| 1. |
Tanaka E, Watanabe M, Fukumoto S, Masaki K, Yamasaki R, Matsushita T, Isobe N, Effect of smoking on disease activity in multiple sclerosis patients treated with dimethyl fumarate or fingolimod, Multiple Sclerosis and related disorders, 70, 104513, 2023.01. |
| 2. |
Zhang X, Kira J, Ogata H, Imamura T, Mitsuishi M, Fujii T, Kobayashi M, Kitagawa K, Namihira Y, Ohya Y, Maimaitijiang G, Yamasaki R, Fukata Y, Fukata M, Isobe N, Nakamura Y, Anti-LGI4 antibody is a novel juxtaparanodal autoantibody for chronic inflammatory demyelinating polyneuropathy, Neuroimmunology and Neuroinflammation, 10, 2, e200081, 2023.01. |
| 3. |
Nishimura Y, Masaki K, Matsuse D, Yamaguchi H, Tanaka T, Matsuo E, Hayashida S, Watanabe M, Matsushita T, Sadashima S, Sasagasako N, Yamasaki R, Isobe N, Iwaki T, Kira J, Early and extensive alterations of glial connexins, distal oligodendrogliopathy type demyelination, and nodal/paranodal pathology are characteristic of multiple system atrophy, Brain pathology, e13131, 2022.12. |
| 4. |
Hashimoto Y, Yamasaki R, Senri K, Matsuo E, Kobayakawa Y, Masaki K, Matsuse D, Isobe N, Connexin 30 deficiency ameliorates disease progression at the early phase in a mouse model of amyotrophic lateral sclerosis by suppressing glial inflammation, IJMS, 23, 24, 16046, 2022.12. |
| 5. |
Yamaguchi M, Nakao S, Wada I, Matoba T, Arima M, Kaizu Y, Shirane M, Ishikawa K, Nakama T, Murakami Y, Mizuochi M, Shiraishi W, Yamasaki R, Hisatomi T, Ishibashi T, Shibuya M, Stitt AW, Sonoda KH, Identifying hyperreflective foci in diabetic retinopathy via VEGF-induced local self-renewal of CX3CR1+ vitreous resident macrophages, Diabetes, 71, 12, 2685-2701, 2022.12. |
| 6. |
Uchikawa T, Matoba T, Kawahara T, Baba I, Katsuki S, Koga JI, Hashimoto Y, Yamasaki R, Ichi I, Akita H, Tsutsui H, Dietary 7-ketocholesterol exacerbates myocardial ischemia-reperfusion injury in mice through monocyte/macrophage-mediated inflammation, Scientific reports, 12, 1, 14902, 2022.12. |
| 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. |
The study of facial expression recognition from facial expression discrimination threshold in patients with temporal lobe epilepsy
The present study investigated the ability of facial emotion recognition in patients with temporal lobe epilepsy (TLE). Total of 12 TLE patients and 32 healthy controls were participated. Two tasks consisted of morphing movie task and static picture task were used. Emotions of happiness, anger, sadness and surprise were examined. In the morphing movie task, movies in which face was gradually morphed from neutral emotion expression to maximum emotion expression were presented to the participants, then they were asked to respond when they judged that facial emotion was changed from neutral expression. Reaction time from onset of movie presentation to response was used to calculate facial emotion discrimination threshold. In the static picture task, static image in which face with maximum facial emotion expression was presented, and participants were asked to judge type of emotion. The results showed that the facial emotion discrimination thresholds in emotions of surprise and anger were significantly higher in TLE patients compared with healthy control in the morphing task. No errors were found in the static picture task. TLE patients were able to recognize the facial expression of static image with maximum emotion expression as well as the healthy group, but showed the increase of facial emotion discrimination threshold. The morphing movie task could be detectable increase of facial emotion discrimination threshold in TLE patients.. |
| 9. |
Yuri Mizuno, Nona Abolhassani, Guianfranco Mazzei, Takashi Saito, Takaomi C Saido, Ryo Yamasaki, Jun-Ichi Kira, Yusaku Nakabeppu, Deficiency of MTH1 and/or OGG1 increases the accumulation of 8-oxoguanine in the brain of the AppNL-G-F/NL-G-F knock-in mouse model of Alzheimer's disease, accompanied by accelerated microgliosis and reduced anxiety-like behavior., Neuroscience research, 10.1016/j.neures.2021.11.009, 177, 118-134, 2022.04, Oxidative stress is a major risk factor for Alzheimer's disease (AD). Among various oxidized molecules, the marked accumulation of an oxidized form of guanine, 8-oxo-7,8-dihydroguanine (8-oxoG), is observed in the AD brain. 8-oxo-2'-deoxyguanosine triphosphatase (MTH1) and 8-oxoG DNA glycosylase (OGG1) minimize the 8-oxoG accumulation in DNA, and their expression is decreased in the AD brain. MTH1 and/or OGG1 may suppress the pathogenesis of AD; however, their exact roles remain unclear. We evaluated the roles of MTH1 and OGG1 during the pathogenesis of AD using AppNL-G-F/NL-G-F knock-in mice (a preclinical AD model). Six-month-old female AppNL-G-F/NL-G-F mice with MTH1 and/or OGG1 deficiency exhibited reduced anxiety-related behavior, but their cognitive and locomotive functions were unchanged; the alteration was less evident in 12-month-old mice. MTH1 and/or OGG1 deficiency accelerated the 8-oxoG accumulation and microgliosis in the amygdala and cortex of six-month-old mice; the alteration was less evident in 12-month-old mice. Astrocytes and neurons were not influenced. We showed that MTH1 and OGG1 are essential for minimizing oxidative DNA damage in the AppNL-G-F/NL-G-F brain, and the effects are age-dependent. MTH1 and/or OGG1 deficiency reduced anxiety-related behavior in AppNL-G-F/NL-G-F mice with a significant acceleration of the 8-oxoG burden and microgliosis, especially in the cortex and amygdala.. |
| 10. |
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. |
| 11. |
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 CYP2C19*2 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.
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| 12. |
Taira Uehara, Hiroshi Shigeto, Takahiko Mukaino, Jun Yokoyama, Toshiki Okadome, Ryo Yamasaki, Katsuya Ogata, Nobutaka Mukae, Ayumi Sakata, Shozo Tobimatsu, Jun-ichi Kira, Rapidly spreading seizures arise from large-scale functional brain networks in focal epilepsy, NEUROIMAGE, 10.1016/j.neuroimage.2021.118104, 237, 118104-118104, 2021.08, A B S T R A C T It remains unclear whether epileptogenic networks in focal epilepsy develop on physiological networks. This work aimed to explore the association between the rapid spread of ictal fast activity (IFA), a proposed biomarker for epileptogenic networks, and the functional connectivity or networks of healthy subjects. We reviewed 45 patients with focal epilepsy who underwent electrocorticographic (ECoG) recordings to identify the patients showing the rapid spread of IFA. IFA power was quantified as normalized beta-gamma band power. Using published resting state functional magnetic resonance imaging databases, we estimated resting-state functional connectivity of healthy subjects (RSFC-HS) and resting-state networks of healthy subjects (RSNs-HS) at the locations corresponding to the patients' electrodes. We predicted the IFA power of each electrode based on RSFC-HS between electrode locations (RSFC-HS-based prediction) using a recently developed method, termed activity flow mapping. RSNsHS were identified using seed-based and atlas-based methods. We compared IFA power with RSFC-HS-based prediction or RSNs-HS using non-parametric correlation coefficients. RSFC and seed-based RSNs of each patient (RSFC-PT and seed-based RSNs-PT) were also estimated using interictal ECoG data and compared with IFA power in the same way as RSFC-HS and seed-based RSNs-HS. Spatial autocorrelation-preserving randomization tests were performed for significance testing. Nine patients met the inclusion criteria. None of the patients had reflex seizures. Six patients showed pathological evidence of a structural etiology. In total, we analyzed 49 seizures (2- 13 seizures per patient). We observed significant correlations between IFA power and RSFC-HS-based prediction, seed-based RSNs-HS, or atlas-based RSNs-HS in 28 (57.1%), 21 (42.9%), and 28 (57.1%) seizures, respectively. Thirty-two (65.3%) seizures showed a significant correlation with either seed-based or atlas-based RSNs-HS, but this ratio varied across patients: 27 (93.1%) of 29 seizures in six patients correlated with either of them. Among atlas-based RSNs-HS, correlated RSNs-HS with IFA power included the default mode, control, dorsal attention, somatomotor, and temporal-parietal networks. We could not obtain RSFC-PT and RSNs-PT in one patient due to frequent interictal epileptiform discharges. In the remaining eight patients, most of the seizures showed significant correlations between IFA power and RSFC-PT-based prediction or seed-based RSNs-PT. Our study provides evidence that the rapid spread of IFA in focal epilepsy can arise from physiological RSNs. This finding suggests an overlap between epileptogenic and functional networks, which may explain why functional networks in patients with focal epilepsy frequently disrupt.. |
| 13. |
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.. |
| 14. |
Yukino Miyachi, Takayuki Fujii, Ryo Yamasaki, Daisuke Tsuchimoto, Kyoko Iinuma, Ayako Sakoda, Shoko Fukumoto, Takuya Matsushita, Katsuhisa Masaki, Noriko Isobe, Yusaku Nakabeppu, Jun-ichi Kira, Serum Anti-oligodendrocyte Autoantibodies in Patients With Multiple Sclerosis Detected by a Tissue-Based Immunofluorescence Assay, Frontiers in Neurology, 10.3389/fneur.2021.681980, 12, 681980-681980, 2021.08, Multiple sclerosis (MS), the most prevalent inflammatory disease of the central nervous system (CNS), is characterized by damaged to myelin sheaths and oligodendrocytes. Because MS patients have variable clinical courses and disease severities, it is important to identify biomarkers that predict disease activity and severity. In this study, we assessed the frequencies of serum autoantibodies against mature oligodendrocytes in MS patients using a tissue-based immunofluorescence assay (IFA) to determine whether anti-oligodendrocyte antibodies are associated with the clinical features of MS patients and whether they might be a biomarker to assess CNS tissue damage in MS patients. We assessed the binding of serum autoantibodies to mouse oligodendrocytes expressing Nogo-A, a reliable mature oligodendrocyte marker, by IFA with mouse brain and sera from 147 MS patients, comprising 103 relapsing–remitting MS (RRMS), 22 secondary progressive MS (SPMS), and 22 primary progressive MS (PPMS) patients, 38 neuromyelitis optica spectrum disorder (NMOSD) patients, 23 other inflammatory neurological disorder (OIND) patients, and 39 healthy controls (HCs). Western blotting (WB) was performed using extracted mouse cerebellum proteins and IgG from anti-oligodendrocyte antibody-positive MS patients. Tissue-based IFA showed that anti-oligodendrocyte antibodies were positive in 3/22 (13.6%) PPMS and 1/22 (4.5%) SPMS patients but not in RRMS, NMOSD, and OIND patients or HCs. WB demonstrated the target CNS proteins recognized by serum anti-oligodendrocyte antibodies were approximately 110 kDa and/or 150 kDa. Compared with anti-oligodendrocyte antibody-negative MS patients, MS patients with anti-oligodendrocyte antibodies were significantly older at the time of serum sampling, scored significantly higher on the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score, and had a higher frequency of mental disturbance. Although the clinical significance of anti-oligodendrocyte antibodies is still unclear because of their low frequency, anti-oligodendrocyte autoantibodies are potential biomarkers for monitoring the disease pathology and progression in MS.. |
| 15. |
Takayuki Fujii, Eun-Jae Lee, Yukino Miyachi, Ryo Yamasaki, Young-Min Lim, Kyoko Iinuma, Ayako Sakoda, Kwang-Kuk Kim, Jun-Ichi Kira, Antiplexin D1 Antibodies Relate to Small Fiber Neuropathy and Induce Neuropathic Pain in Animals., Neurology(R) neuroimmunology & neuroinflammation, 10.1212/NXI.0000000000001028, 8, 5, 2021.07, OBJECTIVES: To assess the prevalence of antiplexin D1 antibodies (plexin D1-immunoglobulin G [IgG]) in small fiber neuropathy (SFN) and the effects of these antibodies in vivo. METHODS: We developed an ELISA for plexin D1-IgG using a recombinant extracellular domain of human plexin D1 containing the major epitope and sera from 58 subjects previously studied with a standard tissue-based indirect immunofluorescence assay (TBA). We screened 63 patients with probable SFN and 55 healthy controls (HCs) for serum plexin D1-IgG using ELISA. The results were confirmed by TBA. IgG from 3 plexin D1-IgG-positive patients, 2 plexin D1-IgG-negative inflammatory disease controls, and 2 HCs was intrathecally injected into mice, which were assessed for mechanical and thermal hypersensitivity 24 and 48 hours after injection. RESULTS: The ELISA had 75% sensitivity and 100% specificity using the TBA as a standard, and the coincidence rate of ELISA to TBA was 96.6% (56/58). The frequency of plexin D1-IgG was higher in patients with SFN than in HCs (12.7% [8/63] vs 0.0% [0/55], p = 0.007). Purified IgG from all 3 plexin D1-IgG-positive patients, but not 2 plexin D1-IgG-negative patients, induced significant mechanical and/or thermal hypersensitivity compared with IgG from HCs. In mice injected with plexin D1-IgG-positive but not D1-IgG-negative patient IgG, phosphorylated extracellular signal-regulated protein kinase immunoreactivity, an activation marker, was confined to small dorsal root ganglion neurons and was significantly more abundant than in mice injected with HC IgG. CONCLUSIONS: Plexin D1-IgG is pathogenic but with low prevalence and is a potential biomarker for immunotherapy in SFN.. |
| 16. |
Ban yu Saitoh, Eizo Tanaka, Norio Yamamoto, Daan van Kruining, Kyoko Iinuma, Yuko Nakamuta, Hiroo Yamaguchi, Ryo Yamasaki, Koichiro Matsumoto, Jun ichi Kira, Early postnatal allergic airway inflammation induces dystrophic microglia leading to excitatory postsynaptic surplus and autism-like behavior, Brain, Behavior, and Immunity, 10.1016/j.bbi.2021.04.008, 95, 362-380, 2021.07, Microglia play key roles in synaptic pruning, which primarily occurs from the postnatal period to adolescence. Synaptic pruning is essential for normal brain development and its impairment is implicated in neuropsychiatric developmental diseases such as autism spectrum disorders (ASD). Recent epidemiological surveys reported a strong link between ASD and atopic/allergic diseases. However, few studies have experimentally investigated the relationship between allergy and ASD-like manifestations, particularly in the early postnatal period, when allergic disorders occur frequently. Therefore, we aimed to characterize how allergic inflammation in the early postnatal period influences microglia and behavior using mouse models of short- and long-term airway allergy. Male mice were immunized by an intraperitoneal injection of aluminum hydroxide and ovalbumin (OVA) or phosphate-buffered saline (control) on postnatal days (P) 3, 7, and 11, followed by intranasal challenge with OVA or phosphate-buffered saline solution twice a week until P30 or P70. In the hippocampus, Iba-1-positive areas, the size of Iba-1-positive microglial cell bodies, and the ramification index of microglia by Sholl analysis were significantly smaller in the OVA group than in the control group on P30 and P70, although Iba-1-positive microglia numbers did not differ significantly between the two groups. In Iba-1-positive cells, postsynaptic density protein 95 (PSD95)-occupied areas and CD68-occupied areas were significantly decreased on P30 and P70, respectively, in the OVA group compared with the control group. Immunoblotting using hippocampal tissues demonstrated that amounts of PSD95, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 2, and N-methyl-D-aspartate (NMDA) receptor 2B were significantly increased in the OVA group compared with the control group on P70, and a similar increasing trend for PSD95 was observed on P30. Neurogenesis was not significantly different between the two groups on P30 or P70 by doublecortin immunohistochemistry. The social preference index was significantly lower in the three chamber test and the number of buried marbles was significantly higher in the OVA group than in the control group on P70 but not on P30, whereas locomotion and anxiety were not different between the two groups. Compared with the control group, serum basal corticosterone levels were significantly elevated and hippocampal glucocorticoid receptor (GR) amounts and nuclear GR translocation in microglia, but not in neurons or astrocytes, were significantly decreased in the OVA group on P70 but not on P30. Gene set enrichment analysis of isolated microglia revealed that genes related to immune responses including Toll-like receptor signaling and chemokine signaling pathways, senescence, and glucocorticoid signaling were significantly upregulated in the OVA group compared with the control group on P30 and P70. These findings suggest that early postnatal allergic airway inflammation induces dystrophic microglia that exhibit defective synaptic pruning upon short- and long-term allergen exposure. Furthermore, long-term allergen exposure induced excitatory postsynaptic surplus and ASD-like behavior. Hypothalamo-pituitary-adrenal axis activation and the compensatory downregulation of microglial GR during long-term allergic airway inflammation may also facilitate these changes.. |
