MS risk variants were associated with susceptibility and MSGB scores were significantly higher in NMOSD than in HCs (P = 0.0095). A SNP in the KCNMA1 (potassium calcium-activated channel subfamily M alpha 1) gene was associated with disability score with genome-wide significance (rs1516512, P = 2.33 × 10-8 ) and transverse myelitis (OR = 1.77, P = 0.011). KCNMA1 was immunohistochemically detected in the perivascular endfeet of astrocytes and its immunoreactivity was markedly diminished in active spinal cord lesions in NMOSD. INTERPRETATION: Specific HLA-DRB1 alleles confer NMOSD susceptibility and KCNMA1 is associated with disability and transverse myelitis in NMOSD..
91.	Ayako Sakoda, Takuya Matsushita, Yuri Nakamura, Mitsuru Watanabe, Koji Shinoda, Katsuhisa Masaki, Noriko Isobe, Ryo Yamasaki, Jun-Ichi Kira, Environmental risk factors for multiple sclerosis in Japanese people., Multiple sclerosis and related disorders, 10.1016/j.msard.2019.101872, 38, 101872-101872, 2020.02, BACKGROUND: The prevalence of multiple sclerosis (MS) has been increasing worldwide in recent years, especially among females. The same increasing trends are even observed in East Asian countries, where the prevalence of MS is relatively low compared with Northern European ancestries. Whether the environmental risk factors for MS are shared between Asian and North European ancestries, and the types of environmental factors that contribute to the low and recent increase in MS prevalence in Asian countries remain unknown. This study provides the first comprehensive survey of environmental risks for MS in East Asia. METHODS: Patients with MS were recruited from the Department of Neurology at Kyushu University Hospital, Japan between 01 April 2017 and 31 March 2018. Healthy controls (HCs) were recruited by public notification. All participants were residents of Kyushu Island and were required to complete medical history and lifestyle questionnaires. Dietary data were collected using a Food Frequency Questionnaire comprising intake of approximately 140 food and beverage items in the past 1 year. One hundred and three patients with MS and 124 healthy controls (HCs) completed the questionnaires. Age at onset and disability score measured by the Kurtzke Expanded Disability Status Scale (EDSS) were obtained from medical records. RESULTS: Frequency of obesity (body mass index ≥25 kg/m2) at present time was higher in MS patients than in HCs (19.4% vs. 7.4%, p = 0.009), while body mass index at age 18-20 years did not differ between the two groups. Frequency of current or ex-smokers was higher in MS patients than in HCs (50.5% vs. 22.8%, p
92.	Dai Matsuse, Ryo Yamasaki, Guzailiayi Maimaitijiang, Hiroo Yamaguchi, Katsuhisa Masaki, Noriko Isobe, Takuya Matsushita, Jun-Ichi Kira, Early decrease in intermediate monocytes in peripheral blood is characteristic of multiple system atrophy-cerebellar type., Journal of neuroimmunology, 10.1016/j.jneuroim.2020.577395, 349, 577395-577395, 2020.12, To identify biomarkers for multiple system atrophy-cerebellar type (MSA-C), we used flow cytometry to measure surface marker expression of peripheral blood monocytes from patients with MSA-C or hereditary spinocerebellar degeneration (hSCD) and from healthy controls (HCs). The percentage of intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs and showed significant positive correlations with disease duration and unified MSA rating scale scores. The percentage of CD62L+ intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs. Early decrease of peripheral blood intermediate monocytes is characteristic of MSA-C and is a biomarker..
93.	Shotaro Hayashida, Katsuhisa Masaki, Satoshi O. Suzuki, Ryo Yamasaki, Mitsuru Watanabe, Sachiko Koyama, Noriko Isobe, Takuya Matsushita, Kazuya Takahashi, Takeshi Tabira, Toru Iwaki, Jun‐ichi Kira, Distinct microglial and macrophage distribution patterns in the concentric and lamellar lesions in Baló's disease and neuromyelitis optica spectrum disorders, Brain Pathology, 10.1111/bpa.12898, 30, 6, 1144-1157, 2020.11, TMEM119 and purinergic receptor P2Y12 (P2RY12), which are not expressed by recruited peripheral blood macrophages, are proposed to discriminate microglia from macrophages. Therefore, we investigated the distribution patterns of microglia and macrophages in 10 concentric lesions from four autopsied Baló's disease cases and one neuromyelitis optica spectrum disorder (NMOSD) case, using quantitative immunohistochemistry for the markers TMEM119, P2RY12, CD68, CD163 and GLUT5. Three cases with Baló's disease had distal oligodendrogliopathy (DO) showing preferential loss of myelin-associated glycoprotein and early active demyelination in the outermost demyelinating layer (termed DMY-MO). In DMY-MO with DO, TMEM119-positive activated microglia expressing upregulated GLUT5 but markedly downregulated P2RY12 were significantly increased. These activated microglia expressed inducible nitric oxide synthase. Oligodendrocytes and their precursors showed apoptotic-like nuclear condensation in DMY-MO. TMEM119-negative and CD68/CD163-positive macrophages were distributed throughout the lesion center of DMY-MO with DO and these cells demonstrated foamy morphology only in the inner portion but not in the outer portion. In concentric demyelinating lesions from another Baló's case and lamellar demyelinating lesions in an NMOSD case, which had late active demyelination without DO, the densities of TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology were significantly increased in myelinated layers but not in demyelinating layers. In particular, in the NMOSD case, TMEM119-positive microglia were confined to the outer portion of the myelinated layers. CD68-positive macrophages with foamy morphology also expressing CD163 accumulated in myelinated as well as in demyelinated layers. These findings suggest that activated microglia expressing TMEM119 and GLUT5, but not P2RY12, are associated with apoptosis of oligodendrocytes in the leading edge of Baló's concentric lesions with DO, whereas TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology are associated with myelin preservation in concentric lesions without DO in Baló's disease and NMOSD. These two types of microglia appear to play distinct roles in the formation of concentric lesions..
94.	Koji Shinoda, Takuya Matsushita, Yuri Nakamura, Katsuhisa Masaki, Shiori Sakai, Haruka Nomiyama, Osamu Togao, Akio Hiwatashi, Masaaki Niino, Noriko Isobe, Jun-Ichi Kira, Contribution of cortical lesions to cognitive impairment in Japanese patients with multiple sclerosis., Scientific reports, 10.1038/s41598-020-61012-3, 10, 1, 5228-5228, 2020.03, Cortical lesions (CLs) have a low prevalence and are associated with physical disabilities in Japanese patients with multiple sclerosis (MS). However, the contribution of CLs to cognitive impairment remains unclear in Asian MS. Sixty-one prospectively enrolled MS patients underwent three-dimensional double inversion recovery MR imaging, the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), the Apathy Scale (AS), the Fatigue Questionnaire (FQ), and the Hospital Anxiety and Depression Scale (HADS) within a 1-week period. The cognitive impairment index (CII) score was calculated to measure patients' overall cognitive impairment. MS patients with CLs had poorer scores than those without CLs in most BRB-N tests, but scored comparably in the FQ, AS, and HADS. The number of CLs correlated negatively with all BRB-N test scores and positively with total CII scores. Leukocortical lesions were more extensively associated with cognitive dysfunction in various domains than intracortical lesions. Stepwise multiple regression analysis revealed that potential confounding factors for the highest quartile of CII score were the number of CLs (odds ratio 2.38, p = 0.0070) and the Expanded Disability Severity Scale score (odds ratio 2.13, p = 0.0003). Our results demonstrate that the presence and number of CLs are robustly associated with cognitive dysfunction in Asian MS patients..
95.	Jun-ichi Kira, Noriko Isobe, Masaaki Niino, Takuya Matsushita, Yuri Nakamura, Ichiro Nakashima, Mitsuru Watanabe, Yasunari Sakai, Ayako Sakoda, Jin Nakahara, Izumi Kawachi, Hirofumi Ochi, Yuji Nakatsuji, Yusei Miyazaki, Juichi Fujimori, Kenji Kufukihara, Tatsusada Okuno, Shoko Fukumoto, Fumie Hayashi, Kousuke Yonemoto, Ryoji Taira, Yoshikazu Nakamura, Koshi Nakamura, Kiyomi Sakata, Rinako Shimada, Makoto Matsui, Continued Increase of Multiple Sclerosis and Neuromyelitis Optica in Japan: Updates from the 5th Nationwide Survey, ANNALS OF NEUROLOGY, 88, S199-S200, 2020.10.
96.	Takayuki Fujii, Ryo Yamasaki, Yukino Miyachi, Satoshi Nagata, Guzailiayi Maimaitijiang, Yuri Nakamura, Koji Shinoda, Takuya Matsushita, Noriko Isobe, Jun-Ichi Kira, Central nervous system-specific antinuclear antibodies in patients with multiple sclerosis., Journal of the neurological sciences, 10.1016/j.jns.2019.116619, 409, 116619-116619, 2020.02, BACKGROUND: Nuclear antigen released from central nervous system (CNS) cells undergoing destruction may induce production of antinuclear antibodies (ANA). We characterized the CNS-specific production of ANA in multiple sclerosis (MS). METHODS: We assessed CNS-ANA binding to mouse cerebellar cell nuclei by immunofluorescence assay (IFA) with sera from 104 MS patients (91 relapsing-remitting; 13 secondary progressive), 30 patients with neuromyelitis optica spectrum disorders (NMOSD), and 30 healthy controls (HCs). Conventional ANA (cANA) was detected by IFA using human epithelial type-2 cells. CNS-ANA-positive cANA-negative patients were termed CNS-specific ANA-positive. Western blotting (WB) was performed using mouse cerebellar nuclear fractions. RESULTS: CNS-specific ANA were more frequent in MS than in NMOSD patients or HCs (13.5% vs 0% for both comparisons, both p
97.	Ryo Yamasaki, Tomomi Yonekawa, Saeko Inamizu, Koji Shinoda, Hirofumi Ochi, Takuya Matsushita, Noriko Isobe, Gaku Tsuji, Shoko Sadashima, Yuki Kuma, Yoshinao Oda, Toru Iwaki, Masutaka Furue, Jun-Ichi Kira, A case of overlapping adult-onset linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic involvement., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12614, 40, 1, 109-115, 2020.02, Linear scleroderma is a variant of localized scleroderma. We report a 43-year-old woman who had developed left arm weakness and linear scleroderma on her back during pregnancy at 25 years of age, followed by left hemifacial atrophy and left leg weakness. She had multiple linear scleroderma lesions on her trunk and left limbs, left eyelid ptosis, impairment of vertical movement and abduction of the left eye, left hemifacial atrophy, and weakness and atrophy of the sternocleidomastoid, trapezius, and proximal limb muscles on the left side. On serology, antibodies to U1-ribonucleoprotein and Jo-1 were positive; anti-scleroderma-70 antibody was negative. Skin biopsy demonstrated increased hypertrophic collagen fibers without inflammatory infiltrates. Needle electromyography of left limb muscles revealed mild neurogenic patterns; left quadriceps muscle biopsy showed chronic neurogenic changes. Brain magnetic resonance imaging revealed mild left hemispheric atrophy. This is a rare case of linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic manifestations..
98.	Ozdemir Ezgi, 山崎亮, 永田諭, 山口浩雄, 真崎勝久, 吉良潤一, 竹内英之, 磯部紀子, アストログリアコネキシン43は慢性多発性硬化症モデルに対する新規治療標的である(Astroglial connexin 43 is a novel therapeutic target for chronic multiple sclerosis model), 神経免疫学, 26, 1, 129-129, 2021.10.
99.	Saúl Reyes, Anthony L Cunningham, Tomas Kalincik, Eva Kubala Havrdová, Noriko Isobe, Julia Pakpoor, Laura Airas, Reem F Bunyan, Anneke van der Walt, Jiwon Oh, Joela Mathews, Farrah J Mateen, Gavin Giovannoni, Update on the management of multiple sclerosis during the COVID-19 pandemic and post pandemic: An international consensus statement., Journal of neuroimmunology, 10.1016/j.jneuroim.2021.577627, 357, 577627-577627, 2021.08, In this consensus statement, we provide updated recommendations on multiple sclerosis (MS) management during the COVID-19 crisis and the post-pandemic period applicable to neurology services around the world. Statements/recommendations were generated based on available literature and the experience of 13 MS expert panelists using a modified Delphi approach online. The statements/recommendations give advice regarding implementation of telemedicine; use of disease-modifying therapies and management of MS relapses; management of people with MS at highest risk from COVID-19; management of radiological monitoring; use of remote pharmacovigilance; impact on MS research; implications for lowest income settings, and other key issues..
100.	Koji Tanaka, Shoji Matsumoto, Gulibahaer Ainiding, Ichiro Nakahara, Hidehisa Nishi, Tetsuya Hashimoto, Tsuyoshi Ohta, Nobutake Sadamasa, Ryota Ishibashi, Masanori Gomi, Makoto Saka, Haruka Miyata, Sadayoshi Watanabe, Takuya Okata, Kazutaka Sonoda, Junpei Koge, Kyoko M. Iinuma, Konosuke Furuta, Izumi Nagata, Keitaro Matsuo, Takuya Matsushita, Noriko Isobe, Ryo Yamasaki, Jun-ichi Kira, PON1 Q192R is associated with high platelet reactivity with clopidogrel in patients undergoing elective neurointervention: A prospective single-center cohort study, PLOS ONE, 10.1371/journal.pone.0254067, 16, 8, e0254067-e0254067, 2021.08, Background and purpose The impact of the paraoxonase-1 (PON1) polymorphism, Q192R, on platelet inhibition in response to clopidogrel remains controversial. We aimed to investigate the association between carrier status of PON1 Q192R and high platelet reactivity (HPR) with clopidogrel in patients undergoing elective neurointervention. Methods Post-clopidogrel platelet reactivity was measured using a VerifyNow^® P2Y12 assay in P2Y12 reaction units (PRU) for consecutive patients before the treatment. Genotype testing was performed for PON1 Q192R and CYP2C192 and 3 (no function alleles), and *17. PRU was corrected on the basis of hematocrit. We investigated associations between factors including carrying ≥1 PON1 192R allele and HPR defined as original and corrected PRU ≥208. Results Of 475 patients (232 men, median age, 68 years), HPR by original and corrected PRU was observed in 259 and 199 patients (54.5% and 41.9%), respectively. Carriers of ≥1 PON1 192R allele more frequently had HPR by original and corrected PRU compared with non-carriers (91.5% vs 85.2%, P = 0.031 and 92.5% vs 85.9%, P = 0.026, respectively). In multivariate analyses, carrying ≥1 PON1 192R allele was associated with HPR by original (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.03–3.76) and corrected PRU (OR 2.34, 95% CI 1.21–4.74) after adjustment for age, sex, treatment with antihypertensive medications, hematocrit, platelet count, total cholesterol, and carrying ≥1 CYP2C19 no function allele. Conclusions Carrying ≥1 PON1 192R allele is associated with HPR by original and corrected PRU with clopidogrel in patients undergoing elective neurointervention, although alternative results related to other genetic polymorphisms cannot be excluded. .