| 17. |
Hayato Une, Ryo Yamasaki, Satoshi Nagata, Hiroo Yamaguchi, Yuko Nakamuta, Ulfa Camelia Indiasari, Yiwen Cui, Koji Shinoda, Katsuhisa Masaki, Magdalena Götz, Jun-Ichi Kira, Brain gray matter astroglia-specific connexin 43 ablation attenuates spinal cord inflammatory demyelination., Journal of neuroinflammation, 10.1186/s12974-021-02176-1, 18, 1, 126-126, 2021.06, BACKGROUND: Brain astroglia are activated preceding the onset of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We characterized the effects of brain astroglia on spinal cord inflammation, focusing on astroglial connexin (Cx)43, because we recently reported that Cx43 has a critical role in regulating neuroinflammation. METHODS: Because glutamate aspartate transporter (GLAST)+ astroglia are enriched in the brain gray matter, we generated Cx43fl/fl;GLAST-CreERT2/+ mice that were brain gray matter astroglia-specific Cx43 conditional knockouts (Cx43 icKO). EAE was induced by immunization with myelin oligodendroglia glycoprotein (MOG) 35-55 peptide 10 days after tamoxifen injection. Cx43fl/fl mice were used as controls. RESULTS: Acute and chronic EAE signs were significantly milder in Cx43 icKO mice than in controls whereas splenocyte MOG-specific responses were unaltered. Histologically, Cx43 icKO mice showed significantly less demyelination and fewer CD45+ infiltrating immunocytes, including F4/80+ macrophages, and Iba1+ microglia in the spinal cord than controls. Microarray analysis of the whole cerebellum revealed marked upregulation of anti-inflammatory A2-specific astroglia gene sets in the pre-immunized phase and decreased proinflammatory A1-specific and pan-reactive astroglial gene expression in the onset phase in Cx43 icKO mice compared with controls. Astroglia expressing C3, a representative A1 marker, were significantly decreased in the cerebrum, cerebellum, and spinal cord of Cx43 icKO mice compared with controls in the peak phase. Isolated Cx43 icKO spinal microglia showed more anti-inflammatory and less proinflammatory gene expression than control microglia in the pre-immunized phase. In particular, microglial expression of Ccl2, Ccl5, Ccl7, and Ccl8 in the pre-immunized phase and of Cxcl9 at the peak phase was lower in Cx43 icKO than in controls. Spinal microglia circularity was significantly lower in Cx43 icKO than in controls in the peak phase. Significantly lower interleukin (IL)-6, interferon-γ, and IL-10 levels were present in cerebrospinal fluid from Cx43 icKO mice in the onset phase compared with controls. CONCLUSIONS: The ablation of Cx43 in brain gray matter astroglia attenuates EAE by promoting astroglia toward an anti-inflammatory phenotype and suppressing proinflammatory activation of spinal microglia partly through depressed cerebrospinal fluid proinflammatory cytokine/chemokine levels. Brain astroglial Cx43 might be a novel therapeutic target for MS.. |
| 18. |
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.. |
| 19. |
Yuko Yamagishi, Motoi Kuwahara, Hidekazu Suzuki, Masahiro Sonoo, Satoshi Kuwabara, Takanori Yokota, Kyoichi Nomura, Atsuro Chiba, Ryuji Kaji, Takashi Kanda, Ken-Ichi Kaida, Tatsuro Mutoh, Ryo Yamasaki, Hiroshi Takashima, Makoto Matsui, Kazutoshi Nishiyama, Gen Sobue, Susumu Kusunoki, Serum IgG anti-GD1a antibody and mEGOS predict outcome in Guillain-Barré syndrome., Journal of neurology, neurosurgery, and psychiatry, 10.1136/jnnp-2020-323960, 91, 12, 1339-1342, 2020.12, OBJECTIVE: Approximately 15%-20% of patients with Guillain-Barré syndrome (GBS) are unable to walk independently at 6 months from the onset of neurological symptom. The modified Erasmus GBS outcome score (mEGOS) has been reported as a prognostic tool.Herein we investigated the association between a poor outcome, inability to walk independently at 6 months and presence of antiganglioside antibodies. METHODS: The clinical and serological data of 177 patients with GBS were retrospectively collected in Japan to assess the associations between a poor outcome and serum IgG antibodies against each ganglioside (GM1, GD1a, GalNAc-GD1a, GQ1b and GT1a). In addition, we investigated whether the combination of mEGOS and serum IgG antibodies against gangliosides is useful in predicting a poor outcome. RESULTS: The patients with IgG anti-GD1a antibodies more frequently showed poor outcomes than those without these antibodies (9 (36%) of 25 vs 8 (6%) of 127 patients, p |
| 20. |
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.. |
| 21. |
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.. |
| 22. |
Yuki Yanagihara, Shintaro Hayashi, Junpei Koge, Hiroyuki Honda, Ryo Yamasaki, Yuichi Yamada, Yoshinao Oda, Toru Iwaki, Jun-Ichi Kira, Immunotherapy-refractory vacuolar myopathy with mucin deposition in scleromyxedema: A possible role of fibroblast growth factor 2., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12659, 40, 5, 492-495, 2020.10, Scleromyxedema (SME) is characterized by widespread waxy papules on the skin, with mucin deposits in the upper dermis. Twenty-one SME cases of myopathy have been reported; of the cases, six showed vacuolar formation, and two showed mucin deposition. We report the first case of SME with mucin-associated vacuolated fibers. A 45-year-old woman with SME developed progressive proximal muscle weakness. Muscle biopsy revealed myopathic changes with numerous vacuoles linked to mucin in the affected muscle fibers, which were heavily immunostained for fibroblast growth factor 2 (FGF2). Despite repeated high dose oral prednisolone and intravenous immunoglobulin administrations, muscle weakness recurred continuingly, culminating in death due to congestive heart failure. Immunotherapy was partly effective in our case, although it was refractory. Treatment responsiveness in patients with SME myopathy varied; however, due to its rarity, the mechanism remains to be elucidated. To address this issue, we investigated muscle specimens immunohistochemically and detected marked upregulation of FGF2 in the affected muscle fibers of our patient. FGF2, a strong myogenesis inhibitor, may exert a suppressive effect on muscle fiber regeneration, which may have conferred refractoriness to our patient's SME myopathy.. |
| 23. |
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.. |
| 24. |
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 (DRB1*15:01 for Caucasians and DRB1*04:05 and DRB1*15:01 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-DRB1*15 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-DRB1*15, DRB1*04 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB1*04:02 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-DRB1*15 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-DRB1*15-carriers, DRB1*04 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023). CONCLUSIONS: HLA-DRB1*15 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB1*15, 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.. |
| 25. |
Pukovisa Prawiroharjo, Ken-Ichiro Yamashita, Koji Yamashita, Osamu Togao, Akio Hiwatashi, Ryo Yamasaki, Jun-Ichi Kira, Disconnection of the right superior parietal lobule from the precuneus is associated with memory impairment in oldest-old Alzheimer's disease patients., Heliyon, 10.1016/j.heliyon.2020.e04516, 6, 7, e04516, 2020.07, There is a wide range of onset age in Alzheimer's disease (AD). Emerging evidence indicates variation of AD manifestations in oldest-old AD (OOAD); however, the pattern of cognitive dysfunctions remains unclear. We aimed to reveal cognitive performance characteristics and changes in brain functional connectivity in OOAD patients by a resting-state fMRI (rs-fMRI) study. We enrolled AD patients who had been referred to Kyushu University Hospital (KUH) or Sanno Hospital, and classified them into middle-old AD (MOAD) (65-79 years old) and OOAD (≥80 years old) according to the age of onset. Our subjects consisted of 19 OOAD, 17 MOAD, and 8 normal subjects. Cognitive performance was evaluated using Mini Mental State Examination-Japanese (MMSE-J) and Clinical Dementia Rating (CDR). rs-fMRI scanning and independent component analysis (ICA) were performed on Sanno Hospital patients and MOAD vs. OOAD patients were compared. The resulting significant regions were used as seeds for ROI-to-ROI analysis of the KUH dataset. Collectively, MMSE-J delayed recall sub-scores were significantly lower in OOAD patients compared with MOAD patients. ICA of the Sanno Hospital data indicated significant connectivity decrease in the default mode network (DMN) in the OOAD group compared with the MOAD group in the right superior parietal lobule (SPL). ROI-to-ROI analysis of the KUH dataset indicated significant disconnection in the OOAD group of the right SPL from the precuneus (p |
| 26. |
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, 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, DRB1*15:01 and DRB1*04:05, 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-DRB1*15:01(+)*04:05(−) and HLA-DRB1*15:01(−)*04:05(+) comprised 25.8% and 31.8% of patients, respectively. HLA-DRB1*15:01 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-DRB1*04:05 carriers. HLA-DRB1*15:01 carriers had a significantly faster reduction in NWBV and NWMV by disease duration and smaller NDGMV than DRB1*15:01 non-carriers, whereas HLA-DRB1*04:05 carriers had a significantly slower increase in FLAIR and T1 lesion volumes than HLA-DRB1*04:05 non-carriers. Conclusions: Our study suggests that distinct HLA-DRB1 alleles could differentially influence brain and lesion volumes over the disease course of MS.. |
| 27. |
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, DRB1*15:01 and DRB1*04:05, 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-DRB1*15:01(+)*04:05(-) and HLA-DRB1*15:01(-)*04:05(+) comprised 25.8% and 31.8% of patients, respectively. HLA-DRB1*15:01 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-DRB1*04:05 carriers. HLA-DRB1*15:01 carriers had a significantly faster reduction in NWBV and NWMV by disease duration and smaller NDGMV than DRB1*15:01 non-carriers, whereas HLA-DRB1*04:05 carriers had a significantly slower increase in FLAIR and T1 lesion volumes than HLA-DRB1*04:05 non-carriers. CONCLUSIONS: Our study suggests that distinct HLA-DRB1 alleles could differentially influence brain and lesion volumes over the disease course of MS.. |
| 28. |
Koji Tanaka, Shoji Matsumoto, Konosuke Furuta, Takeshi Yamada, Sukehisa Nagano, Kei ichiro Takase, Taketo Hatano, Ryo Yamasaki, Jun ichi Kira, Differences between predictive factors for early neurological deterioration due to hemorrhagic and ischemic insults following intravenous recombinant tissue plasminogen activator, Journal of Thrombosis and Thrombolysis, 10.1007/s11239-019-02015-4, 49, 4, 545-550, 2020.05, Early neurological deterioration (END) following intravenous recombinant tissue plasminogen activator (rt-PA) treatment is a serious clinical event that can be caused by hemorrhagic or ischemic insult. We investigated the differences in predictive factors for END due to hemorrhagic and END due to ischemic insults. Consecutive patients from four hospitals who received 0.6 mg/kg intravenous rt-PA for acute ischemic stroke were retrospectively recruited. END was defined as a National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 points within 24 h compared with baseline. END was classified into those due to hemorrhagic (ENDh) or ischemic (ENDi) insult based on computed tomography (CT) or magnetic resonance imaging. Risk factors associated with ENDh and ENDi were investigated by comparison with non-END cases. A total of 744 patients (452 men, median 75 years old) were included. END was observed in 79 patients (10.6%), including 22 ENDh (3.0%) and 57 ENDi (7.7%), which occurred within a median of 7 h after treatment. Multivariate analyses showed that higher pretreatment NIHSS score (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.00–1.13) and pretreatment with antiplatelets (OR 2.84, 95% CI 1.08–7.72) were associated with ENDh. Extensive early ischemic change (Alberta Stroke Program Early CT Score ≤ 7 on CT or ≤ 6 on diffusion-weighted imaging; OR 2.80, 95% CI 1.36–5.64) and large artery occlusions (OR 3.09, 95% CI 1.53–6.57) were associated with ENDi. Distinct factors were predictive for the END subtypes. These findings could help develop preventative measures for END in patients with the identified risk factors.. |
| 29. |
Tomohiro Imamura, Yuki T. Yanagihara, Yasumasa Ohyagi, Norimichi Nakamura, Kyoko M. Iinuma, Ryo Yamasaki, Hirohide Asai, Masahiro Maeda, Kazuma Murakami, Kazuhiro Irie, Jun ichi Kira, Insulin deficiency promotes formation of toxic amyloid-β42 conformer co-aggregating with hyper-phosphorylated tau oligomer in an Alzheimer's disease model, Neurobiology of Disease, 10.1016/j.nbd.2020.104739, 137, 2020.04, The toxic conformer of amyloid β-protein (Aβ) ending at 42 (Aβ42), which contains a unique turn conformation at amino acid residue positions 22 and 23 and tends to form oligomers that are neurotoxic, was reported to play a critical role in the pathomechanisms of Alzheimer's disease (AD), in which diabetes mellitus (DM)-like mechanisms are also suggested to be operative. It remains to be established whether the attenuation of insulin signaling is involved in an increase of toxic Aβ42 conformer levels. The present study investigated the association between impaired insulin metabolism and formation of toxic Aβ42 conformers in the brains of an AD mouse model. In particular, we studied whether insulin deficiency or resistance affected the formation of toxic Aβ42 conformers in vivo. We induced insulin deficiency and resistance in 3xTg-AD mice, a mouse AD model harboring two familial AD-mutant APP (KM670/671NL) and PS1 (M146 V) genes and a mutant TAU (P301L) gene, by streptozotocin (STZ) injection and a high fructose diet (HFuD), respectively. Cognitive impairment was significantly worsened by STZ injection but not by HFuD. Dot blot analysis revealed significant increases in total Aβ42 levels and the ratio of toxic Aβ42 conformer/total Aβ42 in STZ-treated mice compared with control and HFuD-fed mice. Immunostaining showed the accumulation of toxic Aβ42 conformers and hyper-phosphorylated tau protein (p-tau), which was more prominent in the cortical and hippocampal neurons of STZ-treated mice compared with HFuD-fed and control mice. HFuD-fed mice showed only a mild-to-moderate increase of these proteins compared with controls. Toxic Aβ42 conformers were co-localized with p-tau oligomers (Pearson's correlation coefficient = 0.62) in the hippocampus, indicating their co-aggregation. Toxic Aβ42 conformer levels were inversely correlated with pancreatic insulin secretion capacity as shown by fasting immunoreactive insulin levels in STZ-treated mice (correlation coefficient = −0.5879, p =.04441), but not HFuD-fed mice, suggesting a decrease in serum insulin levels correlates with toxic Aβ42 conformer formation. Levels of p-Akt and phosphorylated glycogen synthase kinase-3β measured by a homogeneous time-resolved fluorescence assay were significantly lower in STZ-treated mice than in HFuD-fed mice, suggesting a greater inhibition of brain insulin signaling by STZ than HFuD, although both levels were significantly decreased in these groups compared with controls. Iba1-positive and NOS2-positive areas in the cortex and hippocampus were significantly increased in STZ-treated mice and to a lesser extent in HFuD-fed mice compared with controls. These findings suggest that insulin deficiency rather than insulin resistance and the resultant impairment of brain insulin signaling facilitates the formation of toxic Aβ42 conformer and its co-aggregation with p-tau oligomers, and that insulin deficiency is an important pathogenic factor in the progression of AD.. |
| 30. |