101.	Mitsuru Watanabe, Yuri Nakamura, Shinya Sato, Masaaki Niino, Hikoaki Fukaura, Masami Tanaka, Hirofumi Ochi, Takashi Kanda, Yukio Takeshita, Takanori Yokota, Yoichiro Nishida, Makoto Matsui, Shigemi Nagayama, Susumu Kusunoki, Katsuichi Miyamoto, Masanori Mizuno, Izumi Kawachi, Etsuji Saji, Takashi Ohashi, Shun Shimohama, Shin Hisahara, Kazutoshi Nishiyama, Takahiro Iizuka, Yuji Nakatsuji, Tatsusada Okuno, Kazuhide Ochi, Akio Suzumura, Ken Yamamoto, Yuji Kawano, Shoji Tsuji, Makoto Hirata, Ryuichi Sakate, Tomonori Kimura, Yuko Shimizu, Akiko Nagaishi, Kazumasa Okada, Fumie Hayashi, Ayako Sakoda, Katsuhisa Masaki, Koji Shinoda, Noriko Isobe, Takuya Matsushita, Jun-Ichi Kira, HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data., Scientific reports, 10.1038/s41598-020-79833-7, 11, 1, 607-607, 2021.01, HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB104:05, DRB115:01 and DPB103:01 correlated with MS susceptibility and DRB101:01, DRB109:01, DRB113:02 and DPB104:01 were protective against MS. HLA-DRB115:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB104:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB103:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB101:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB109:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB113:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB108:02 and DPB105:01 were associated with susceptibility and DRB109:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD..
102.	Fumie Hayashi, Noriko Isobe, Davide Cossu, Kazumasa Yokoyama, Ayako Sakoda, Takuya Matsushita, Nobutaka Hattori, Jun-Ichi Kira, Elevated mycobacterium avium subsp. paratuberculosis (MAP) antibody titer in Japanese multiple sclerosis., Journal of neuroimmunology, 10.1016/j.jneuroim.2021.577701, 360, 577701-577701, 2021.11, To investigate whether antibody production against mycobacterium avium subsp. paratuberculosis (MAP) is related to clinical characteristics of multiple sclerosis (MS) and human leukocyte antigen (HLA) alleles, IgG antibody against three MAP peptides and two human peptides homologous to MAP were measured in sera from 103 MS patients and 50 healthy controls (HCs). MS patients had higher IgG levels against MAP2694295-303 (MAP2694-IgG) than HCs, while the other antibodies were comparable. Multivariate analysis demonstrated that higher MAP2694-IgG titers were associated with higher EDSS scores, but not with HLA alleles or dairy product consumption. Immune response against MAP may worsen MS disability..
103.	Wataru Shiraishi, Ryo Yamasaki, Yu Hashimoto, Senri Ko, Yuko Kobayakawa, Noriko Isobe, Takuya Matsushita, Jun-Ichi Kira, Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression., Scientific reports, 10.1038/s41598-021-96064-6, 11, 1, 16438-16438, 2021.08, Macrophages expressing C-C chemokine receptor type 2 (CCR2) infiltrate the central and peripheral neural tissues of amyotrophic lateral sclerosis (ALS) patients. To identify the functional role of CCR2+ macrophages in the pathomechanisms of ALS, we used an ALS animal model, mutant Cu/Zn superoxide dismutase 1G93A (mSOD1)-transgenic (Tg) mice. To clarify the CCR2 function in the model, we generated SOD1G93A/CCR2Red fluorescence protein (RFP)/Wild type (WT)/CX3CR1Green fluorescence protein (GFP)/WT-Tg mice, which heterozygously express CCR2-RFP and CX3CR1-GFP, and SOD1G93A/CCR2RFP/RFP-Tg mice, which lack CCR2 protein expression and present with a CCR2-deficient phenotype. In mSOD1-Tg mice, mSOD1 accumulated in the sciatic nerve earlier than in the spinal cord. Furthermore, spinal cords of SOD1G93A/CCR2RFP/WT/CX3CR1GFP/WT mice showed peripheral macrophage infiltration that emerged at the end-stage, whereas in peripheral nerves, macrophage infiltration started from the pre-symptomatic stage. Before disease onset, CCR2+ macrophages harboring mSOD1 infiltrated sciatic nerves earlier than the lumbar cord. CCR2-deficient mSOD1-Tg mice showed an earlier onset and axonal derangement in the sciatic nerve than CCR2-positive mSOD1-Tg mice. CCR2-deficient mSOD1-Tg mice showed an increase in deposited mSOD1 in the sciatic nerve compared with CCR2-positive mice. These findings suggest that CCR2+ and CX3CR1+ macrophages exert neuroprotective functions in mSOD1 ALS via mSOD1 clearance from the peripheral nerves..
104.	Kuriko Kudo, Noriko Isobe, Shintaro Ueda, Shunta Tomimatsu, Tomohiko Moriyama, Shuji Shimizu, Barriers to International Telemedicine Conferencing: A Survey of the National University Hospital Council of Japan., Telemedicine journal and e-health : the official journal of the American Telemedicine Association, 10.1089/tmj.2021.0046, 28, 3, 433-439, 2021.06, Background: Telemedicine conferencing is expected to become commonly used internationally. However, national reports on internationally related telemedicine are limited, and related activities and challenges in each country are unclear. In this study, we aimed to clarify the current status and barriers to international telemedicine conferencing in Japan. Methods: The questionnaire was sent to the Internationalization Project Team (I-PT) representatives in all 43 Japanese National University Hospitals. The total of 167 assigned staff comprised 86 medical staff in charge of internationalization (MI) and 81 technical staff in telemedicine (TT). Results: The response rate was 93% (40/43 universities) from 88 staff (44 MI and 44 TT). Most respondents (75%) stated that they had not been active in international telemedicine conferencing during the past 3 years, although a videoconferencing system was installed in 93% of universities. A total of 65% respondents felt that barriers to promoting telemedicine and conferencing existed. Most (43%) respondents reported staff shortage as the most serious barrier overall. Five TT (19%) felt that the most serious barrier was difficulty with English communication, although no MI selected this as a barrier. More MI than TT felt that technical issues were the most serious barrier (MI: 4/29, TT: 1/27). Conclusions: International telemedicine conferencing was found to be insufficiently active in I-PT of Japan, although the installed equipment and technical expertise of TT seemed adequate. This indicates that merely assigning MI and TT to an I-PT is not enough and that improved cooperation between both MI and TT at each university hospital is needed. Establishment of a structured international telemedicine center in each university hospital is to be suggested to accelerate the activities in Japan..
105.	Fumie Hayashi, Noriko Isobe, Jacob Glanville, Takuya Matsushita, Guzailiayi Maimaitijiang, Shoko Fukumoto, Mitsuru Watanabe, Katsuhisa Masaki, Jun-Ichi Kira, A new clustering method identifies multiple sclerosis-specific T-cell receptors., Annals of clinical and translational neurology, 10.1002/acn3.51264, 8, 1, 163-176, 2021.01, OBJECTIVE: To characterize T-cell receptors (TCRs) and identify target epitopes in multiple sclerosis (MS). METHODS: Peripheral blood mononuclear cells were obtained from 39 MS patients and 19 healthy controls (HCs). TCR repertoires for α/β/δ/γ chains, TCR diversity, and V/J usage were determined by next-generation sequencing. TCR β chain repertoires were compared with affectation status using a novel clustering method, Grouping of Lymphocyte Interactions by Paratope Hotspots (GLIPH). Cytomegalovirus (CMV)-IgG was measured in an additional 113 MS patients and 93 HCs. Regulatory T cells (Tregs) were measured by flow cytometry. RESULTS: TCR diversity for all four chains decreased with age. TCRα and TCRβ diversity was higher in MS patients (P = 0.0015 and 0.024, respectively), even after age correction. TRAJ56 and TRBV4-3 were more prevalent in MS patients than in HCs (pcorr = 0.027 and 0.040, respectively). GLIPH consolidated 208,674 TCR clones from MS patients into 1,294 clusters, among which two candidate clusters were identified. The TRBV4-3 cluster was shared by HLA-DRB104:05-positive patients (87.5%) and predicted to recognize CMV peptides (CMV-TCR). MS Severity Score (MSSS) was lower in patients with CMV-TCR than in those without (P = 0.037). CMV-IgG-positivity was associated with lower MSSS in HLA-DRB104:05 carriers (P = 0.0053). HLA-DRB104:05-positive individuals demonstrated higher CMV-IgG titers than HLA-DRB104:05-negative individuals (P = 0.017). CMV-IgG-positive patients had more Tregs than CMV-IgG-negative patients (P = 0.054). INTERPRETATION: High TCRα/TCRβ diversity, regardless of age, is characteristic of MS. Association of a CMV-recognizing TCR with mild disability indicates CMV's protective role in HLA-DRB1*04:05-positive MS..
106.	Hengameh Shams, Xiaorong Shao, Adam Santaniello, Gina Kirkish, Adil Harroud, Qin Ma, Noriko Isobe, Catherine Schaefer, Jacob L McCauley, Bruce A C Cree, Alessandro Didonna, Sergio E Baranzini, Nikolaos A Patsopoulos, Stephen L Hauser, Lisa F Barcellos, Roland G Henry, Jorge R Oksenberg, Polygenic risk score association with multiple sclerosis susceptibility and phenotype in Europeans., Brain : a journal of neurology, 10.1093/brain/awac092, 146, 2, 645-656, 2022.03, Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the central nervous system. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both disease status and severity in cohorts of European descent. The largest genome-wide association dataset for multiple sclerosis to date (n = 41,505) was leveraged to generate PRS scores, serving as an informative susceptibility marker, tested in two independent datasets, UK Biobank [UKBB, area under the curve (AUC) = 0.73, 95% CI: 0.72-0.74, P = 6.41e-146] and Kaiser Permanente in Northern California (KPNC, AUC = 0.8, 95% CI: 0.76-0.82, P = 1.5e-53). Individuals within the top 10% of PRS were at greater than five-fold increased risk in UK Biobank (95% CI: 4.7-6, P = 2.8e-45) and fifteen-fold higher risk in KPNC (95% CI: 10.4-24, P = 3.7e-11), relative to the median decile. The cumulative absolute risk of developing multiple sclerosis from age 20 onwards was significantly higher in genetically predisposed individuals according to PRS. Furthermore, inclusion of PRS increased the risk discrimination by 13% to 26% over models based only on conventional multiple sclerosis risk factors, such as smoking and mononucleosis infection, in UKBB and KPNC, respectively. Stratifying disease risk by gene sets representative of curated cellular signaling cascades, nominated promising genetic candidate programs for functional characterization. These pathways include inflammatory signaling mediation, response to viral infection, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression to be among significant contributors to multiple sclerosis susceptibility. This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multi-case families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P
107.	Junpei Koge, Kanta Tanaka, Takeshi Yoshimoto, Masayuki Shiozawa, Yuji Kushi, Tsuyoshi Ohta, Tetsu Satow, Hiroharu Kataoka, Masafumi Ihara, Masatoshi Koga, Noriko Isobe, Kazunori Toyoda, Internal Carotid Artery Tortuosity: Impact on Mechanical Thrombectomy., Stroke, 10.1161/STROKEAHA.121.037904, 53, 8, 101161STROKEAHA121037904-2467, 2022.04, BACKGROUND: Although tortuosity of the internal carotid artery (ICA) can pose a significant challenge when performing mechanical thrombectomy, few studies have examined the impact of ICA tortuosity on mechanical thrombectomy outcomes. METHODS: In a registry-based hospital cohort, consecutive patients with anterior circulation stroke in whom mechanical thrombectomy was attempted were divided into 2 groups: those with tortuosity in the extracranial or cavernous ICA (tortuous group) and those without (nontortuous group). The extracranial ICA tortuosity was defined as the presence of coiling or kinking. The cavernous ICA tortuosity was defined by the posterior deflection of the posterior genu or the shape resembling Simmons-type catheter. Outcomes included first pass effect (FPE; extended Thrombolysis in Cerebral Infarction score 2c/3 after first pass), favorable outcome (3-month modified Rankin Scale score of 0-2), and intracranial hemorrhage. RESULTS: Of 370 patients, 124 were in the tortuous group (extracranial ICA tortuosity, 35; cavernous ICA tortuosity, 70; tortuosity at both sites, 19). The tortuous group showed a higher proportion of women and atrial fibrillation than the nontortuous group. FPE was less frequently achieved in the tortuous group than the nontortuous group (21% versus 39%; adjusted odds ratio, 0.45 [95% CI, 0.26-0.77]). ICA tortuosity was independently associated with the longer time from puncture to extended Thrombolysis in Cerebral Infarction ≥2b reperfusion (β=23.19 [95% CI, 13.44-32.94]). Favorable outcome was similar between groups (46% versus 48%; P=0.87). Frequencies of any intracranial hemorrhage (54% versus 42%; adjusted odds ratio, 1.61 [95% CI, 1.02-2.53]) and parenchymal hematoma (11% versus 6%; adjusted odds ratio, 2.41 [95% CI, 1.04-5.58]) were higher in the tortuous group. In the tortuous group, the FPE rate was similar in patients who underwent combined stent retriever and contact aspiration thrombectomy and in those who underwent either procedure alone (22% versus 19%; P=0.80). However, in the nontortuous group, the FPE rate was significantly higher in patients who underwent combined stent retriever and contact aspiration (52% versus 35%; P=0.02). CONCLUSIONS: ICA tortuosity was independently associated with reduced likelihood of FPE and increased risk of postmechanical thrombectomy intracranial hemorrhage. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02251665..