Tomohiro Imamura, Yuki T Yanagihara, Yasumasa Ohyagi, Norimichi Nakamura, Kyoko M Iinuma, Ryo Yamasaki, Hirohide Asai, Masahiro Maeda, Kazuma Murakami, Kazuhiro Irie, Jun-Ichi Kira, Insulin deficiency promotes formation of toxic amyloid-β42 conformer co-aggregating with hyper-phosphorylated tau oligomer in an Alzheimer's disease model., Neurobiology of disease, 10.1016/j.nbd.2020.104739, 137, 104739-104739, 2020.04, The toxic conformer of amyloid β-protein (Aβ) ending at 42 (Aβ42), which contains a unique turn conformation at amino acid residue positions 22 and 23 and tends to form oligomers that are neurotoxic, was reported to play a critical role in the pathomechanisms of Alzheimer's disease (AD), in which diabetes mellitus (DM)-like mechanisms are also suggested to be operative. It remains to be established whether the attenuation of insulin signaling is involved in an increase of toxic Aβ42 conformer levels. The present study investigated the association between impaired insulin metabolism and formation of toxic Aβ42 conformers in the brains of an AD mouse model. In particular, we studied whether insulin deficiency or resistance affected the formation of toxic Aβ42 conformers in vivo. We induced insulin deficiency and resistance in 3xTg-AD mice, a mouse AD model harboring two familial AD-mutant APP (KM670/671NL) and PS1 (M146 V) genes and a mutant TAU (P301L) gene, by streptozotocin (STZ) injection and a high fructose diet (HFuD), respectively. Cognitive impairment was significantly worsened by STZ injection but not by HFuD. Dot blot analysis revealed significant increases in total Aβ42 levels and the ratio of toxic Aβ42 conformer/total Aβ42 in STZ-treated mice compared with control and HFuD-fed mice. Immunostaining showed the accumulation of toxic Aβ42 conformers and hyper-phosphorylated tau protein (p-tau), which was more prominent in the cortical and hippocampal neurons of STZ-treated mice compared with HFuD-fed and control mice. HFuD-fed mice showed only a mild-to-moderate increase of these proteins compared with controls. Toxic Aβ42 conformers were co-localized with p-tau oligomers (Pearson's correlation coefficient = 0.62) in the hippocampus, indicating their co-aggregation. Toxic Aβ42 conformer levels were inversely correlated with pancreatic insulin secretion capacity as shown by fasting immunoreactive insulin levels in STZ-treated mice (correlation coefficient = -0.5879, p = .04441), but not HFuD-fed mice, suggesting a decrease in serum insulin levels correlates with toxic Aβ42 conformer formation. Levels of p-Akt and phosphorylated glycogen synthase kinase-3β measured by a homogeneous time-resolved fluorescence assay were significantly lower in STZ-treated mice than in HFuD-fed mice, suggesting a greater inhibition of brain insulin signaling by STZ than HFuD, although both levels were significantly decreased in these groups compared with controls. Iba1-positive and NOS2-positive areas in the cortex and hippocampus were significantly increased in STZ-treated mice and to a lesser extent in HFuD-fed mice compared with controls. These findings suggest that insulin deficiency rather than insulin resistance and the resultant impairment of brain insulin signaling facilitates the formation of toxic Aβ42 conformer and its co-aggregation with p-tau oligomers, and that insulin deficiency is an important pathogenic factor in the progression of AD.. |
| 31. |
Takayuki Fujii, Ryo Yamasaki, Yukino Miyachi, Kyoko Iinuma, Jun ichi Kira, Anti-plexin D1 antibody–mediated neuropathic pain, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12570, 11, S1, 48-52, 2020.03, Neuropathic pain (NeP) is an intractable pain caused by a lesion or disease of the somatosensory nervous system. NeP is often challenging to manage because most of the mechanisms remain to be elucidated. Recent investigations in the field of autoimmune neurology have demonstrated that specific autoantibodies against antigens in the somatosensory pathway can cause NeP. Detection of pathogenic autoantibodies in NeP adds to the understanding of the mechanism of pain, which might aid in the development of novel immunotherapies. Therefore, it is necessary to explore novel NeP-related autoantibodies to improve the management of intractable pain. Recently, we screened serum autoantibodies that bound to pain-conducting small dorsal root ganglion (DRG) neurons and their nerve terminals in the dorsal horns of NeP patients. We detected a novel autoantibody that bound to unmyelinated C-fiber–type small DRG neurons. The positive rate in patients with NeP was 10%. We identified plexin D1 as the target antigen. NeP patients with plexin D1-IgG developed burning pain and thermal hyperalgesia. The main comorbidities were allergy, collagen vascular disease, and cancer. Plasma exchange and intravenous methylprednisolone pulse therapy are effective for NeP in patients with plexin D1-IgG, indicating that these autoantibodies might be pathogenic in NeP. Indeed, our in vitro study demonstrated that plexin D1-IgG induced the membrane hyperpermeability of DRG neurons. In this review, we describe the discovery of plexin D1-IgG and discuss the association between plexin D1 and pain, allergy, and cancer.. |
| 32. |
Motoi Yoshimura, Taira Uehara, Eizo Tanaka, Toshiki Okadome, Takahiro Yamaguchi, Yasuhiro Maeda, Noriko Isobe, Takuya Matsushita, Ryo Yamasaki, Jun ichi Kira, Double positivity for anti-N-methyl-d-aspartate receptor and anti-aquaporin-4 antibodies in a patient presenting with hypersomnolence, personality change, and reduced spontaneity, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12571, 11, S1, 53-56, 2020.03, Background: Recently, the coexistence of anti-aquaporin-4 antibody (AQP4-ab) and anti-N-methyl-d-aspartate receptor antibody (NMDAR-ab) were reported in a single case. However, its clinical significance is not well defined. Case presentation: A 42-year-old woman developed hypersomnolence, personality change, and childish or bizarre behavior. Four months later, she exhibited marked reduction of verbal and motor spontaneity. Serum AQP4-ab was positive. Cerebrospinal fluid (CSF) was positive for oligoclonal bands. Brain magnetic resonance imaging (MRI) detected multiple T2-hyperintense lesions without gadolinium enhancement in the pons, midbrain, bilateral internal capsule, basal ganglia, corpus callosum, and deep cerebral white matter. Spinal MRI was negative. Because clinical symptoms and clinical course were atypical for neuromyelitis optica spectrum disorders (NMOSD), CSF NMDAR-ab was tested and found to be positive. Whole-body examination revealed cystic lesions in the right ovary, which were later found not to be malignant tumors. In accordance with the proposed algorithm for the treatment of NMDAR encephalitis (NMDARE), she was treated with three courses of intravenous methylprednisolone pulse therapy, followed by oral prednisolone, intravenous immunoglobulin therapy, and five courses of bimonthly intravenous cyclophosphamide pulse therapy. Her symptoms gradually improved, and she returned to her daily life without major sequelae. Conclusions: Although her main symptoms were compatible with NMDARE, MRI findings were more compatible with NMOSD. Therefore, we interpreted her clinical and imaging features as a mixed phenotype of NMOSD and NMDARE. This case report provides additional evidence that double positivity for AQP4-ab and NMDAR-ab is associated with a mixed phenotype of NMOSD and NMDARE.. |
| 33. |
Ryo Yamasaki, Novel animal model of multiple sclerosis
The glial connexin gap junction as an environmental tuner for neuroinflammation, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12568, 11, S1, 34-40, 2020.03, Connexins, which comprise gap junctions (GJs) via homotypic/heterotypic oligomerization, act as channels to connect opposing cells, mainly in solid organs such as the skin, liver, heart, and central/peripheral nervous system. Connexins are synthesized in the endoplasmic reticulum, assembled in the Golgi apparatus as hexamers, and inserted into the cell membrane as hemichannels. These hemichannels are closed under normal conditions until they combine to form clusters and connect to neighboring cells via GJs in a head-to-head configuration. Opening of hemichannels, which depends on the intra- or extracellular environment, allows various bioactive molecules to enter into or be released from the host cells. Recent pathological studies on human demyelinating diseases have revealed alterations of connexin expression patterns in demyelinating lesions. To elucidate the molecular mechanisms of connexins in the pathomechanisms of inflammatory demyelination, we induced experimental autoimmune encephalomyelitis (EAE) in connexin 30 (Cx30)-deficient mice, oligodendroglia-specific Cx47-ablated mice, and astroglia-specific Cx43-ablated mice. We found that both astroglial-Cx30-deficient mice and Cx43-ablated mice showed amelioration of the clinical course of EAE, while oligodendroglial-Cx47-ablated mice showed aggravation. These findings indicate the distinct role of connexins expressed in different cell types and the substantial contribution of connexin-mediated pathology to demyelinating disorders. The imbalance in connexin expression, which is caused by the inflammatory environment, results in an increase in hemichannels in glial cells. The release of proinflammatory molecules induced by the increase in hemichannels on activated glial cells is a crucial mechanism of demyelinating disorders.. |
| 34. |
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, 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.. |
| 35. |
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, 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 |
| 36. |
Mitsunori Shimmura, Taira Uehara, Katsuya Ogata, Hiroshi Shigeto, Tomoko Maeda, Ayumi Sakata, Ryo Yamasaki, Jun ichi Kira, Corrigendum to “Higher postictal parasympathetic activity following greater ictal heart rate increase in right- than left-sided seizures” (Epilepsy & Behavior (2019) 97 (161–168), (S1525505019300174), (10.1016/j.yebeh.2019.05.026)), Epilepsy and Behavior, 10.1016/j.yebeh.2019.106865, 103, 2020.02, The authors regret that the legend of Fig. 4 in the above article contained errors. The sample sizes for right-sided seizures (n = 27) and left-sided seizures (n = 27) are wrong. The corrected sentence is as follows: Red lines indicate right-sided seizures (n = 24), and blue lines indicate left-sided seizures (n = 24). This is a simple typographical error and does not change the conclusions of the paper. The authors would like to apologize for any inconvenience caused.. |
| 37. |
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, 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 |
| 38. |
Minako Kawaguchi, Kazuhiro Samura, Yasushi Miyagi, Tsuyoshi Okamoto, Ryo Yamasaki, Nobutaka Sakae, Fumiaki Yoshida, Koji Iihara, The effects of chronic subthalamic stimulation on nonmotor symptoms in advanced Parkinson’s disease, revealed by an online questionnaire program, Acta Neurochirurgica, 10.1007/s00701-019-04182-y, 162, 2, 247-255, 2020.02, Background: This study was designed to detect and assess the frequency and severity of nonmotor symptoms (NMSs) in advanced Parkinson’s disease (PD) and to investigate the effects of subthalamic nucleus deep brain stimulation (STN-DBS) on NMSs. Methods: We developed an online PC–based questionnaire program to assess NMSs in PD. Twenty-six PD patients who underwent bilateral STN-DBS were assessed. The NMS questionnaire consisted of 54 NMSs in three categories, based on Witjas et al. (2002). For each NMS, the patients were asked whether or not it was present, whether or not the fluctuating manifestations correlated with the timing of levodopa-induced motor fluctuations, and how severe the NMS was. Patients were assessed by this system before surgery and at the follow-up visit, 3 to 6 months after surgery. At the postoperative assessment, patients were also assessed on preoperative NMSs using recall. Results: The most frequent preoperative NMSs were constipation and visual disorders, while the most frequent postoperative NMSs were difficulty in memorizing and pollakiuria. The ranking of most frequent NMSs changed from before to after surgery. NMSs of drenching sweats, dysphagia, and constipation were significantly ameliorated, while NMSs of dyspnea and slowness of thinking were significantly deteriorated after surgery. The preoperative assessment by postoperative recall gave very different results from that of the preoperative assessment. Conclusion: An online questionnaire system to assess NMSs in patients with advanced PD suggested that STN-DBS might influence the frequencies of some kinds of NMSs.. |
| 39. |
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, 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-DRB1*15:01-DRB5*01:01-DQA1*01:02-DQB1*06:02 or -(A*24:02)-B*52:01-C*12:02-DRB1*15:02-DRB5*01:02-DQA1*01:03-DQB1*06:01, resulting in significantly increased HLA-DRB1*15, -DRB1*15:01, -DQB1*06:01/06:02, -DQB1*06:02, and -DRB1*15:01-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.. |
| 40. |
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.. |
| 41. |
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 |
| 42. |
Mitsunori Shimmura, Taira Uehara, Katsuya Ogata, Hiroshi Shigeto, Tomoko Maeda, Ayumi Sakata, Ryo Yamasaki, Jun-Ichi Kira, Corrigendum to "Higher postictal parasympathetic activity following greater ictal heart rate increase in right- than left-sided seizures" [Epilepsy Behav 97 (2019) 161-168]., Epilepsy & behavior : E&B, 10.1016/j.yebeh.2019.106865, 103, Pt A, 106865-106865, 2020.02. |
| 43. |
Minako Kawaguchi, Kazuhiro Samura, Yasushi Miyagi, Tsuyoshi Okamoto, Ryo Yamasaki, Nobutaka Sakae, Fumiaki Yoshida, Koji Iihara, The effects of chronic subthalamic stimulation on nonmotor symptoms in advanced Parkinson's disease, revealed by an online questionnaire program., Acta neurochirurgica, 10.1007/s00701-019-04182-y, 162, 2, 247-255, 2020.02, BACKGROUND: This study was designed to detect and assess the frequency and severity of nonmotor symptoms (NMSs) in advanced Parkinson's disease (PD) and to investigate the effects of subthalamic nucleus deep brain stimulation (STN-DBS) on NMSs. METHODS: We developed an online PC-based questionnaire program to assess NMSs in PD. Twenty-six PD patients who underwent bilateral STN-DBS were assessed. The NMS questionnaire consisted of 54 NMSs in three categories, based on Witjas et al. (2002). For each NMS, the patients were asked whether or not it was present, whether or not the fluctuating manifestations correlated with the timing of levodopa-induced motor fluctuations, and how severe the NMS was. Patients were assessed by this system before surgery and at the follow-up visit, 3 to 6 months after surgery. At the postoperative assessment, patients were also assessed on preoperative NMSs using recall. RESULTS: The most frequent preoperative NMSs were constipation and visual disorders, while the most frequent postoperative NMSs were difficulty in memorizing and pollakiuria. The ranking of most frequent NMSs changed from before to after surgery. NMSs of drenching sweats, dysphagia, and constipation were significantly ameliorated, while NMSs of dyspnea and slowness of thinking were significantly deteriorated after surgery. The preoperative assessment by postoperative recall gave very different results from that of the preoperative assessment. CONCLUSION: An online questionnaire system to assess NMSs in patients with advanced PD suggested that STN-DBS might influence the frequencies of some kinds of NMSs.. |
| 44. |
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-DRB1*15:01-DRB5*01:01-DQA1*01:02-DQB1*06:02 or -(A*24:02)-B*52:01-C*12:02-DRB1*15:02-DRB5*01:02-DQA1*01:03-DQB1*06:01, resulting in significantly increased HLA-DRB1*15, -DRB1*15:01, -DQB1*06:01/06:02, -DQB1*06:02, and -DRB1*15:01-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.. |
| 45. |
Hayato Une, Dai Matsuse, Taira Uehara, Yoshikazu Kikuchi, Saeko Inamizu, Ryo Yamasaki, Shozo Tobimatsu, Hiroshi Shibasaki, Jun ichi Kira, Branchial myorhythmia in a case of systemic lupus erythematosus, Journal of the Neurological Sciences, 10.1016/j.jns.2019.116501, 408, 2020.01. |
| 46. |
Yuki Yanagihara, Shintaro Hayashi, Junpei Koge, Hiroyuki Honda, Ryo Yamasaki, Yuichi Yamada, Yoshinao Oda, Toru Iwaki, Jun ichi Kira, Immunotherapy-refractory vacuolar myopathy with mucin deposition in scleromyxedema
A possible role of fibroblast growth factor 2, Neuropathology, 10.1111/neup.12659, 2020.01, Scleromyxedema (SME) is characterized by widespread waxy papules on the skin, with mucin deposits in the upper dermis. Twenty-one SME cases of myopathy have been reported; of the cases, six showed vacuolar formation, and two showed mucin deposition. We report the first case of SME with mucin-containing vacuolated fibers. A 45-year-old woman with SME developed progressive proximal muscle weakness. Muscle biopsy revealed myopathic changes with numerous vacuoles linked to mucin in the affected muscle fibers, which were heavily immunostained for fibroblast growth factor 2 (FGF2). Despite repeated high dose oral prednisolone and intravenous immunoglobulin administrations, muscle weakness recurred continuingly, culminating in death due to congestive heart failure. Immunotherapy was partly effective in our case, although it was refractory. Treatment responsiveness in patients with SME myopathy varied; however, due to its rarity, the mechanism remains to be elucidated. To address this issue, we investigated muscle specimens immunohistochemically and detected marked upregulation of FGF2 in the affected muscle fibers of our patient. FGF2, a strong myogenesis inhibitor, may exert a suppressive effect on muscle fiber regeneration, which may have conferred refractoriness to our patient's SME myopathy.. |