108.	Jannis Müller, Tim Sinnecker, Maria Janina Wendebourg, Regina Schläger, Jens Kuhle, Sabine Schädelin, Pascal Benkert, Tobias Derfuss, Philippe Cattin, Christoph Jud, Florian Spiess, Michael Amann, Therese Lincke, Muhamed Barakovic, Alessandro Cagol, Charidimos Tsagkas, Katrin Parmar, Anne-Katrin Pröbstel, Sophia Reimann, Susanna Asseyer, Ankelien Duchow, Alexander Brandt, Klemens Ruprecht, Nouchine Hadjikhani, Shoko Fukumoto, Mitsuru Watanabe, Katsuhisa Masaki, Takuya Matsushita, Noriko Isobe, Jun-Ichi Kira, Ludwig Kappos, Jens Würfel, Cristina Granziera, Friedemann Paul, Özgür Yaldizli, Choroid Plexus Volume in Multiple Sclerosis vs Neuromyelitis Optica Spectrum Disorder: A Retrospective, Cross-sectional Analysis., Neurology(R) neuroimmunology & neuroinflammation, 10.1212/NXI.0000000000001147, 9, 3, 2022.05, BACKGROUND AND OBJECTIVES: The choroid plexus has been shown to play a crucial role in CNS inflammation. Previous studies found larger choroid plexus in multiple sclerosis (MS) compared with healthy controls. However, it is not clear whether the choroid plexus is similarly involved in MS and in neuromyelitis optica spectrum disorder (NMOSD). Thus, the aim of this study was to compare the choroid plexus volume in MS and NMOSD. METHODS: In this retrospective, cross-sectional study, patients were included by convenience sampling from 4 international MS centers. The choroid plexus of the lateral ventricles was segmented fully automatically on T1-weighted MRI sequences using a deep learning algorithm (Multi-Dimensional Gated Recurrent Units). Uni- and multivariable linear models were applied to investigate associations between the choroid plexus volume, clinically meaningful disease characteristics, and MRI parameters. RESULTS: We studied 180 patients with MS and 98 patients with NMOSD. In total, 94 healthy individuals and 47 patients with migraine served as controls. The choroid plexus volume was larger in MS (median 1,690 µL, interquartile range [IQR] 648 µL) than in NMOSD (median 1,403 µL, IQR 510 µL), healthy individuals (median 1,533 µL, IQR 570 µL), and patients with migraine (median 1,404 µL, IQR 524 µL; all p
109.	Ban-Yu Saitoh, Takahisa Tateishi, Motoi Yoshimura, Satoshi O Suzuki, Noriko Isobe, Toru Iwaki, Jun-Ichi Kira, A Case of Cerebral Tuberculoma with Mild Posterior Cervical Pain as the Main Symptom Despite Extensive Brain Lesions., Internal medicine (Tokyo, Japan), 10.2169/internalmedicine.9020-21, 61, 19, 2941-2945, 2022.03, A 59-year-old woman with a diabetes history experienced mild neck pain. A neurological examination revealed only mild neck stiffness. Magnetic resonance imaging showed extensive T2-weighted high-intensity lesions with patchy gadolinium enhancement mainly involving the white matter in the right parietal lobe. A cerebrospinal fluid analysis revealed increased protein levels and pleocytosis. While QuantiFERON-TB Gold was positive, computed tomography (CT) and fluorodeoxyglucose on positron emission tomography-CT of the whole body showed no abnormal accumulation, suggesting tuberculosis. A brain biopsy revealed cerebral tuberculoma. As cerebral tuberculoma can show minimal neurological symptoms despite extensive lesions, a cautious examination and early treatment are required to prevent a devastating prognosis..
110.	Fumie Hayashi, Noriko Isobe, Jacob Glanville, Takuya Matsushita, Guzailiayi Maimaitijiang, Shoko Fukumoto, Mitsuru Watanabe, Katsuhisa Masaki, Jun‐ichi Kira, A new clustering method identifies multiple sclerosis‐specific T‐cell receptors, Annals of Clinical and Translational Neurology, 10.1002/acn3.51264, 8, 1, 163-176, 2021.01.
111.	Mitsuru Watanabe, Yuri Nakamura, Shinya Sato, Masaaki Niino, Hikoaki Fukaura, Masami Tanaka, Hirofumi Ochi, Takashi Kanda, Yukio Takeshita, Takanori Yokota, Yoichiro Nishida, Makoto Matsui, Shigemi Nagayama, Susumu Kusunoki, Katsuichi Miyamoto, Masanori Mizuno, Izumi Kawachi, Etsuji Saji, Takashi Ohashi, Shun Shimohama, Shin Hisahara, Kazutoshi Nishiyama, Takahiro Iizuka, Yuji Nakatsuji, Tatsusada Okuno, Kazuhide Ochi, Akio Suzumura, Ken Yamamoto, Yuji Kawano, Shoji Tsuji, Makoto Hirata, Ryuichi Sakate, Tomonori Kimura, Yuko Shimizu, Akiko Nagaishi, Kazumasa Okada, Fumie Hayashi, Ayako Sakoda, Katsuhisa Masaki, Koji Shinoda, Noriko Isobe, Takuya Matsushita, Jun-Ichi Kira, HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data., Scientific reports, 10.1038/s41598-020-79833-7, 11, 1, 607-607, 2021.01.
112.	Ryo Yamasaki, Tomomi Yonekawa, Saeko Inamizu, Koji Shinoda, Hirofumi Ochi, Takuya Matsushita, Noriko Isobe, Gaku Tsuji, Shoko Sadashima, Yuki Kuma, Yoshinao Oda, Toru Iwaki, Masutaka Furue, Jun-Ichi Kira, A case of overlapping adult-onset linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic involvement., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12614, 40, 1, 109-115, 2020.02.
113.	Takayuki Fujii, Ryo Yamasaki, Yukino Miyachi, Satoshi Nagata, Guzailiayi Maimaitijiang, Yuri Nakamura, Koji Shinoda, Takuya Matsushita, Noriko Isobe, Jun-Ichi Kira, Central nervous system-specific antinuclear antibodies in patients with multiple sclerosis., Journal of the neurological sciences, 10.1016/j.jns.2019.116619, 409, 116619-116619, 2020.02.
114.	Koji Shinoda, Takuya Matsushita, Yuri Nakamura, Katsuhisa Masaki, Shiori Sakai, Haruka Nomiyama, Osamu Togao, Akio Hiwatashi, Masaaki Niino, Noriko Isobe, Jun-Ichi Kira, Contribution of cortical lesions to cognitive impairment in Japanese patients with multiple sclerosis., Scientific reports, 10.1038/s41598-020-61012-3, 10, 1, 5228-5228, 2020.03.
115.	Dai Matsuse, Ryo Yamasaki, Guzailiayi Maimaitijiang, Hiroo Yamaguchi, Katsuhisa Masaki, Noriko Isobe, Takuya Matsushita, Jun-Ichi Kira, Early decrease in intermediate monocytes in peripheral blood is characteristic of multiple system atrophy-cerebellar type., Journal of neuroimmunology, 10.1016/j.jneuroim.2020.577395, 349, 577395-577395, 2020.09.
116.	Ayako Sakoda, Takuya Matsushita, Yuri Nakamura, Mitsuru Watanabe, Koji Shinoda, Katsuhisa Masaki, Noriko Isobe, Ryo Yamasaki, Jun-Ichi Kira, Environmental risk factors for multiple sclerosis in Japanese people., Multiple sclerosis and related disorders, 10.1016/j.msard.2019.101872, 38, 101872-101872, 2020.02.
117.	Yinan Zhao, Ryo Yamasaki, Hiroo Yamaguchi, Satoshi Nagata, Hayato Une, Yiwen Cui, Katsuhisa Masaki, Yuko Nakamuta, Kyoko Iinuma, Mitsuru Watanabe, Takuya Matsushita, Noriko Isobe, Jun-Ichi Kira, Oligodendroglial connexin 47 regulates neuroinflammation upon autoimmune demyelination in a novel mouse model of multiple sclerosis., Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1901294117, 117, 4, 2160-2169, 2020.01.