| 47. |
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 injuryresponse 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.. |
| 48. |
Y. Nakamura, Z. Liu, S. Fukumoto, K. Shinoda, A. Sakoda, T. Matsushita, S. Hayashida, N. Isobe, M. Watanabe, A. Hiwatashi, R. Yamasaki, J. i. Kira, Spinal cord involvement by atrophy and associations with disability are different between multiple sclerosis and neuromyelitis optica spectrum disorder, European Journal of Neurology, 10.1111/ene.14038, 27, 1, 92-99, 2020.01, Background and purpose: The cervical and thoracic cross-sectional spinal cord area (CS-SCA) in multiple sclerosis (MS) correlates with disability, whilst such a correlation remains to be established in neuromyelitis optica spectrum disorder (NMOSD). Our aim was to clarify differences between MS and NMOSD in spinal cord segments where CS-SCA is associated with disability. Methods: The CS-SCA at C2/C3, C3/C4, T8/T9 and T9/T10 vertebral disc levels was measured in 140 MS patients (111 with relapsing–remitting MS and 29 with progressive MS) and 42 NMOSD patients with anti-aquaporin-4 immunoglobulin G. Disability was evaluated by Expanded Disability Status Scale (EDSS) scores. Multivariate associations between CS-SCA and disability were assessed by stepwise forward multiple linear regression. Results: Thoracic CS-SCA was significantly smaller in NMOSD patients than in MS patients even after adjusting for age, sex and disease duration (P = 0.002 at T8/T9), whilst there was no difference in cervical CS-SCA between the two diseases. Cervical and thoracic CS-SCA had a negative correlation with EDSS scores in MS patients (P |
| 49. |
Hayato Une, Dai Matsuse, Taira Uehara, Yoshikazu Kikuchi, Saeko Inamizu, Ryo Yamasaki, Shozo Tobimatsu, Hiroshi Shibasaki, Jun-Ichi Kira, Branchial myorhythmia in a case of systemic lupus erythematosus., Journal of the neurological sciences, 10.1016/j.jns.2019.116501, 408, 116501-116501, 2020.01. |
| 50. |
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.. |
| 51. |
Takayuki Fujii, Ryo Yamasaki, Jun Ichi Kira, Novel Neuropathic Pain Mechanisms Associated With Allergic Inflammation, Frontiers in Neurology, 10.3389/fneur.2019.01337, 10, 2019.12, Allergic diseases are associated with central and peripheral nervous system diseases such as autism spectrum disorders and eosinophilic granulomatosis with polyangiitis, which frequently causes mononeuritis multiplex. Thus, it is possible that patients with an atopic constitution might develop multifocal inflammation in central and peripheral nervous system tissues. In a previous study in Japan, we reported a rare form of myelitis with persistent neuropathic pain (NeP) in patients with allergic disorders. However, the underlying mechanism of allergic inflammation-related NeP remains to be elucidated. First, we analyzed the effect of allergic inflammation on the nociceptive system in the spinal cord. Mice with atopy showed microglial and astroglial activation in the spinal cord and tactile allodynia. In a microarray analysis of isolated microglia from the spinal cord, endothelin receptor type B (EDNRB) was the most upregulated cell surface receptor in mice with atopy. Immunohistochemical analysis demonstrated EDNRB expression was upregulated in microglia and astroglia. The EDNRB antagonist BQ788 abolished glial activation and allodynia. These findings indicated that allergic inflammation induced widespread glial activation through the EDNRB pathway and NeP. Second, we investigated whether autoantibody-mediated pathogenesis underlies allergic inflammation-related NeP. We detected specific autoantibodies to small dorsal root ganglion (DRG) neurons and their nerve terminals in the dorsal horns of NeP patients with allergic disorders. An analysis of IgG subclasses revealed a predominance of IgG2. These autoantibodies were mostly colocalized with isolectin B4- and P2X3-positive unmyelinated C-fiber type small DRG neurons. By contrast, immunostaining for S100β, a myelinated DRG neuron marker, showed no colocalization with patient IgG. Immunoprecipitation and liquid chromatography-tandem mass spectrometry identified plexin D1 as a target autoantigen. Patients with anti-plexin D1 antibodies often present with burning pain and thermal hyperalgesia. Immunotherapies, including plasma exchange, are effective for NeP management. Therefore, anti-plexin D1 antibodies may be pathogenic for immune-mediated NeP, especially under allergic inflammation conditions. Thus, allergic inflammation may induce NeP through glial inflammation in the spinal cord and the anti-plexin D1 antibody-mediated impairment of small DRG neurons.. |
| 52. |
Koji Tanaka, Shoji Matsumoto, Konosuke Furuta, Takeshi Yamada, Sukehisa Nagano, Kei-Ichiro Takase, Taketo Hatano, Ryo Yamasaki, Jun-Ichi Kira, Differences between predictive factors for early neurological deterioration due to hemorrhagic and ischemic insults following intravenous recombinant tissue plasminogen activator., Journal of thrombosis and thrombolysis, 10.1007/s11239-019-02015-4, 49, 4, 545-550, 2019.12, Early neurological deterioration (END) following intravenous recombinant tissue plasminogen activator (rt-PA) treatment is a serious clinical event that can be caused by hemorrhagic or ischemic insult. We investigated the differences in predictive factors for END due to hemorrhagic and END due to ischemic insults. Consecutive patients from four hospitals who received 0.6 mg/kg intravenous rt-PA for acute ischemic stroke were retrospectively recruited. END was defined as a National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 points within 24 h compared with baseline. END was classified into those due to hemorrhagic (ENDh) or ischemic (ENDi) insult based on computed tomography (CT) or magnetic resonance imaging. Risk factors associated with ENDh and ENDi were investigated by comparison with non-END cases. A total of 744 patients (452 men, median 75 years old) were included. END was observed in 79 patients (10.6%), including 22 ENDh (3.0%) and 57 ENDi (7.7%), which occurred within a median of 7 h after treatment. Multivariate analyses showed that higher pretreatment NIHSS score (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.00-1.13) and pretreatment with antiplatelets (OR 2.84, 95% CI 1.08-7.72) were associated with ENDh. Extensive early ischemic change (Alberta Stroke Program Early CT Score ≤ 7 on CT or ≤ 6 on diffusion-weighted imaging; OR 2.80, 95% CI 1.36-5.64) and large artery occlusions (OR 3.09, 95% CI 1.53-6.57) were associated with ENDi. Distinct factors were predictive for the END subtypes. These findings could help develop preventative measures for END in patients with the identified risk factors.. |
| 53. |
Jun ichi Kira, Ryo Yamasaki, Hidenori Ogata, Anti-neurofascin autoantibody and demyelination, Neurochemistry International, 10.1016/j.neuint.2018.12.011, 130, 2019.11, Demyelination diseases involving the central and peripheral nervous systems are etiologically heterogeneous with both cell-mediated and humoral immunities playing pathogenic roles. Recently, autoantibodies against nodal and paranodal proteins, such as neurofascin186 (NF186), neurofascin155 (NF155), contactin-1 (CNTN1), contactin-associated protein 1 (CASPR1) and gliomedin, have been discovered in not only chronic demyelinating conditions, such as multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy, but also in acute demyelinating conditions, such as Guillain-Barré syndrome. Only a minority of these patients harbor anti-nodal/paranodal protein antibodies; however, these autoantibodies, especially IgG4 subclass autoantibodies to paranodal proteins, are associated with unique features and these conditions are collectively termed nodopathy or paranodopathy. Establishing a concept of IgG4-related nodopathy/paranodopathy contributes to diagnosis and treatment strategy because IgG4 autoantibody-related neurological diseases are often refractory to conventional immunotherapies. IgG4 does not fix complements, or internalize the target antigens, because IgG4 exists in a monovalent bispecific form in vivo. IgG4 autoantibodies can bock protein-protein interaction. Thus, the primary role of IgG4 anti-paranodal protein antibodies may be blockade of interactions between NF155 and CNTN1/CASPR1, leading to conduction failure, which is consistent with the sural nerve pathology presenting paranodal terminal loop detachment from axons with intact internodes in the absence of inflammation. However, it still remains to be elucidated how these autoantibodies belonging to the same IgG4 subclass can cause each IgG4 autoantibody-specific manifestation. Another important issue is to clarify the mechanism by which IgG4 antibodies to nodal/paranodal proteins emerge. IgG4 antibodies develop on chronic antigenic stimulation and can block antibodies that alleviate allergic inflammation by interfering with the binding of allergen-specific IgE to allergens. Thus, environmental antigens cross-reacting with nodal and paranodal proteins may warrant future study.. |
| 54. |
Jun Yokoyama, Hiroo Yamaguchi, Junpei Koge, Takuya Matsushita, Noriko Isobe, Ryo Yamasaki, Jun ichi Kira, Brainstem posterior reversible encephalopathy syndrome in a case with Guillain–Barré syndrome, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12530, 10, 4, 267-271, 2019.11, Background: Posterior reversible encephalopathy syndrome (PRES) is characterized by reversible vasogenic brain edema on magnetic resonance imaging. PRES is frequently associated with blood pressure (BP) fluctuation. Although Guillain–Barré syndrome (GBS) is often complicated by BP fluctuation, PRES is rarely reported. Here, we describe the first reported case of GBS in a patient who developed PRES mainly affecting the brainstem. Case presentation: A 43-year-old man presented with impaired consciousness and was hospitalized after a diagnosis of infectious meningoencephalitis. His consciousness was improved by treatment; however, he presented with polyneuropathy and BP fluctuation. We diagnosed him with GBS and started intravenous immunoglobulin therapy (IVIg); however, his consciousness became impaired again after IVIg. Brain magnetic resonance imaging showed hyperintense areas of the pons, cerebellar peduncle, midbrain and basal ganglia in the apparent diffusion coefficient image and the fluid-attenuated inversion recovery image. Diffusion-weighted imaging showed that hyperintense and hypointense lesions were present within the same regions. We diagnosed brainstem PRES complicated with GBS. Achievement of BP control improved his consciousness and hyperintense lesions on the diffusion-weighted imaging and apparent diffusion coefficient image map. Conclusions: BP fluctuation and IVIg might have caused PRES in the present case. Neurologists should consider PRES as a differential diagnosis when consciousness is impaired in GBS, especially at the time of IVIg therapy or BP fluctuation.. |
| 55. |
Ryo Yamasaki, Current understanding of autoimmune encephalitis and encephalopathy, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12544, 10, 4, 209-210, 2019.11. |
| 56. |
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.. |
| 57. |
Koji Tanaka, Shoji Matsumoto, Takeshi Yamada, Sukehisa Nagano, Kei ichiro Takase, Taketo Hatano, Ryo Yamasaki, Jun ichi Kira, Temporal Trends in Clinical Characteristics and Door-to-Needle Time in Patients Receiving Intravenous Tissue Plasminogen Activator
A Retrospective Study of 4 Hospitals in Japan, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2019.104305, 28, 11, 2019.11, Background: Intravenous recombinant tissue plasminogen activator (rt-PA) has become a common treatment for acute ischemic stroke and has highly time-dependent benefits. We aimed to clarify temporal trends regarding the frequency and characteristics of patients receiving rt-PA and explore factors associated with door-to-needle time (DNT) in Japanese emergency hospitals. Methods: Consecutive patients who received intravenous rt-PA for acute ischemic stroke from October 2005 to December 2015 were retrospectively registered from 4 hospitals. Temporal trends in the frequency and characteristics of patients receiving rt-PA and factors associated with DNT were investigated. Results: A total of 750 patients, including 688 (420 men, median 75 years old) with out-of-hospital stroke, were registered. The frequency of patients receiving intravenous rt-PA for acute ischemic stroke continuously increased from 1.8% in 2005 to 9.5% in 2015. The proportion of patients who were elderly or had prestroke disability increased over time, while pretreatment stroke severity declined. The DNT gradually decreased (median 105 minutes in 2005, 61 minutes in 2015). According to multivariate regression analysis with correction for multiple comparisons, activation of a code stroke system (standardized partial regression coefficient (β) −.50, P |
| 58. |
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, 2019.11, 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 |
| 59. |
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.. |
| 60. |
Koji Tanaka, Shoji Matsumoto, Konosuke Furuta, Takeshi Yamada, Sukehisa Nagano, Kei-Ichiro Takase, Taketo Hatano, Ryo Yamasaki, Jun-Ichi Kira, Modified diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score including deep white matter lesions predicts symptomatic intracerebral hemorrhage following intravenous thrombolysis., Journal of thrombosis and thrombolysis, 10.1007/s11239-019-01979-7, 50, 1, 174-180, 2019.11, The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used for the assessment of early ischemic changes (EICs) before thrombolysis. However, for symptomatic intracerebral hemorrhage (sICH) following intravenous recombinant tissue plasminogen activator (rt-PA), the prediction abilities of CT-ASPECTS, diffusion-weighted imaging (DWI)-ASPECTS, and DWI-ASPECTS including EICs in deep white matter (DWI-ASPECTS + W) are unclear. We investigated associations between each score and sICH following intravenous rt-PA. Data from consecutive patients who received intravenous rt-PA for acute ischemic stroke from 2005 to 2015 in four hospitals were retrospectively screened. We included data from patients who had undergone both CT and magnetic resonance imaging before thrombolysis and without evidence of posterior circulation stroke. We analyzed the ability of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W to predict sICH, accompanied by an increase in the National Institutes of Health Stroke Scale (NIHSS) score of ≥ 4 within the initial 36 h. Of 455 patients (273 men, median 75 years old), sICH occurred in 15 patients (3.3%). Receiver operating characteristics curve analysis showed that the optimal cut-offs of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W for predicting sICH were ≤ 9 (sensitivity 60.0%, specificity 59.8%, c-statistic 0.625), ≤ 6 (sensitivity 53.3%, specificity 80.9%, c-statistic 0.718), and ≤ 8 (sensitivity 86.7%, specificity 55.9%, c-statistic 0.756), respectively. A DWI-ASPECTS + W of ≤ 8 was independently associated with sICH (odds ratio 5.21, 95% confidence interval 1.30-35.31) after adjustment for pretreatment with antithrombotic agents, pretreatment NIHSS score, and large artery occlusions. DWI-ASPECTS + W predicted sICH in patients with acute anterior circulation stroke receiving intravenous rt-PA.. |
| 61. |