118.	Hidenori Ogata, Xu Zhang, Saeko Inamizu, Ken-Ichiro Yamashita, Ryo Yamasaki, Takuya Matsushita, Noriko Isobe, Akio Hiwatashi, Shozo Tobimatsu, Jun-Ichi Kira, Optic, trigeminal, and facial neuropathy related to anti-neurofascin 155 antibody., Annals of clinical and translational neurology, 10.1002/acn3.51220, 7, 11, 2297-2309, 2020.11.
119.	Takayuki Fujii, Ryo Yamasaki, Yukino Miyachi, Kyoko Iinuma, Yu Hashimoto, Noriko Isobe, Takuya Matsushita, Jun-Ichi Kira, Painful trigeminal neuropathy associated with anti-Plexin D1 antibody., Neurology(R) neuroimmunology & neuroinflammation, 10.1212/NXI.0000000000000819, 7, 5, 2020.09.
120.	Shoko Fukumoto, Yuri Nakamura, Mitsuru Watanabe, Noriko Isobe, Takuya Matsushita, Ayako Sakoda, Akio Hiwatashi, Koji Shinoda, Ryo Yamasaki, Akira Tsujino, Jun-Ichi Kira, Risk HLA-DRB1 alleles differentially influence brain and lesion volumes in Japanese patients with multiple sclerosis., Journal of the neurological sciences, 10.1016/j.jns.2020.116768, 413, 116768-116768, 2020.06.
121.	Nathan Nakatsuka, Nick Patterson, Nikolaos A Patsopoulos, Nicolas Altemose, Arti Tandon, Ashley H Beecham, Jacob L McCauley, Noriko Isobe, Stephen Hauser, Philip L De Jager, David A Hafler, Jorge R Oksenberg, David Reich, Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans., Scientific reports, 10.1038/s41598-020-74035-7, 10, 1, 16902-16902, 2020.10.
122.	Mitsuru Watanabe, Yuri Nakamura, Noriko Isobe, Masami Tanaka, Ayako Sakoda, Fumie Hayashi, Yuji Kawano, Ryo Yamasaki, Takuya Matsushita, Jun-Ichi Kira, Two susceptible HLA-DRB1 alleles for multiple sclerosis differentially regulate anti-JC virus antibody serostatus along with fingolimod., Journal of neuroinflammation, 10.1186/s12974-020-01865-7, 17, 1, 206-206, 2020.07.
123.	Hidenori Ogata, Noriko Isobe, Xu Zhang, Ryo Yamasaki, Takayuki Fujii, Akira Machida, Nobutoshi Morimoto, Kenichi Kaida, Teruaki Masuda, Yukio Ando, Motoi Kuwahara, Susumu Kusunoki, Yuri Nakamura, Takuya Matsushita, Jun-Ichi Kira, Unique HLA haplotype associations in IgG4 anti-neurofascin 155 antibody-positive chronic inflammatory demyelinating polyneuropathy., Journal of neuroimmunology, 10.1016/j.jneuroim.2019.577139, 339, 577139-577139, 2020.02.
124.	Ban-Yu Saitoh, Ryo Yamasaki, Akio Hiwatashi, Takuya Matsushita, Shintaro Hayashi, Yoshihiro Mitsunaga, Yasuhiro Maeda, Noriko Isobe, Kunihiro Yoshida, Shu-Ichi Ikeda, Jun-Ichi Kira, Discriminative clinical and neuroimaging features of motor-predominant hereditary diffuse leukoencephalopathy with axonal spheroids and primary progressive multiple sclerosis: A preliminary cross-sectional study., Multiple sclerosis and related disorders, 10.1016/j.msard.2019.03.008, 31, 22-31, 2019.06.
125.	Jun-Ichi Kira, Noriko Isobe, Helicobacter pylori infection and demyelinating disease of the central nervous system., Journal of neuroimmunology, 10.1016/j.jneuroim.2018.06.017, 329, 14-19, 2019.04.
126.	Yuri Mizuno, Koji Shinoda, Mitsuru Watanabe, Hidenori Ogata, Noriko Isobe, Takuya Matsushita, Ryo Yamasaki, Kimihiro Tanaka, Haruki Koike, Masahisa Katsuno, Jun-Ichi Kira, Intractable axonal neuropathy with multifocal peripheral nerve swelling in neuromyelitis optica spectrum disorders: A case report., Multiple sclerosis and related disorders, 10.1016/j.msard.2019.06.033, 35, 16-18, 2019.10.
127.	Hidenori Ogata, Xu Zhang, Ryo Yamasaki, Takayuki Fujii, Akira Machida, Nobutoshi Morimoto, Kenichi Kaida, Teruaki Masuda, Yukio Ando, Motoi Kuwahara, Susumu Kusunoki, Yuri Nakamura, Takuya Matsushita, Noriko Isobe, Jun-Ichi Kira, Intrathecal cytokine profile in neuropathy with anti-neurofascin 155 antibody., Annals of clinical and translational neurology, 10.1002/acn3.50931, 6, 11, 2304-2316, 2019.11.
128.	Noriko Isobe, Link between HLA alleles and anti-NMDAR encephalitis., Journal of neurology, neurosurgery, and psychiatry, 10.1136/jnnp-2018-319925, 90, 6, 626-626, 2019.06.
129.	Guzailiayi Maimaitijiang, Mitsuru Watanabe, Koji Shinoda, Noriko Isobe, Yuri Nakamura, Katsuhisa Masaki, Takuya Matsushita, Yasunobu Yoshikai, Jun-Ichi Kira, Long-term use of interferon-β in multiple sclerosis increases Vδ1-Vδ2-Vγ9- γδ T cells that are associated with a better outcome., Journal of neuroinflammation, 10.1186/s12974-019-1574-5, 16, 1, 179-179, 2019.09.
130.	Toshikazu Baba, Koji Shinoda, Mitsuru Watanabe, Shoko Sadashima, Dai Matsuse, Noriko Isobe, Ryo Yamasaki, Kimihiko Kaneko, Toshiyuki Takahashi, Toru Iwaki, Jun-Ichi Kira, MOG antibody disease manifesting as progressive cognitive deterioration and behavioral changes with primary central nervous system vasculitis., Multiple sclerosis and related disorders, 10.1016/j.msard.2019.01.053, 30, 48-50, 2019.05.
131.	Masakazu Kawajiri, Junpei Koge, Tetsuya Hashimoto, Takeshi Yamada, Noriko Isobe, Jun-Ichi Kira, Recurrent rhombencephalomyelitis associated with allergen immunotherapy by mite antigen sublingual tablets., eNeurologicalSci, 10.1016/j.ensci.2019.100190, 15, 100190-100190, 2019.06.
132.	Mitsuru Watanabe, Yuri Nakamura, Zuzanna Michalak, Noriko Isobe, Christian Barro, David Leppert, Takuya Matsushita, Fumie Hayashi, Ryo Yamasaki, Jens Kuhle, Jun-Ichi Kira, Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD., Neurology, 10.1212/WNL.0000000000008160, 93, 13, e1299-e1311, 2019.09.
133.	Alessandro Didonna, Ester Cantó, Hengameh Shams, Noriko Isobe, Chao Zhao, Stacy J Caillier, Carlo Condello, Hana Yamate-Morgan, Seema K Tiwari-Woodruff, Mohammad R K Mofrad, Stephen L Hauser, Jorge R Oksenberg, Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation., Journal of autoimmunity, 10.1016/j.jaut.2019.04.003, 101, 56-69, 2019.07.