Koji Tanaka, Shoji Matsumoto, Takeshi Yamada, Sukehisa Nagano, Kei-Ichiro Takase, Taketo Hatano, Ryo Yamasaki, Jun-Ichi Kira, Temporal Trends in Clinical Characteristics and Door-to-Needle Time in Patients Receiving Intravenous Tissue Plasminogen Activator: A Retrospective Study of 4 Hospitals in Japan., Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 10.1016/j.jstrokecerebrovasdis.2019.104305, 28, 11, 104305-104305, 2019.11, BACKGROUND: Intravenous recombinant tissue plasminogen activator (rt-PA) has become a common treatment for acute ischemic stroke and has highly time-dependent benefits. We aimed to clarify temporal trends regarding the frequency and characteristics of patients receiving rt-PA and explore factors associated with door-to-needle time (DNT) in Japanese emergency hospitals. METHODS: Consecutive patients who received intravenous rt-PA for acute ischemic stroke from October 2005 to December 2015 were retrospectively registered from 4 hospitals. Temporal trends in the frequency and characteristics of patients receiving rt-PA and factors associated with DNT were investigated. RESULTS: A total of 750 patients, including 688 (420 men, median 75 years old) with out-of-hospital stroke, were registered. The frequency of patients receiving intravenous rt-PA for acute ischemic stroke continuously increased from 1.8% in 2005 to 9.5% in 2015. The proportion of patients who were elderly or had prestroke disability increased over time, while pretreatment stroke severity declined. The DNT gradually decreased (median 105 minutes in 2005, 61 minutes in 2015). According to multivariate regression analysis with correction for multiple comparisons, activation of a code stroke system (standardized partial regression coefficient (β) -.50, P |
| 62. |
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.. |
| 63. |
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.. |
| 64. |
今村 友裕, 浅井 宏英, 山崎 亮, 吉良 潤一, Possible regulatory roles of miRNAs in APP-KI AD model mice(和訳中), Dementia Japan, 33, 4, 551-551, 2019.10. |
| 65. |
Yuka Harada, Jing Zhang, Kazuhisa Imari, Ryo Yamasaki, Junjun Ni, Zhou Wu, Kenji Yamamoto, Jun Ichi Kira, Hiroshi Nakanishi, Yoshinori Hayashi, Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis, Pain, 10.1097/j.pain.0000000000001596, 160, 9, 2050-2062, 2019.09, Pain is a frequent and disabling symptom in patients with multiple sclerosis (MS); however, the underlying mechanisms of MS-related pain are not fully understood. Here, we demonstrated that cathepsin E (CatE) in neutrophils contributes to the generation of mechanical allodynia in experimental autoimmune encephalomyelitis, an animal model of MS. We showed that CatE-deficient (CatE) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG35-55)-induced mechanical allodynia. After MOG35-55 immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG35-55-stimulated wild-type neutrophils into the dorsal root ganglion induced mechanical allodynia in the recipient C57BL/6 mice. However, the pain threshold did not change when MOG35-55-stimulated CatE neutrophils were transferred into the recipient C57BL/6 mice. MOG35-55 stimulation caused CatE-dependent secretion of elastase in neutrophils. Behavioral analyses revealed that sivelestat, a selective neutrophil elastase inhibitor, suppressed mechanical allodynia induced by adoptively transferred MOG35-55-stimulated neutrophils. MOG35-55 directly bound to toll-like receptor 4, which led to increased production of CatE in neutrophils. Our findings suggest that inhibition of CatE-dependent elastase production in neutrophil might be a potential therapeutic target for pain in patients with MS.. |
| 66. |
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, ObjectiveTo 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).MethodsLevels 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.ResultsFor 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 |
| 67. |
Yuka Harada, Jing Zhang, Kazuhisa Imari, Ryo Yamasaki, Junjun Ni, Zhou Wu, Kenji Yamamoto, Jun-Ichi Kira, Hiroshi Nakanishi, Yoshinori Hayashi, Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis., Pain, 10.1097/j.pain.0000000000001596, 160, 9, 2050-2062, 2019.09, Pain is a frequent and disabling symptom in patients with multiple sclerosis (MS); however, the underlying mechanisms of MS-related pain are not fully understood. Here, we demonstrated that cathepsin E (CatE) in neutrophils contributes to the generation of mechanical allodynia in experimental autoimmune encephalomyelitis, an animal model of MS. We showed that CatE-deficient (CatE) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG35-55)-induced mechanical allodynia. After MOG35-55 immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG35-55-stimulated wild-type neutrophils into the dorsal root ganglion induced mechanical allodynia in the recipient C57BL/6 mice. However, the pain threshold did not change when MOG35-55-stimulated CatE neutrophils were transferred into the recipient C57BL/6 mice. MOG35-55 stimulation caused CatE-dependent secretion of elastase in neutrophils. Behavioral analyses revealed that sivelestat, a selective neutrophil elastase inhibitor, suppressed mechanical allodynia induced by adoptively transferred MOG35-55-stimulated neutrophils. MOG35-55 directly bound to toll-like receptor 4, which led to increased production of CatE in neutrophils. Our findings suggest that inhibition of CatE-dependent elastase production in neutrophil might be a potential therapeutic target for pain in patients with MS.. |
| 68. |
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 |
| 69. |
趙 奕楠, 山崎 亮, 山口 浩雄, 吉良 潤一, 基礎研究 Cx47は神経炎を調節する 二次性進行型多発性硬化症モデルの作製(Basic research Cx47 regulates neuro-inflammation: creation of a 1 secondary-progressive multiple sclerosis model), 神経免疫学, 24, 1, 123-123, 2019.09. |
| 70. |
Mitsunori Shimmura, Taira Uehara, Katsuya Ogata, Hiroshi Shigeto, Tomoko Maeda, Ayumi Sakata, Ryo Yamasaki, Jun ichi Kira, Higher postictal parasympathetic activity following greater ictal heart rate increase in right- than left-sided seizures, Epilepsy and Behavior, 10.1016/j.yebeh.2019.05.026, 97, 161-168, 2019.08, Objectives: The objectives of this study were to determine how hemispheric laterality of seizure activity influences periictal heart rate variability (HRV) and investigate the ability of HRV parameters to discriminate right- and left-sided seizures. Methods: Long-term video electroencephalogram-electrocardiogram recordings of 54 focal seizures in 25 patients with focal epilepsy were reviewed. Using linear mixed models, we examined the effect of seizure laterality on linear (standard deviation of R-R intervals [SDNN], root mean square of successive differences [RMSSD], low frequency [LF] and high frequency [HF] power of HRV, and LF/HF) and nonlinear (standard deviation [SD]1, SD2, and SD2/SD1 derived from Poincaré plots) periictal HRV parameters, the magnitude of heart rate (HR) changes, and the onset time of increased HR. Receiver operating characteristics (ROC) were used to determine the ability of these parameters to discriminate between right- and left-sided seizures. Results: Postictal SDNN, RMSSD, LF, HF, SD1, and SD2 were higher in right- than left-sided seizures. Root mean square of successive difference and HF were decreased after left- but not right-sided seizures. Standard deviation of R-R intervals, LF, and SD1 were increased after right- but not left-sided seizures. Increased ictal HR was earlier and larger in right- than left-sided seizures. Postictal HF showed the greatest area under the ROC curve (AUC) (0.87) for discriminating right- and left-sided seizures. Conclusions: Our data suggest that postictal parasympathetic activity is higher, whereas ictal HR increase is greater, in right- than left-sided seizures. Involvement of the right hemisphere may be associated with postictal autonomic instability. Postictal HRV parameters may provide useful information on hemispheric laterality of seizure activity.. |
| 71. |
Mitsunori Shimmura, Taira Uehara, Katsuya Ogata, Hiroshi Shigeto, Tomoko Maeda, Ayumi Sakata, Ryo Yamasaki, Jun-Ichi Kira, Higher postictal parasympathetic activity following greater ictal heart rate increase in right- than left-sided seizures., Epilepsy & behavior : E&B, 10.1016/j.yebeh.2019.05.026, 97, 161-168, 2019.08, OBJECTIVES: The objectives of this study were to determine how hemispheric laterality of seizure activity influences periictal heart rate variability (HRV) and investigate the ability of HRV parameters to discriminate right- and left-sided seizures. METHODS: Long-term video electroencephalogram-electrocardiogram recordings of 54 focal seizures in 25 patients with focal epilepsy were reviewed. Using linear mixed models, we examined the effect of seizure laterality on linear (standard deviation of R-R intervals [SDNN], root mean square of successive differences [RMSSD], low frequency [LF] and high frequency [HF] power of HRV, and LF/HF) and nonlinear (standard deviation [SD]1, SD2, and SD2/SD1 derived from Poincaré plots) periictal HRV parameters, the magnitude of heart rate (HR) changes, and the onset time of increased HR. Receiver operating characteristics (ROC) were used to determine the ability of these parameters to discriminate between right- and left-sided seizures. RESULTS: Postictal SDNN, RMSSD, LF, HF, SD1, and SD2 were higher in right- than left-sided seizures. Root mean square of successive difference and HF were decreased after left- but not right-sided seizures. Standard deviation of R-R intervals, LF, and SD1 were increased after right- but not left-sided seizures. Increased ictal HR was earlier and larger in right- than left-sided seizures. Postictal HF showed the greatest area under the ROC curve (AUC) (0.87) for discriminating right- and left-sided seizures. CONCLUSIONS: Our data suggest that postictal parasympathetic activity is higher, whereas ictal HR increase is greater, in right- than left-sided seizures. Involvement of the right hemisphere may be associated with postictal autonomic instability. Postictal HRV parameters may provide useful information on hemispheric laterality of seizure activity.. |
| 72. |
Takayuki Fujii, Hiroyuki Honda, Ryo Yamasaki, Toru Iwaki, Jun-Ichi Kira, Multiple mtDNA deletions due to mitochondrion toxicity of anti-hepadnaviral drugs: Comments to the letter from J. Finsterer., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12563, 39, 4, 326-327, 2019.08. |
| 73. |
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.. |
| 74. |
Yuka Urata, Masayuki Nakamura, Natsuki Sasaki, Nari Shiokawa, Yoshiaki Nishida, Kaoru Arai, Hanae Hiwatashi, Izumi Yokoyama, Shinsuke Narumi, Yasuo Terayama, Takenobu Murakami, Yoshikazu Ugawa, Hiroki Sakamoto, Satoshi Kaneko, Yusuke Nakazawa, Ryo Yamasaki, Shoko Sadashima, Toshiaki Sakai, Hiroaki Arai, Akira Sano, Novel pathogenic XK mutations in McLeod syndrome and interaction between XK protein and chorein, Neurology: Genetics, 10.1212/NXG.0000000000000328, 5, 3, 2019.06, ObjectiveTo identify XK pathologic mutations in 6 patients with suspected McLeod syndrome (MLS) and a possible interaction between the chorea-acanthocytosis (ChAc)- A nd MLS-responsible proteins: Chorein and XK protein.MethodsErythrocyte membrane proteins from patients with suspected MLS and patients with ChAc, ChAc mutant carriers, and normal controls were analyzed by XK and chorein immunoblotting. We performed mutation analysis and XK immunoblotting to molecularly diagnose the patients with suspected MLS. Lysates of cultured cells were co-immunoprecipitated with anti-XK and anti-chorein antibodies.ResultsAll suspected MLS cases were molecularly diagnosed with MLS, and novel mutations were identified. The average onset age was 46.8 ± 8 years, which was older than that of the patients with ChAc. The immunoblot analysis revealed remarkably reduced chorein immunoreactivity in all patients with MLS. The immunoprecipitation analysis indicated a direct or indirect chorein-XK interaction.ConclusionsIn this study, XK pathogenic mutations were identified in all 6 MLS cases, including novel mutations. Chorein immunoreactions were significantly reduced in MLS erythrocyte membranes. In addition, we demonstrated a possible interaction between the chorein and XK protein via molecular analysis. The reduction in chorein expression is similar to that between Kell antigens and XK protein, although the chorein-XK interaction is a possibly noncovalent binding unlike the covalent Kell-XK complex. Our results suggest that reduced chorein levels following lack of XK protein are possibly associated with molecular pathogenesis in MLS.. |
| 75. |
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.. |
| 76. |
Yuka Urata, Masayuki Nakamura, Natsuki Sasaki, Nari Shiokawa, Yoshiaki Nishida, Kaoru Arai, Hanae Hiwatashi, Izumi Yokoyama, Shinsuke Narumi, Yasuo Terayama, Takenobu Murakami, Yoshikazu Ugawa, Hiroki Sakamoto, Satoshi Kaneko, Yusuke Nakazawa, Ryo Yamasaki, Shoko Sadashima, Toshiaki Sakai, Hiroaki Arai, Akira Sano, Novel pathogenic XK mutations in McLeod syndrome and interaction between XK protein and chorein., Neurology. Genetics, 10.1212/NXG.0000000000000328, 5, 3, e328, 2019.06, Objective: To identify XK pathologic mutations in 6 patients with suspected McLeod syndrome (MLS) and a possible interaction between the chorea-acanthocytosis (ChAc)- and MLS-responsible proteins: chorein and XK protein. Methods: Erythrocyte membrane proteins from patients with suspected MLS and patients with ChAc, ChAc mutant carriers, and normal controls were analyzed by XK and chorein immunoblotting. We performed mutation analysis and XK immunoblotting to molecularly diagnose the patients with suspected MLS. Lysates of cultured cells were co-immunoprecipitated with anti-XK and anti-chorein antibodies. Results: All suspected MLS cases were molecularly diagnosed with MLS, and novel mutations were identified. The average onset age was 46.8 ± 8 years, which was older than that of the patients with ChAc. The immunoblot analysis revealed remarkably reduced chorein immunoreactivity in all patients with MLS. The immunoprecipitation analysis indicated a direct or indirect chorein-XK interaction. Conclusions: In this study, XK pathogenic mutations were identified in all 6 MLS cases, including novel mutations. Chorein immunoreactions were significantly reduced in MLS erythrocyte membranes. In addition, we demonstrated a possible interaction between the chorein and XK protein via molecular analysis. The reduction in chorein expression is similar to that between Kell antigens and XK protein, although the chorein-XK interaction is a possibly noncovalent binding unlike the covalent Kell-XK complex. Our results suggest that reduced chorein levels following lack of XK protein are possibly associated with molecular pathogenesis in MLS.. |
| 77. |
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.. |
| 78. |
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.. |
| 79. |
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.. |
| 80. |
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.. |
| 81. |
Takayuki Fujii, Kei ichiro Takase, Hiroyuki Honda, Nobutoshi Kawamura, Ryo Yamasaki, Michiyo Urata, Takeshi Uchiumi, Toru Iwaki, Jun ichi Kira, Toxic myopathy with multiple deletions in mitochondrial DNA associated with long-term use of oral anti-viral drugs for hepatitis B
A case study, Neuropathology, 10.1111/neup.12548, 39, 2, 162-167, 2019.04, Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy.. |
| 82. |
Takayuki Fujii, Kei-Ichiro Takase, Hiroyuki Honda, Nobutoshi Kawamura, Ryo Yamasaki, Michiyo Urata, Takeshi Uchiumi, Toru Iwaki, Jun-Ichi Kira, Toxic myopathy with multiple deletions in mitochondrial DNA associated with long-term use of oral anti-viral drugs for hepatitis B: A case study., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12548, 39, 2, 162-167, 2019.04, Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy.. |
| 83. |
Yiwen Cui, Katsuhisa Masaki, Xu Zhang, Ryo Yamasaki, Takayuki Fujii, Hidenori Ogata, Shotaro Hayashida, Hiroo Yamaguchi, Fuminori Hyodo, Hinako Eto, Sachiko Koyama, Kyoko Iinuma, Tomomi Yonekawa, Takuya Matsushita, Mari Yoshida, Kazunori Yamada, Mitsuhiro Kawano, Marie Malissen, Bernard Malissen, Jun-Ichi Kira, A novel model for treatment of hypertrophic pachymeningitis, Annals of Clinical and Translational Neurology, 10.1002/acn3.715, 6, 3, 431-444, 2019.03, Objective: Immunoglobulin (Ig)G4-related disease is a major cause of hypertrophic pachymeningitis (HP), presenting as a progressive thickening of the dura mater. HP lacks an animal model to determine its underlying mechanisms. We developed a suitable animal model for the treatment of HP. Methods: We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced type 2 T helper (Th2) cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were therapeutically administered daily oral irbesartan from 3 to 6 weeks of age. Human IgG4-related, anti-neutrophil cytoplasmic antibody-related, and idiopathic HP dura were also immunohistochemically examined. Results: LATY136F mice showing dural gadolinium enhancement on magnetic resonance imaging had massive infiltration of B220+ B cells, IgG1+ cells, CD138+ plasma cells, CD3+ T cells, F4/80+ macrophages, and polymorphonuclear leukocytes in the dura at 3 weeks of age, followed by marked fibrotic thickening. In dural lesions, transforming growth factor (TGF)-β1 was produced preferentially in B cells and macrophages while TGF-β receptor I (TGF-βRI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-β1, TGF-βRI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF-βRI, SMAD2/SMAD3, and phosphorylated SMAD2/SMAD3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammatory cell infiltration and fibrotic thickening in all treated LATY136F mice with reduced TGF-β1 and nonphosphorylated and phosphorylated SMAD2/SMAD3. Interpretation: TGF-β1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target.. |