134.	Ester Canto, Noriko Isobe, Alessandro Didonna, Stephen L Hauser, Jorge R Oksenberg, Aberrant STAT phosphorylation signaling in peripheral blood mononuclear cells from multiple sclerosis patients., Journal of neuroinflammation, 10.1186/s12974-018-1105-9, 15, 1, 72-72, 2018.03.
135.	Mitsuru Watanabe, Wataru Shiraishi, Ryo Yamasaki, Noriko Isobe, Motohiro Sawatsubashi, Ryuji Yasumatsu, Takashi Nakagawa, Jun-Ichi Kira, Oral phase dysphagia in facial onset sensory and motor neuronopathy., Brain and behavior, 10.1002/brb3.999, 8, 6, e00999, 2018.06.
136.	Noriko Isobe, Anisha Keshavan, Pierre-Antoine Gourraud, Alyssa H Zhu, Esha Datta, Regina Schlaeger, Stacy J Caillier, Adam Santaniello, Antoine Lizée, Daniel S Himmelstein, Sergio E Baranzini, Jill Hollenbach, Bruce A C Cree, Stephen L Hauser, Jorge R Oksenberg, Roland G Henry, Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis., JAMA neurology, 10.1001/jamaneurol.2016.0980, 73, 7, 795-802, 2016.07.
137.	Noriko Isobe, Jorge R Oksenberg, Roland G Henry, HLA Genetic Risk Burden in Multiple Sclerosis-Reply., JAMA neurology, 10.1001/jamaneurol.2016.4326, 73, 12, 1501-1502, 2016.12.
138.	Yuri Nakamura, Takuya Matsushita, Shinya Sato, Masaaki Niino, Toshiyuki Fukazawa, Satoshi Yoshimura, Shin Hisahara, Noriko Isobe, Shun Shimohama, Mitsuru Watanabe, Kazuto Yoshida, Hideki Houzen, Yusei Miyazaki, Ryo Yamasaki, Seiji Kikuchi, Jun-Ichi Kira, Latitude and HLA-DRB104:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study., Journal of neuroinflammation*, 10.1186/s12974-016-0695-3, 13, 1, 239-239, 2016.09.
139.	Alessandro Didonna, Noriko Isobe, Stacy J Caillier, Kathy H Li, Alma L Burlingame, Stephen L Hauser, Sergio E Baranzini, Nikolaos A Patsopoulos, Jorge R Oksenberg, A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome., Human molecular genetics, 10.1093/hmg/ddv412, 24, 24, 7151-8, 2015.12.
140.	Noriko Isobe, Lohith Madireddy, Pouya Khankhanian, Takuya Matsushita, Stacy J Caillier, Jayaji M Moré, Pierre-Antoine Gourraud, Jacob L McCauley, Ashley H Beecham, Laura Piccio, Joseph Herbert, Omar Khan, Jeffrey Cohen, Lael Stone, Adam Santaniello, Bruce A C Cree, Suna Onengut-Gumuscu, Stephen S Rich, Stephen L Hauser, Stephen Sawcer, Jorge R Oksenberg, An ImmunoChip study of multiple sclerosis risk in African Americans., Brain : a journal of neurology, 10.1093/brain/awv078, 138, Pt 6, 1518-30, 2015.06.
141.	Shinya Sato, Ken Yamamoto, Takuya Matsushita, Noriko Isobe, Yuji Kawano, Kyoko Iinuma, Masaaki Niino, Toshiyuki Fukazawa, Yuri Nakamura, Mitsuru Watanabe, Tomomi Yonekawa, Katsuhisa Masaki, Satoshi Yoshimura, Hiroyuki Murai, Ryo Yamasaki, Jun-Ichi Kira, Copy number variations in multiple sclerosis and neuromyelitis optica., Annals of neurology, 10.1002/ana.24511, 78, 5, 762-74, 2015.11.
142.	Masaaki Niino, Shinya Sato, Toshiyuki Fukazawa, Satoshi Yoshimura, Shin Hisahara, Takuya Matsushita, Noriko Isobe, Kazuto Yoshida, Hideki Houzen, Yusei Miyazaki, Shun Shimohama, Seiji Kikuchi, Jun-ichi Kira, Latitude and HLA-DRB1 alleles independently affect the emergence of cerebrospinal fluid IgG abnormality in multiple sclerosis., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458514560924, 21, 9, 1112-20, 2015.08.
143.	Dorothee Nickles, Lohith Madireddy, Nihar Patel, Noriko Isobe, Bruce L Miller, Sergio E Baranzini, Joel H Kramer, Jorge R Oksenberg, Whole genome sequences of 2 octogenarians with sustained cognitive abilities., Neurobiology of aging, 10.1016/j.neurobiolaging.2014.11.003, 36, 3, 1435-8, 2015.03.
144.	Wataru Shiraishi, Shintaro Hayashi, Takashi Kamada, Noriko Isobe, Ryo Yamasaki, Hiroyuki Murai, Yasumasa Ohyagi, Jun-ichi Kira, A case of neuromyelitis optica harboring both anti-aquaporin-4 antibodies and a pathogenic mitochondrial DNA mutation for Leber's hereditary optic neuropathy., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458513513057, 20, 2, 258-60, 2014.02.
145.	Tomomi Yonekawa, Hiroyuki Murai, Satoshi Utsuki, Takuya Matsushita, Katsuhisa Masaki, Noriko Isobe, Ryo Yamasaki, Mari Yoshida, Susumu Kusunoki, Kiyomi Sakata, Kiyotaka Fujii, Jun-ichi Kira, A nationwide survey of hypertrophic pachymeningitis in Japan., Journal of neurology, neurosurgery, and psychiatry, 10.1136/jnnp-2013-306410, 85, 7, 732-9, 2014.07.
146.	Gulibahaer Ainiding, Yuji Kawano, Shinya Sato, Noriko Isobe, Takuya Matsushita, Satoshi Yoshimura, Tomomi Yonekawa, Ryo Yamasaki, Hiroyuki Murai, Jun-ichi Kira, Interleukin 2 receptor α chain gene polymorphisms and risks of multiple sclerosis and neuromyelitis optica in southern Japanese., Journal of the neurological sciences, 10.1016/j.jns.2013.11.037, 337, 1-2, 147-50, 2014.02.
147.	Hanne F Harbo, Noriko Isobe, Pål Berg-Hansen, Steffan D Bos, Stacy J Caillier, Marte W Gustavsen, Inger-Lise Mero, Elisabeth Gulowsen Celius, Stephen L Hauser, Jorge R Oksenberg, Pierre-Antoine Gourraud, Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458513506503, 20, 6, 660-8, 2014.05.
148.	Jian Huang, Satoshi Yoshimura, Noriko Isobe, Takuya Matsushita, Tomomi Yonekawa, Shinya Sato, Ryo Yamasaki, Jun-ichi Kira, A NOTCH4 missense mutation confers resistance to multiple sclerosis in Japanese., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458513482512, 19, 13, 1696-703, 2013.11.
149.	Noriko Isobe, Tomomi Yonekawa, Takuya Matsushita, Katsuhisa Masaki, Satoshi Yoshimura, Jakub Fichna, Shu Chen, Jadwiga Furmaniak, Bernard Rees Smith, Jun-Ichi Kira, Clinical relevance of serum aquaporin-4 antibody levels in neuromyelitis optica., Neurochemical research, 10.1007/s11064-013-1009-0, 38, 5, 997-1001, 2013.05.