| 84. |
Yiwen Cui, Katsuhisa Masaki, Xu Zhang, Ryo Yamasaki, Takayuki Fujii, Hidenori Ogata, Shotaro Hayashida, Hiroo Yamaguchi, Fuminori Hyodo, Hinako Eto, Sachiko Koyama, Kyoko Iinuma, Tomomi Yonekawa, Takuya Matsushita, Mari Yoshida, Kazunori Yamada, Mitsuhiro Kawano, Marie Malissen, Bernard Malissen, Junichi Kira, A novel model for treatment of hypertrophic pachymeningitis., Annals of clinical and translational neurology, 10.1002/acn3.715, 6, 3, 431-444, 2019.03, Objective: Immunoglobulin (Ig)G4-related disease is a major cause of hypertrophic pachymeningitis (HP), presenting as a progressive thickening of the dura mater. HP lacks an animal model to determine its underlying mechanisms. We developed a suitable animal model for the treatment of HP. Methods: We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced type 2 T helper (Th2) cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were therapeutically administered daily oral irbesartan from 3 to 6 weeks of age. Human IgG4-related, anti-neutrophil cytoplasmic antibody-related, and idiopathic HP dura were also immunohistochemically examined. Results: LATY136F mice showing dural gadolinium enhancement on magnetic resonance imaging had massive infiltration of B220+ B cells, IgG1+ cells, CD138+ plasma cells, CD3+ T cells, F4/80+ macrophages, and polymorphonuclear leukocytes in the dura at 3 weeks of age, followed by marked fibrotic thickening. In dural lesions, transforming growth factor (TGF)-β1 was produced preferentially in B cells and macrophages while TGF-β receptor I (TGF-β RI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-β1, TGF-β RI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF-β RI, SMAD2/SMAD3, and phosphorylated SMAD2/SMAD3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammatory cell infiltration and fibrotic thickening in all treated LATY136F mice with reduced TGF-β1 and nonphosphorylated and phosphorylated SMAD2/SMAD3. Interpretation: TGF-β1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target.. |
| 85. |
糖尿病網膜症におけるCD206+CX3CR1+硝子体界面マクロファージ局所増殖. |
| 86. |
Takayuki Fujii, Ryo Yamasaki, Jun-Ichi Kira, Anti-plexin D1 antibodies are a novel biomarker for immune-mediated neuropathic pain, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12488, 10, 1, 7-8, 2019.02. |
| 87. |
kenichiro yamashita, Taira Uehara, Pukovisa Prawiroharjo, Koji Yamashita, Osamu Togao, Hiwatashi Akio, Yoshihide Taniwaki, Hidetsuna Utsunomiya, Takuya Matsushita, Ryo Yamasaki, Jun-Ichi Kira, Functional connectivity change between posterior cingulate cortex and ventral attention network relates to the impairment of orientation for time in Alzheimer’s disease patients, Brain Imaging and Behavior, 10.1007/s11682-018-9860-x, 13, 1, 154-161, 2019.02, Alzheimer’s disease (AD) patients exhibit various cognitive dysfunctions, including impairment of orientation for time (OT). The brain regions underlying OT impairment remain to be elucidated. A previous single-photon emission computed tomography study has indicated hypoperfusion of the posterior cingulate cortex (PCC) in relation to deterioration of OT. In this study, we investigated whole brain functional connectivity changes of PCC using resting-state functional magnetic resonance imaging. Voxel-based functional connectivity with PCC was analyzed in OT-poor or OT-good AD patients, classified according to the mean OT scores of the Mini-Mental State Examination subscale. The connectivities of dorsal frontal lobe, and lateral parietal and lateral temporal lobes with PCC in the right hemisphere were reduced in the OT-poor AD group compared with the OT-good AD group. A subtraction connectivity map of OT score differences (OT-good minus OT-poor) revealed the right middle temporal gyrus near the temporo-parietal junction as a significantly connected region with PCC. These results suggest that the right posterior part of the middle temporal gyrus may play an important role in OT in conjunction with PCC, and that disconnection between PCC and the right ventral attention network may cause OT disturbance in AD patients.. |
| 88. |
Ken-Ichiro Yamashita, Taira Uehara, Pukovisa Prawiroharjo, Koji Yamashita, Osamu Togao, Akio Hiwatashi, Yoshihide Taniwaki, Hidetsuna Utsunomiya, Takuya Matsushita, Ryo Yamasaki, Jun-Ichi Kira, Functional connectivity change between posterior cingulate cortex and ventral attention network relates to the impairment of orientation for time in Alzheimer's disease patients., Brain imaging and behavior, 10.1007/s11682-018-9860-x, 13, 1, 154-161, 2019.02, Alzheimer's disease (AD) patients exhibit various cognitive dysfunctions, including impairment of orientation for time (OT). The brain regions underlying OT impairment remain to be elucidated. A previous single-photon emission computed tomography study has indicated hypoperfusion of the posterior cingulate cortex (PCC) in relation to deterioration of OT. In this study, we investigated whole brain functional connectivity changes of PCC using resting-state functional magnetic resonance imaging. Voxel-based functional connectivity with PCC was analyzed in OT-poor or OT-good AD patients, classified according to the mean OT scores of the Mini-Mental State Examination subscale. The connectivities of dorsal frontal lobe, and lateral parietal and lateral temporal lobes with PCC in the right hemisphere were reduced in the OT-poor AD group compared with the OT-good AD group. A subtraction connectivity map of OT score differences (OT-good minus OT-poor) revealed the right middle temporal gyrus near the temporo-parietal junction as a significantly connected region with PCC. These results suggest that the right posterior part of the middle temporal gyrus may play an important role in OT in conjunction with PCC, and that disconnection between PCC and the right ventral attention network may cause OT disturbance in AD patients.. |
| 89. |
Hiwatashi Akio, Osamu Togao, Koji Yamashita, kazufumi kikuchi, Daichi Momosaka, Hiroshi Nakatake, Ryo Yamasaki, Hidenori Ogata, Masami Yoneyama, Jun-Ichi Kira, Hiroshi Honda, Simultaneous MR neurography and apparent T2 mapping in brachial plexus
Evaluation of patients with chronic inflammatory demyelinating polyradiculoneuropathy, Magnetic Resonance Imaging, 10.1016/j.mri.2018.09.025, 55, 112-117, 2019.01, Purpose: MR neurography is known to be useful to evaluate nerve pathology. The purpose of this study was to evaluate the usefulness of simultaneous apparent T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) to distinguish patients with chronic inflammatory demyelinating polyneuropathy (CIDP) from healthy subjects. Materials and methods: This retrospective study included 13 patients with CIDP and five healthy subjects from 2015 to 2017. The T2 relaxation time and the size of the cervical ganglia and roots of the brachial plexus were measured. Statistical analyses were performed with the Mann-Whitney U test and receiver operating characteristics (ROC) analysis. Results: The T2 relaxation times of the ganglia and roots were longer in patients with CIDP (119.31 ± 35.53 msec and 111.15 ± 33.82 msec) than in healthy subjects (101.42 ± 26.42 msec and 85.29 ± 13.22 msec, P = 0.0007 and P |
| 90. |
Shoji Matsumoto, Hiroshi Koyama, Ichiro Nakahara, Akira Ishii, Taketo Hatano, Tsuyoshi Ohta, Koji Tanaka, Mitsushige Ando, Hideo Chihara, Wataru Takita, Keisuke Tokunaga, Takuro Hashikawa, Yusuke Funakoshi, Takahiko Kamata, Eiji Higashi, Sadayoshi Watanabe, Daisuke Kondo, Atsushi Tsujimoto, Konosuke Furuta, Takuma Ishihara, Tetsuya Hashimoto, Junpei Koge, Kazutaka Sonoda, Takako Torii, Hideaki Nakagaki, Ryo Yamasaki, Izumi Nagata, Jun Ichi Kira, A visual task management application for acute ischemic stroke care, Frontiers in Neurology, 10.3389/fneur.2019.01118, 10, OCT, 2019.01, Background: To maximize the effect of intravenous (IV) thrombolysis and/or endovascular therapy (EVT) for acute ischemic stroke (AIS), stroke centers need to establish a parallel workflow on the basis of a code stroke (CS) protocol. At Kokura Memorial Hospital (KMH), we implemented a CS system in January 2014; however, the process of information sharing within the team has occasionally been burdensome. Objective: To solve this problem using information communication technology (ICT), we developed a novel application for smart devices, named “Task Calc. Stroke” (TCS), and aimed to investigate the impact of TCS on AIS care. Methods: TCS can visualize the real-time progress of crucial tasks for AIS on a dashboard by changing color indicators. From August 2015 to March 2017, we installed TCS at KMH and recommended its use during normal business hours (NBH). We compared the door-to-computed tomography time, the door-to-complete blood count (door-to-CBC) time, the door-to-needle for IV thrombolysis time, and the door-to-puncture for EVT time among three treatment groups, one using TCS (“TCS-based CS”), one not using TCS (“phone-based CS”), and one not based on CS (“non-CS”). A questionnaire survey regarding communication problems was conducted among the CS teams at 3 months after the implementation of TCS. Results: During the study period, 74 patients with AIS were transported to KMH within 4.5 h from onset during NBH, and 53 were treated using a CS approach (phone-based CS: 26, TSC-based CS: 27). The door-to-CBC time was significantly reduced in the TCS-based CS group compared to the phone-based CS group, from 31 to 19 min (p = 0.043). Other processing times were also reduced, albeit not significantly. The rate of IV thrombosis was higher in the TCS-based CS group (78% vs. 46%, p = 0.037). The questionnaire was correctly filled in by 34/38 (89%) respondents, and 82% of the respondents felt a reduction in communication burden by using the TCS application. Conclusions: TCS is a novel approach that uses ICT to support information sharing in a parallel CS workflow in AIS care. It shortens the processing times of critical tasks and lessens the communication burden among team members.. |
| 91. |
Toshiki Okadome, Taira Uehara, Koji Shinoda, Ken Ichiro Yamashita, Hiroyuki Murai, Noriko Isobe, Ryo Yamasaki, Jun Ichi Kira, Creutzfeldt–Jakob disease-like diffusion-weighted imaging hyperintensity paralleled with neuropsychiatric symptoms in a patient with limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12525, 10, 3, 204-206, 2019.01. |
| 92. |
Koji Tanaka, Shoji Matsumoto, Konosuke Furuta, Takeshi Yamada, Sukehisa Nagano, Kei ichiro Takase, Taketo Hatano, Ryo Yamasaki, Jun ichi Kira, Modified diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score including deep white matter lesions predicts symptomatic intracerebral hemorrhage following intravenous thrombolysis, Journal of Thrombosis and Thrombolysis, 10.1007/s11239-019-01979-7, 2019.01, The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used for the assessment of early ischemic changes (EICs) before thrombolysis. However, for symptomatic intracerebral hemorrhage (sICH) following intravenous recombinant tissue plasminogen activator (rt-PA), the prediction abilities of CT-ASPECTS, diffusion-weighted imaging (DWI)-ASPECTS, and DWI-ASPECTS including EICs in deep white matter (DWI-ASPECTS + W) are unclear. We investigated associations between each score and sICH following intravenous rt-PA. Data from consecutive patients who received intravenous rt-PA for acute ischemic stroke from 2005 to 2015 in four hospitals were retrospectively screened. We included data from patients who had undergone both CT and magnetic resonance imaging before thrombolysis and without evidence of posterior circulation stroke. We analyzed the ability of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W to predict sICH, accompanied by an increase in the National Institutes of Health Stroke Scale (NIHSS) score of ≥ 4 within the initial 36 h. Of 455 patients (273 men, median 75 years old), sICH occurred in 15 patients (3.3%). Receiver operating characteristics curve analysis showed that the optimal cut-offs of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W for predicting sICH were ≤ 9 (sensitivity 60.0%, specificity 59.8%, c-statistic 0.625), ≤ 6 (sensitivity 53.3%, specificity 80.9%, c-statistic 0.718), and ≤ 8 (sensitivity 86.7%, specificity 55.9%, c-statistic 0.756), respectively. A DWI-ASPECTS + W of ≤ 8 was independently associated with sICH (odds ratio 5.21, 95% confidence interval 1.30–35.31) after adjustment for pretreatment with antithrombotic agents, pretreatment NIHSS score, and large artery occlusions. DWI-ASPECTS + W predicted sICH in patients with acute anterior circulation stroke receiving intravenous rt-PA.. |
| 93. |
Ryo Yamasaki, Jun ichi Kira, Multiple Sclerosis, Advances in Experimental Medicine and Biology, 10.1007/978-981-32-9636-7_14, 217-247, 2019.01, Multiple sclerosis (MS) is an inflammatory demyelinating disorder. Although all MS patients initially show a relapsing-remitting course, 20–50% subsequently enter a chronic progressive course at 10–20 years after onset that greatly influences their activities of daily living. There are 2.5 million MS patients worldwide with large regional and racial differences. In particular, there are many MS patients among Caucasians living in Europe, while the disease is relatively rare in Asians and Africans. Although MS is regarded as an autoimmune disease, many factors such as genetic background, environmental factors, and sex are involved in its pathogenesis. While the immunological mechanisms remain to be fully elucidated, invasion of autoreactive T cells into the central nervous system (CNS) tissue is considered the first step of the disease. These T cells react with myelin antigens and initiate demyelination of the CNS by activating cytotoxic T cells, macrophages, and B cells through the release of inflammatory cytokines. As a treatment option, disease-modifying therapies have recently been developed to prevent the recurrence of MS in addition to conventional treatment with corticosteroids for acute relapse. However, there are still few effective treatments for the chronic progressive phase, and it is thus imperative to decipher the mechanism for chronic progression.. |
| 94. |
Takayuki Fujii, Hiroyuki Honda, Ryo Yamasaki, Toru Iwaki, Jun Ichi Kira, Multiple mtDNA deletions due to mitochondrion toxicity of anti-hepadnaviral drugs
Comments to the letter from J. Finsterer, Neuropathology, 10.1111/neup.12563, 39, 4, 326-327, 2019.01. |
| 95. |
Akio Hiwatashi, Osamu Togao, Koji Yamashita, Kazufumi Kikuchi, Daichi Momosaka, Hiroshi Nakatake, Ryo Yamasaki, Hidenori Ogata, Masami Yoneyama, Jun-Ichi Kira, Hiroshi Honda, Simultaneous MR neurography and apparent T2 mapping in brachial plexus: Evaluation of patients with chronic inflammatory demyelinating polyradiculoneuropathy., Magnetic resonance imaging, 10.1016/j.mri.2018.09.025, 55, 112-117, 2019.01, PURPOSE: MR neurography is known to be useful to evaluate nerve pathology. The purpose of this study was to evaluate the usefulness of simultaneous apparent T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) to distinguish patients with chronic inflammatory demyelinating polyneuropathy (CIDP) from healthy subjects. MATERIALS AND METHODS: This retrospective study included 13 patients with CIDP and five healthy subjects from 2015 to 2017. The T2 relaxation time and the size of the cervical ganglia and roots of the brachial plexus were measured. Statistical analyses were performed with the Mann-Whitney U test and receiver operating characteristics (ROC) analysis. RESULTS: The T2 relaxation times of the ganglia and roots were longer in patients with CIDP (119.31 ± 35.53 msec and 111.15 ± 33.82 msec) than in healthy subjects (101.42 ± 26.42 msec and 85.29 ± 13.22 msec, P = 0.0007 and P |
| 96. |
Guangrui Li, Ryo Yamasaki, Mei Fang, Katsuhisa Masaki, Hirofumi Ochi, Takuya Matsushita, Jun-Ichi Kira, Novel disease-modifying anti-rheumatic drug iguratimod suppresses chronic experimental autoimmune encephalomyelitis by down-regulating activation of macrophages/microglia through an NF-κB pathway, Scientific Reports, 10.1038/s41598-018-20390-5, 8, 1, 2018.12, We aimed to elucidate the effects of iguratimod, a widely used anti-rheumatic drug with no severe side effects, on chronic experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Iguratimod was orally administered to mice immunised with myelin oligodendrocyte glycoprotein peptide 35-55. Preventive administration of iguratimod from the time of immunisation was found to markedly reduce the clinical severity of acute and chronic EAE. Pathologically, iguratimod treatment significantly reduced demyelination and infiltration of CD3 + T, F4/80 + , and CD169 + cells into the spinal cord, and suppressed macrophage/microglia activation in the parenchyma at the acute and chronic stages compared with vehicle treatment. Therapeutic administration of iguratimod after the onset of clinical symptoms significantly ameliorated the clinical severity of chronic EAE and reduced demyelination, T helper (Th)1/Th17 cell infiltration, macrophage/microglia activation, and nuclear factor (NF)-κB p65 and cyclooxygenase-2 expression in the spinal cord. In vitro, iguratimod treatment inhibited nuclear translocation of NF-κB p65 and down-regulated pro-inflammatory responses in macrophages and microglia. Our results suggest that iguratimod ameliorates acute and chronic EAE by suppressing inflammatory cell infiltration and immune cell activation, partly through inhibition of NF-κB p65, supporting the therapeutic potential of this drug for not only acute, but also chronic MS.. |
| 97. |
Naomi Mezaki, Takeshi Miura, Kotaro Ogaki, Makoto Eriguchi, Yuri Mizuno, Kenichi Komatsu, Hiroki Yamazaki, Natsuki Suetsugi, Sumihiro Kawajiri, Ryo Yamasaki, Takanobu Ishiguro, Takuya Konno, Hiroaki Nozaki, Kensaku Kasuga, Yasuyuki Okuma, Jun-Ichi Kira, Hideo Hara, Osamu Onodera, Takeshi Ikeuchi, Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy, Neurology: Genetics, 10.1212/NXG.0000000000000292, 4, 6, 2018.12, Objective To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). Methods Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. Results We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. Conclusions We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.. |
| 98. |
Naomi Mezaki, Takeshi Miura, Kotaro Ogaki, Makoto Eriguchi, Yuri Mizuno, Kenichi Komatsu, Hiroki Yamazaki, Natsuki Suetsugi, Sumihiro Kawajiri, Ryo Yamasaki, Takanobu Ishiguro, Takuya Konno, Hiroaki Nozaki, Kensaku Kasuga, Yasuyuki Okuma, Jun-Ichi Kira, Hideo Hara, Osamu Onodera, Takeshi Ikeuchi, Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy., Neurology. Genetics, 10.1212/NXG.0000000000000292, 4, 6, e292, 2018.12, Objective: To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). Methods: Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. Results: We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. Conclusions: We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.. |
| 99. |
Akio Hiwatashi, Osamu Togao, Koji Yamashita, Kazufumi Kikuchi, Daichi Momosaka, Hiroshi Nakatake, Ryo Yamasaki, Hidenori Ogata, Masami Yoneyama, Jun-Ichi Kira, Hiroshi Honda, Lumbar plexus in patients with chronic inflammatory demyelinating polyradiculoneuropathy: evaluation with simultaneous T2 mapping and neurography method with SHINKEI., The British journal of radiology, 10.1259/bjr.20180501, 91, 1092, 20180501-20180501, 2018.12, OBJECTIVE:: To evaluate the usefulness of simultaneous T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) in the lumbar plexus to distinguish patients with chronic inflammatory demyelinating polyneuropathy (CIDP) from healthy controls. METHODS:: Our institutional review boards approved this retrospective study, and written informed consent was waived. 10 patients with CIDP from 2015 to 2017 were studied along with 5 healthy controls on a 3 T scanner. The T2 relaxation time and the size of the dorsal root ganglia and nerves of the lumbar plexus at L3-S1 were measured. Statistical analyses were performed with the Mann-Whitney U test and a receiver operating characteristics analysis. RESULTS:: The T2 relaxation times of the dorsal root ganglia and the nerves of the lumbar plexus were longer in the CIDP patients (133.34 ± 41.36 and 130.40 ± 47.78 ms) compared to the healthy controls (114.69 ± 24.90 and 83.72 ± 17.51 ms, p = 0.0265 and p |
| 100. |
多系統萎縮症の病態形成における自然免疫の関与とバイオマーカーの探索. |
| 101. |
安静時機能的MRIを用いたアルツハイマー病治療薬による脳機能的結合変化の研究. |
| 102. |
急性期虚血性脳卒中に対する経静脈的血栓溶解療法後の早期神経症候増悪例の頻度と特徴. |
| 103. |
抗Neurofascin 155抗体陽性CIDPの分子生物的基盤と臨床像. |
| 104. |
膜性腎症を伴うCIDPにおける抗paranode、抗podocyte抗体、並びに抗contactin1抗体陽性CIDPとの病像の比較. |
| 105. |
Yu Hashimoto, Hidenori Ogata, Ryo Yamasaki, Takakazu Sasaguri, Senri Ko, kenichiro yamashita, Zhang Xu, Takuya Matsushita, Takahisa Tateishi, Shin'Ichi Akiyama, Shoichi Maruyama, Akifumi Yamamoto, Jun-Ichi Kira, Chronic inflammatory demyelinating polyneuropathy with concurrent membranous nephropathy
An anti-paranode and podocyte protein antibody study and literature survey, Frontiers in Neurology, 10.3389/fneur.2018.00997, 9, NOV, 2018.11, Background: Several case reports have described the concurrence of chronic inflammatory demyelinating polyneuropathy (CIDP) and membranous nephropathy (MN). The presence of autoantibodies against podocyte antigens phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain containing 7A (THSD7A) in MN suggests an autoimmune mechanism. Some CIDP patients also harbor autoantibodies against paranodal proteins such as neurofascin 155 (NF155) and contactin-1 (CNTN1). We investigated the relationship between CIDP and MN by assaying autoantibodies against paranodal and podocyte antigens in a CIDP patient with MN, and by a literature survey on the clinical features of CIDP with MN. Methods: Anti-CNTN1 and NF155 antibodies were measured by flow cytometry using HEK293 cell lines stably expressing human CNTN1 or NF155. Binding capacity of antibodies was validated by immunostaining mouse teased sciatic nerve fibers. Anti-PLA2R antibodies were measured by enzyme-linked sorbent assay and anti-THSD7A antibodies by indirect immunofluorescence assay. Clinical features between 14 CIDP with MN cases including two with anti-CNTN1 antibodies and 20 anti-CNTN1 antibody-positive CIDP cases were compared. Results: A patient whose ages was in the late 70 s complained of progressive weakness and superficial and deep sensory impairment in four extremities over 6 months. Nerve conduction studies showed prominent demyelination patterns. The patient presented with nephrotic syndrome. Renal biopsy disclosed basement membrane thickening with local subepithelial projections and glomerular deposits of IgG4, compatible with MN. Autoantibody assays revealed the presence of IgG4 and IgG1 anti-CNTN1 antibodies, but an absence of anti-NF155, anti-PLA2R, and anti-THSD7A antibodies. The patient's serum stained paranodes of teased sciatic nerves. CIDP with MN and anti-CNTN1 antibody-positive CIDP commonly showed male preponderance, relatively higher age of onset, acute to subacute onset in 35-50% of cases, distal dominant sensorimotor neuropathy, proprioceptive impairment leading to sensory ataxia, and very high cerebrospinal fluid protein levels. However, 11 of 13 CIDP patients with MN had a favorable response to mono- or combined immunotherapies whereas anti-CNTN1 antibody-positive CIDP was frequently refractory to corticosteroids and intravenous immunoglobulin administration. Conclusion: CIDP with MN and anti-CNTN1 antibody-positive CIDP show considerable overlap but are not identical. CIDP with MN is probably heterogeneous and some cases harbor anti-CNTN1 antibodies.. |
| 106. |
Mei Fang, Ryo Yamasaki, Guangrui Li, Katsuhisa Masaki, Hiroo Yamaguchi, Atsushi Fujita, Noriko Isobe, Jun-Ichi Kira, Connexin 30 deficiency attenuates chronic but not acute phases of experimental autoimmune encephalomyelitis through induction of neuroprotective microglia, Frontiers in Immunology, 10.3389/fimmu.2018.02588, 9, NOV, 2018.11, Glial connexins (Cxs) form gap junction channels through which a pan-glial network plays key roles in maintaining homeostasis of the central nervous system (CNS). In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), expression of astrocytic Cx43 is lost in acute lesions but upregulated in chronic plaques, while astrocytic Cx30 is very low in normal white matter and changes in its expression have not been convincingly shown. In Cx30 or Cx43 single knockout (KO) mice and even in Cx30/Cx43 double KO mice, acute EAE is unaltered. However, the effects of Cx30/Cx43 deficiency on chronic EAE remains to be elucidated. We aimed to clarify the roles of Cx30 in chronic neuroinflammation by studying EAE induced by myelin oligodendrocyte glycoprotein peptide 35-55 in Cx30 KO mice. We found that Cx30 deficiency improved the clinical symptoms and demyelination of chronic but not acute EAE without influencing CD3+ T cell infiltration. Furthermore, increased ramified microglia in the naïve state and induced earlier and stronger microglial activation in the acute and chronic phases of EAE was observed. These activated microglia had an anti-inflammatory phenotype, as shown by the upregulation of arginase-1 and brain-derived neurotrophic factor and the downregulation of nitric oxide synthase 2. In the naïve state, Cx30 deficiency induced modest enlargement of astrocytic processes in the spinal cord gray matter and a partial reduction of Cx43 expression in the spinal cord white matter. These astrocytes in Cx30 KO mice showed earlier and stronger activation during the acute phase of EAE, with upregulated A2 astrocyte markers and a significant decrease in Cx43 in the chronic phases. Spinal cord neurons and axons were more preserved in Cx30 KO mice than in littermates in the chronic phase of EAE. These findings suggest that Cx30 deficiency increased ramified microglia in the CNS in the naïve state and improved chronic EAE through redirecting microglia toward an anti-inflammatory phenotype, suggesting a hitherto unknown critical role of astrocytic Cx30 in regulating microglial number and functional state.. |
| 107. |
Yuko Kobayakawa, Katsuhisa Masaki, Ryo Yamasaki, Wataru Shiraishi, Shotaro Hayashida, Shintaro Hayashi, Koichi Okamoto, Takuya Matsushita, Jun-Ichi Kira, Downregulation of neuronal and dendritic Connexin36-made electrical synapses without glutamatergic axon terminals in spinal anterior horn cells from the early stage of amyotrophic lateral sclerosis, Frontiers in Neuroscience, 10.3389/fnins.2018.00894, 12, NOV, 2018.11, Connexin36 (Cx36) forms gap junctions between neurons, which are called electrical synapses, enabling adjacent neurons to communicate directly. The participation of chemical synapses in neurodegeneration in amyotrophic lateral sclerosis (ALS) has long been indicated, but it remains unclear whether electrical synapses are involved in the pathogenesis of ALS. We performed extensive immunopathological analyses using mutant superoxide dismutase 1 (SOD1G93A) transgenic mice and their littermates to investigate whether Cx36-made electrical synapses are affected in motor neuron diseases. We found that in the lamina IX of the lumbar spinal cord from wild type mice, about half of the Cx36 puncta existed independently of chemical synapse markers, while the rest coexisted with chemical synapse markers, such as vesicular glutamate transporter 1 (VGLUT1), which is a glutamatergic axon terminal marker, and/or glutamate decarboxylase 65 (GAD65), which is a GABAergic axon terminal marker. Cx36 single or Cx36/GAD65 double positive puncta, but not VGLUT1-containing puncta, were preferentially decreased on neuronal and dendritic surfaces of the anterior horn cells in the early stage of SOD1G93A ALS mice. Moreover, in five human autopsied sporadic ALS cases with bulbar or upper limb onset, Cx36 immunoreactivity was diminished in the proximal dendrites and neuropils of well-preserved large motor neurons in the lumbar anterior horns. These findings suggest that downregulation of neuronal and dendritic Cx36 in the spinal anterior horns commonly occurs from the early stage of hereditary and sporadic ALS. Cx36-made electrical synapses without glutamatergic signaling appear to be more vulnerable than other chemical synapses and electrical synapses with glutamatergic signaling in the early stage of motor neuron degeneration, suggesting involvement of Cx36-made electrical synapses in the pathogenesis of human ALS.. |
| 108. |
Facial onset sensory and motor neuronopathy症候群は早期からoral phase dysphagiaを呈する. |
| 109. |
GBS/CIDP:病態と治療の新たな展開-1 GBS/CIDPの自己抗体 蛋白抗原. |
| 110. |
抗neurofascin155抗体陽性CIDPにおける免疫遺伝学的背景因子とT細胞性免疫の関与. |
| 111. |
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, 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 mm
3
vs. 85 mm
3
, p |
| 112. |
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 |
| 113. |
趙 奕楠, 山崎 亮, バイエリン・マリオン, 山口 浩雄, 吉良 潤一, 基礎研究・動物モデル 希突起神経膠細胞特異的Cx47欠失により産生した新規続発性進行性MSモデル(Oligodendroglia-specific Cx47 deletion produces a novel secondary-progressive MS model), 神経免疫学, 23, 1, 110-110, 2018.09. |
| 114. |
Takayuki Fujii, Ryo Yamasaki, Kyoko Iinuma, Daisuke Tsuchimoto, Yoshinori Hayashi, Ban yu Saitoh, Takuya Matsushita, Mizuho A. Kido, Shinichi Aishima, Hiroshi Nakanishi, Yusaku Nakabeppu, Jun ichi Kira, A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain, Annals of Neurology, 10.1002/ana.25279, 84, 2, 208-224, 2018.08, Objective: To identify novel autoantibodies for neuropathic pain (NeP). Methods: We screened autoantibodies that selectively bind to mouse unmyelinated C-fiber type dorsal root ganglion (DRG) neurons using tissue-based indirect immunofluorescence assays (IFA) with sera from 110 NeP patients with various inflammatory and allergic neurologic diseases or other neuropathies, and 50 controls without NeP including 20 healthy subjects and 30 patients with neurodegenerative diseases or systemic inflammatory diseases. IgG purified from IFA-positive patients' sera was subjected to Western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify target autoantigens. Results: Antiunmyelinated C-fiber type DRG neuron antibodies were more frequent in patients with NeP than non-NeP subjects (10% vs 0%; p |
| 115. |
Atsushi Fujita, hiroo yamaguchi, Ryo Yamasaki, Yiwen Cui, Yuta Matsuoka, Ken-Ichi Yamada, Jun-Ichi Kira, Connexin 30 deficiency attenuates A2 astrocyte responses and induces severe neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride Parkinson's disease animal model, Journal of Neuroinflammation, 10.1186/s12974-018-1251-0, 15, 1, 2018.08, Background: The first pathology observed in Parkinson's disease (PD) is 'dying back' of striatal dopaminergic (DA) terminals. Connexin (Cx)30, an astrocytic gap junction protein, is upregulated in the striatum in PD, but its roles in neurodegeneration remain elusive. We investigated Cx30 function in an acute PD model by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to wild-type (WT) and Cx30 knockout (KO) mice. Methods: On days 1 and 7 after MPTP administration, we evaluated changes in astrocytic Cx30, Cx43, glial fibrillary acidic protein, and ionised calcium-binding adapter molecule 1 expression by immunostaining and biochemical analysis. Loss of DA neurons was evaluated by tyrosine hydroxylase immunostaining. Gene expression was analysed using A1, A2, pan-reactive astrocyte microarray gene sets, and M1, M2, and M1/M2 mixed microglial microarray gene sets. Real-time PCR and in situ hybridisation were performed to evaluate glial cell-derived neurotrophic factor (Gdnf) and S100a10 expression. Striatal GDNF protein levels were determined by enzyme-linked immunosorbent assay. Results: MPTP treatment induced upregulation of Cx30 and Cx43 levels in the striatum of WT and KO mice. DA neuron loss was accelerated in Cx30 KO compared with WT mice after MPTP administration, despite no change in the striatal concentration of methyl-4-phenylpyridinium
+
. Astrogliosis in the striatum of Cx30 KO mice was attenuated by MPTP, whereas microglial activation was unaffected. Microarrays of the striatum showed reduced expression of pan-reactive and A2 astrocyte genes after MPTP treatment in Cx30 KO compared with WT mice, while M1, M2, and M1/M2 mixed microglial gene expression did not change. MPTP reduced the number of striatal astrocytes co-expressing Gdnf mRNA and S100β protein or S100a10 mRNA and S100β protein and also reduced the level of GDNF in the striatum of Cx30 KO compared with WT mice. Conclusions: These findings indicate that Cx30 plays critical roles in astrocyte neuroprotection in an MPTP PD model.. |
| 116. |
Koji Tanaka, Shoji Matsumoto, Takeshi Yamada, Daisuke Kondo, Hideo Chihara, Motohisa Koga, Taketo Hatano, Tomoya Miyagi, Ryo Yamasaki, Jun-Ichi Kira, Elevated end-diastolic ratio of the common carotid artery due to cerebral arteriovenous malformation