150.	Satoshi Yoshimura, Noriko Isobe, Takuya Matsushita, Tomomi Yonekawa, Katsuhisa Masaki, Shinya Sato, Yuji Kawano, Jun-ichi Kira, Distinct genetic and infectious profiles in Japanese neuromyelitis optica patients according to anti-aquaporin 4 antibody status., Journal of neurology, neurosurgery, and psychiatry, 10.1136/jnnp-2012-302925, 84, 1, 29-34, 2013.01.
151.	Noriko Isobe, Pierre-Antoine Gourraud, Hanne F Harbo, Stacy J Caillier, Adam Santaniello, Pouya Khankhanian, Martin Maiers, Stephen Spellman, Nezih Cereb, SooYoung Yang, Marcelo J Pando, Laura Piccio, Anne H Cross, Philip L De Jager, Bruce A C Cree, Stephen L Hauser, Jorge R Oksenberg, Genetic risk variants in African Americans with multiple sclerosis., Neurology, 10.1212/WNL.0b013e31829bfe2f, 81, 3, 219-27, 2013.07.
152.	Gulibahaer Ainiding, Ken-ichiro Yamashita, Takako Torii, Konosuke Furuta, Noriko Isobe, Takuya Matsushita, Katsuhisa Masaki, Shoji Matsumoto, Jun-ichi Kira, Clinical disability progression and platelet GP IIb/IIIa values in patients with atopic myelitis., Journal of neuroimmunology, 10.1016/j.jneuroim.2012.03.009, 246, 1-2, 108-12, 2012.05.
153.	Riwanti Estiasari, Takuya Matsushita, Katsuhisa Masaki, Takuya Akiyama, Tomomi Yonekawa, Noriko Isobe, Jun-ichi Kira, Comparison of clinical, immunological and neuroimaging features between anti-aquaporin-4 antibody-positive and antibody-negative Sjogren's syndrome patients with central nervous system manifestations., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458511431727, 18, 6, 807-16, 2012.06.
154.	Katsuhisa Masaki, Satoshi O Suzuki, Takuya Matsushita, Tomomi Yonekawa, Takeshi Matsuoka, Noriko Isobe, Kyoko Motomura, Xiao-Mu Wu, Takeshi Tabira, Toru Iwaki, Jun-ichi Kira, Extensive loss of connexins in Baló's disease: evidence for an auto-antibody-independent astrocytopathy via impaired astrocyte-oligodendrocyte/myelin interaction., Acta neuropathologica, 10.1007/s00401-012-0972-x, 123, 6, 887-900, 2012.06.
155.	Noriko Isobe, Yuji Kanamori, Tomomi Yonekawa, Takuya Matsushita, Hiroshi Shigeto, Nobutoshi Kawamura, Jun-ichi Kira, First diagnostic criteria for atopic myelitis with special reference to discrimination from myelitis-onset multiple sclerosis., Journal of the neurological sciences, 10.1016/j.jns.2012.02.007, 316, 1-2, 30-5, 2012.05.
156.	Shinya Sato, Noriko Isobe, Satoshi Yoshimura, Yuji Kanamori, Katsuhisa Masaki, Takuya Matsushita, Jun-Ichi Kira, HLA-DPB10201 is associated with susceptibility to atopic myelitis in Japanese., Journal of neuroimmunology*, 10.1016/j.jneuroim.2012.07.007, 251, 1-2, 110-3, 2012.10.
157.	Noriko Isobe, Tomomi Yonekawa, Takuya Matsushita, Yuji Kawano, Katsuhisa Masaki, Satoshi Yoshimura, Jakub Fichna, Shu Chen, Jadwiga Furmaniak, Bernard Rees Smith, Jun-ichi Kira, Quantitative assays for anti-aquaporin-4 antibody with subclass analysis in neuromyelitis optica., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458512443917, 18, 11, 1541-51, 2012.11.
158.	Hiroyuki Murai, Natsumi Yamashita, Makoto Watanabe, Yoshiko Nomura, Masakatsu Motomura, Hiroaki Yoshikawa, Yosikazu Nakamura, Naoki Kawaguchi, Hiroshi Onodera, Shigeru Araga, Noriko Isobe, Masaki Nagai, Jun-ichi Kira, Characteristics of myasthenia gravis according to onset-age: Japanese nationwide survey., Journal of the neurological sciences, 10.1016/j.jns.2011.03.004, 305, 1-2, 97-102, 2011.06.
159.	Koji Shinoda, Takuya Matsushita, Konosuke Furuta, Noriko Isobe, Tomomi Yonekawa, Yasumasa Ohyagi, Jun-ichi Kira, Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome in a patient with neuromyelitis optica spectrum disorder and anti-aquaporin-4 antibody., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458510391690, 17, 7, 885-7, 2011.07.
160.	Satoshi Yoshimura, Hirofumi Ochi, Noriko Isobe, Takuya Matsushita, Kyoko Motomura, Takeshi Matsuoka, Motozumi Minohara, Jun-ichi Kira, Altered production of brain-derived neurotrophic factor by peripheral blood immune cells in multiple sclerosis., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458510375706, 16, 10, 1178-88, 2010.10.
161.	Takahisa Tateishi, Ryo Yamasaki, Masahito Tanaka, Takuya Matsushita, Hitoshi Kikuchi, Noriko Isobe, Yasumasa Ohyagi, Jun-ichi Kira, CSF chemokine alterations related to the clinical course of amyotrophic lateral sclerosis., Journal of neuroimmunology, 10.1016/j.jneuroim.2010.03.004, 222, 1-2, 76-81, 2010.05.
162.	Takuya Matsushita, Noriko Isobe, Hua Piao, Takeshi Matsuoka, Takaaki Ishizu, Hikaru Doi, Katsuhisa Masaki, Takashi Yoshiura, Ryo Yamasaki, Yasumasa Ohyagi, Jun-Ichi Kira, Reappraisal of brain MRI features in patients with multiple sclerosis and neuromyelitis optica according to anti-aquaporin-4 antibody status., Journal of the neurological sciences, 10.1016/j.jns.2010.01.009, 291, 1-2, 37-43, 2010.04.
163.	Wei Li, Motozumi Minohara, Hua Piao, Takuya Matsushita, Katsuhisa Masaki, Takeshi Matsuoka, Noriko Isobe, Jen Jen Su, Yasumasa Ohyagi, Jun-ichi Kira, Association of anti-Helicobacter pylori neutrophil-activating protein antibody response with anti-aquaporin-4 autoimmunity in Japanese patients with multiple sclerosis and neuromyelitis optica., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458509348961, 15, 12, 1411-21, 2009.12.
164.	Akihiro Watanabe, Takuya Matsushita, Hikaru Doi, Takashi Matsuoka, Hiroshi Shigeto, Noriko Isobe, Yuji Kawano, Shozo Tobimatsu, Jun-ichi Kira, Multimodality-evoked potential study of anti-aquaporin-4 antibody-positive and -negative multiple sclerosis patients., Journal of the neurological sciences, 10.1016/j.jns.2009.02.371, 281, 1-2, 34-40, 2009.06.
165.	Jun-Ichi Kira, Noriko Isobe, Yuji Kawano, Manabu Osoegawa, Yasumasa Ohyagi, Futoshi Mihara, Hiroyuki Murai, Atopic myelitis with focal amyotrophy: a possible link to Hopkins syndrome., Journal of the neurological sciences, 10.1016/j.jns.2008.01.009, 269, 1-2, 143-51, 2008.06.

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