Two case reports, Radiology Case Reports, 10.1016/j.radcr.2018.06.007, 13, 4, 917-920, 2018.08, An elevated end-diastolic (ED) ratio of the common carotid artery (CCA) is an indicator of occlusive lesions of the distal portion of the internal carotid artery. We report 2 cases of cerebral arteriovenous malformation (AVM) showing an elevated ED ratio of the CCA, which decreased after surgery. Case 1 was a 28-year-old man with chronic recurrent headache with aura, and case 2 was a 29-year-old woman with sudden-onset headache and intracerebral hemorrhage without neurologic abnormality. In both cases, digital subtraction angiography revealed a Spetzler-Martin Grade IV AVM, which was mainly fed by branches of the left middle cerebral artery with venous drainage into superficial and deep cerebral veins. Preoperative carotid ultrasonography showed an elevated CCA ED ratio (1.38 in case 1 and 1.47 in case 2; left > right) without atherosclerotic lesions. Patients’ AVMs were successfully resected. In both cases, the ED ratio was decreased after surgery (to 1.05 in case 1 and 1.20 in case 2). A decrease in vascular resistance on 1 side caused by cerebral AVM can result in an increase in the CCA ED ratio comparable to that of carotid axis occlusion.. |
| 117. |
Takayuki Fujii, Ryo Yamasaki, Kyoko Iinuma, Daisuke Tsuchimoto, Yoshinori Hayashi, Ban-Yu Saitoh, Takuya Matsushita, Mizuho A Kido, Shinichi Aishima, Hiroshi Nakanishi, Yusaku Nakabeppu, Jun-Ichi Kira, A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain., Annals of neurology, 10.1002/ana.25279, 84, 2, 208-224, 2018.08, OBJECTIVE: To identify novel autoantibodies for neuropathic pain (NeP). METHODS: We screened autoantibodies that selectively bind to mouse unmyelinated C-fiber type dorsal root ganglion (DRG) neurons using tissue-based indirect immunofluorescence assays (IFA) with sera from 110 NeP patients with various inflammatory and allergic neurologic diseases or other neuropathies, and 50 controls without NeP including 20 healthy subjects and 30 patients with neurodegenerative diseases or systemic inflammatory diseases. IgG purified from IFA-positive patients' sera was subjected to Western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify target autoantigens. RESULTS: Antiunmyelinated C-fiber type DRG neuron antibodies were more frequent in patients with NeP than non-NeP subjects (10% vs 0%; p |
| 118. |
Atsushi Fujita, Hiroo Yamaguchi, Ryo Yamasaki, Yiwen Cui, Yuta Matsuoka, Ken-Ichi Yamada, Jun-Ichi Kira, Connexin 30 deficiency attenuates A2 astrocyte responses and induces severe neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride Parkinson's disease animal model., Journal of neuroinflammation, 10.1186/s12974-018-1251-0, 15, 1, 227-227, 2018.08, BACKGROUND: The first pathology observed in Parkinson's disease (PD) is 'dying back' of striatal dopaminergic (DA) terminals. Connexin (Cx)30, an astrocytic gap junction protein, is upregulated in the striatum in PD, but its roles in neurodegeneration remain elusive. We investigated Cx30 function in an acute PD model by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to wild-type (WT) and Cx30 knockout (KO) mice. METHODS: On days 1 and 7 after MPTP administration, we evaluated changes in astrocytic Cx30, Cx43, glial fibrillary acidic protein, and ionised calcium-binding adapter molecule 1 expression by immunostaining and biochemical analysis. Loss of DA neurons was evaluated by tyrosine hydroxylase immunostaining. Gene expression was analysed using A1, A2, pan-reactive astrocyte microarray gene sets, and M1, M2, and M1/M2 mixed microglial microarray gene sets. Real-time PCR and in situ hybridisation were performed to evaluate glial cell-derived neurotrophic factor (Gdnf) and S100a10 expression. Striatal GDNF protein levels were determined by enzyme-linked immunosorbent assay. RESULTS: MPTP treatment induced upregulation of Cx30 and Cx43 levels in the striatum of WT and KO mice. DA neuron loss was accelerated in Cx30 KO compared with WT mice after MPTP administration, despite no change in the striatal concentration of methyl-4-phenylpyridinium+. Astrogliosis in the striatum of Cx30 KO mice was attenuated by MPTP, whereas microglial activation was unaffected. Microarrays of the striatum showed reduced expression of pan-reactive and A2 astrocyte genes after MPTP treatment in Cx30 KO compared with WT mice, while M1, M2, and M1/M2 mixed microglial gene expression did not change. MPTP reduced the number of striatal astrocytes co-expressing Gdnf mRNA and S100β protein or S100a10 mRNA and S100β protein and also reduced the level of GDNF in the striatum of Cx30 KO compared with WT mice. CONCLUSIONS: These findings indicate that Cx30 plays critical roles in astrocyte neuroprotection in an MPTP PD model.. |
| 119. |
Koji Tanaka, Shoji Matsumoto, Takeshi Yamada, Daisuke Kondo, Hideo Chihara, Motohisa Koga, Taketo Hatano, Tomoya Miyagi, Ryo Yamasaki, Jun-Ichi Kira, Elevated end-diastolic ratio of the common carotid artery due to cerebral arteriovenous malformation: Two case reports., Radiology case reports, 10.1016/j.radcr.2018.06.007, 13, 4, 917-920, 2018.08, An elevated end-diastolic (ED) ratio of the common carotid artery (CCA) is an indicator of occlusive lesions of the distal portion of the internal carotid artery. We report 2 cases of cerebral arteriovenous malformation (AVM) showing an elevated ED ratio of the CCA, which decreased after surgery. Case 1 was a 28-year-old man with chronic recurrent headache with aura, and case 2 was a 29-year-old woman with sudden-onset headache and intracerebral hemorrhage without neurologic abnormality. In both cases, digital subtraction angiography revealed a Spetzler-Martin Grade IV AVM, which was mainly fed by branches of the left middle cerebral artery with venous drainage into superficial and deep cerebral veins. Preoperative carotid ultrasonography showed an elevated CCA ED ratio (1.38 in case 1 and 1.47 in case 2; left > right) without atherosclerotic lesions. Patients' AVMs were successfully resected. In both cases, the ED ratio was decreased after surgery (to 1.05 in case 1 and 1.20 in case 2). A decrease in vascular resistance on 1 side caused by cerebral AVM can result in an increase in the CCA ED ratio comparable to that of carotid axis occlusion.. |
| 120. |
Haruki Koike, Ryoji Nishi, Shohei Ikeda, Yuichi Kawagashira, Masahiro Iijima, Naoki Atsuta, Tomohiko Nakamura, Masaaki Hirayama, Hidenori Ogata, Ryo Yamasaki, Jun-Ichi Kira, Masahisa Katsuno, Gen Sobue, Restoration of a Conduction Block after the Long-term Treatment of CIDP with Anti-neurofascin 155 Antibodies: Follow-up of a Case over 23 Years., Internal medicine (Tokyo, Japan), 10.2169/internalmedicine.0455-17, 57, 14, 2061-2066, 2018.07, We herein report a woman with chronic inflammatory demyelinating polyneuropathy (CIDP) in whom positivity for anti-neurofascin 155 antibodies was revealed 23 years after the onset of neuropathy. The patient initially reported numbness in the face at 50 years of age and subsequently manifested features compatible to typical CIDP. Steroid administration initiated at 54 years of age ameliorated her neuropathic symptoms. Although the nerve conduction indices at 59 years of age deteriorated, those at 68, 72, and 73 years of age showed a gradual recovery. The deterioration and subsequent restoration of compound muscle action potential amplitudes was the most dramatic, suggesting that a conduction block can be reversed earlier than other electrophysiological indices.. |
| 121. |
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, 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.. |
| 122. |
, Sonoko Misawa, Satoshi Kuwabara, Yasunori Sato, Nobuko Yamaguchi, Kengo Nagashima, Kanako Katayama, Yukari Sekiguchi, Yuta Iwai, Hiroshi Amino, Tomoki Suichi, Takanori Yokota, Yoichiro Nishida, Tadashi Kanouchi, Nobuo Kohara, Michi Kawamoto, Junko Ishii, Motoi Kuwahara, Hidekazu Suzuki, Koichi Hirata, Norito Kokubun, Ray Masuda, Juntaro Kaneko, Ichiro Yabe, Hidenao Sasaki, Ken ichi Kaida, Hiroshi Takazaki, Norihiro Suzuki, Shigeaki Suzuki, Hiroyuki Nodera, Naoko Matsui, Shoji Tsuji, Haruki Koike, Ryo Yamasaki, Susumu Kusunoki, S. Misawa, S. Kuwabara, Y. Sato, N. Yamaguchi, K. Nagashima, K. Katayama, Y. Sekiguchi, Y. Iwai, H. Amino, T. Suichi, T. Yokota, Y. Nishida, T. Kanouchi, N. Kohara, M. Kawamoto, Hidenori Ogata, Safety and efficacy of eculizumab in Guillain-Barré syndrome
a multicentre, double-blind, randomised phase 2 trial, The Lancet Neurology, 10.1016/S1474-4422(18)30114-5, 17, 6, 519-529, 2018.06, Background: Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. Methods: This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3–5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. Findings: Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42–78; n=14) in the eculizumab group, and 45% (20–73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. Interpretation: The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. Funding: The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.. |
| 123. |
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.. |
| 124. |
Misawa S, Kuwabara S, Sato Y, Yamaguchi N, Nagashima K, Katayama K, Sekiguchi Y, Iwai Y, Amino H, Suichi T, Yokota T, Nishida Y, Kanouchi T, Kohara N, Kawamoto M, Ishii J, Kuwahara M, Suzuki H, Hirata K, Kokubun N, Masuda R, Kaneko J, Yabe I, Sasaki H, Kaida KI, Takazaki H, Suzuki N, Suzuki S, Nodera H, Matsui N, Tsuji S, Koike H, Yamasaki R, Kusunoki S, Japanese Eculizumab Trial for GBS, JET-GBS, Study Group, Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial., The Lancet. Neurology, 10.1016/S1474-4422(18)30114-5, 17, 6, 519-529, 2018.06. |
| 125. |
Koji Shinoda, Takuya Matsushita, yuri nakamura, Katsuhisa Masaki, Ryo Yamasaki, Jun-Ichi Kira, HLA genotype and cortical lesions
Response to the letter from Spencer et al., Multiple Sclerosis, 10.1177/1352458517734072, 24, 6, 819-820, 2018.05. |
| 126. |
Fumie Hayashi, Shintaro Hayashi, Dai Matsuse, Ryo Yamasaki, Keiji Yonekura, Jun-Ichi Kira, Hopkins syndrome following the first episode of bronchial asthma associated with enterovirus D68
A case report, BMC Neurology, 10.1186/s12883-018-1075-7, 18, 1, 2018.05, Background: Hopkins syndrome (HS) is a rare disorder presenting with acute flaccid paralysis of the limbs following an asthma attack. Neurologists encounter a diagnostic challenge if patients without a history of bronchial asthma develop neurologic features mimicking HS following acute respiratory distress. We report a case of HS occurring after a first episode of bronchial asthma associated with enterovirus D68 infection. Case presentation: A 5-year-old girl developed acute respiratory distress. On the fourth hospital day, both her legs became paralyzed except for slight muscle contraction in the right lower limb. Tendon reflexes in the lower limbs were diminished and there was a positive Babinski sign on the right. Sensation was normal in all modalities, and there was no uro-rectal disturbance. Spinal magnetic resonance imaging identified T2-hyperintense lesions with spinal cord edema, mainly involving the bilateral T11 to L1 anterior horns, with left side dominance extending to the left posterior horn. The neurological and neuro-radiological findings of our case were suggestive of HS; however, she had no history of bronchial asthma. An acetylcholine inhalation challenge eventually proved the presence of reversible airway hyper-responsiveness, allowing us to diagnose HS. We identified enterovirus D68 in the patient's intratracheal aspirates using a sensitive polymerase chain reaction assay. Intravenous immunoglobulin administrations at 2 g/kg2 for 5 consecutive days were repeated every month up to four times. After these treatments, the muscle strength of her right lower limb slightly improved while her left lower leg remained completely paralyzed. Conclusion: This case emphasizes the importance of provocation tests to reveal the presence of airway hyper-responsiveness when a child shows neurological signs mimicking HS following acute respiratory distress. Furthermore, the present case suggests a possible link between HS and acute flaccid paralysis following lower respiratory tract infection by enterovirus D68.. |
| 127. |
Tomohiro Ohgomori, Ryo Yamasaki, Jun-Ichi Kira, Shozo Jinno, Upregulation of Vesicular Glutamate Transporter 2 and STAT3 Activation in the Spinal Cord of Mice Receiving 3,3′-Iminodipropionitrile, Neurotoxicity Research, 10.1007/s12640-017-9822-x, 33, 4, 768-780, 2018.05, Chronic administration of 3,3′-iminodipropionitrile (IDPN) causes axonal impairment. Although controversy still remains, it has been suggested that IDPN intoxication mimics the axonopathy of amyotrophic lateral sclerosis (ALS). Interestingly, recent studies including our own showed that signal transducer and activator of transcription 3 (STAT3) in spinal α-motoneurons was activated in both IDPN-treated mice and SOD1G93A mice, a genetic model of familial ALS. Because activation of STAT3 occurs in response to various stimuli, such as axonal injury, ischemia, and excessive glutamate, here we focused on a potential link between phosphorylated STAT3 (pSTAT3, an active form) and vesicular glutamate transporter 2 (VGluT2, a regulator of glutamate storage and release) in IDPN-treated mice and SOD1G93A mice. Impairment of axonal transport was confirmed by western blot analysis: the expression levels of phosphorylated neurofilament H were elevated in both models. As shown in SOD1G93A mice, the expression frequencies of VGluT2 in synaptophysin-positive (SYP)+ presynaptic terminals around spinal α-motoneurons were significantly higher in IDPN-treated mice than in vehicle controls. The coverages of spinal α-motoneurons by VGluT2+ presynaptic terminals were more elevated around pSTAT3+ cells than around pSTAT3− cells in IDPN-treated mice and SOD1G93A mice. Considering that excessive glutamate is shown to be involved in axonal impairment and STAT3 activation, the present results suggest that IDPN-induced upregulation of VGluT2 may result in an increase in glutamate, which might cause axonopathy and induction of pSTAT3. The link between upregulation of VGluT2 and activation of STAT3 via glutamate may represent a common pathological feature of IDPN-treated mice and SOD1G93A mice.. |
| 128. |
Hiroyuki Murai, Ken Ichi Kaida, Yuji Nakatsuji, Hideyuki Takeuchi, Koji Yamanaka, Ryo Yamasaki, Renewal of the Editorial Board members
The dawn of a new era, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12456, 9, 2, 79-80, 2018.05. |
| 129. |
Koji Shinoda, Takuya Matsushita, Yuri Nakamura, Katsuhisa Masaki, Ryo Yamasaki, Jun-Ichi Kira, HLA genotype and cortical lesions: Response to the letter from Spencer et al., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458517734072, 24, 6, 819-820, 2018.05. |
| 130. |
Koji Shinoda, Takuya Matsushita, Yuri Nakamura, Katsuhisa Masaki, Ryo Yamasaki, Hiroo Yamaguchi, Osamu Togao, Akio Hiwatashi, Jun-Ichi Kira, HLA-DRB1*04:05 allele is associated with intracortical lesions on three-dimensional double inversion recovery images in Japanese patients with multiple sclerosis., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458517707067, 24, 6, 710-720, 2018.05, BACKGROUND: Cortical lesions (CLs) frequently observed in Caucasian patients with multiple sclerosis (MS) contribute to disability. However, it remains unclear whether CLs are associated with clinical features and genetic risk factors, such as HLA-DRB1*15:01 and -DRB1*04:05 in Asian MS patients. OBJECTIVE: To elucidate the frequency of CLs and their association with HLA-DRB1 and DPB1 alleles in Japanese MS patients. METHODS: Three-dimensional double inversion recovery imaging and clinical information were retrospectively obtained from 92 Japanese MS patients. RESULTS: CLs of any type, intracortical lesions (ICLs), and leukocortical lesions (LCLs) were detected in 39.1%, 26.1%, and 28.3% of patients, respectively. MS patients with ICLs had a significantly higher frequency of secondary progression and greater Expanded Disability Status Scale (EDSS) scores than those without ICLs. Similar trends were observed with CLs and LCLs. The number of all three lesion types positively correlated with EDSS scores. The frequency and number of ICLs were significantly higher in HLA-DRB1*15:01 carriers than in HLA-DRB1*15:01 non-carriers, but significantly lower in HLA-DRB1*04:05 carriers than in HLA-DRB1*04:05 non-carriers. Multivariate logistic regression analysis revealed a negative association of HLA-DRB1*04:05 with ICLs. CONCLUSION: ICLs are associated with greater disease severity in Japanese MS patients and are partly suppressed by the HLA-DRB1*04:05 allele.. |
| 131. |
Fumie Hayashi, Shintaro Hayashi, Dai Matsuse, Ryo Yamasaki, Keiji Yonekura, Jun-Ichi Kira, Hopkins syndrome following the first episode of bronchial asthma associated with enterovirus D68: a case report., BMC neurology, 10.1186/s12883-018-1075-7, 18, 1, 71-71, 2018.05, BACKGROUND: Hopkins syndrome (HS) is a rare disorder presenting with acute flaccid paralysis of the limbs following an asthma attack. Neurologists encounter a diagnostic challenge if patients without a history of bronchial asthma develop neurologic features mimicking HS following acute respiratory distress. We report a case of HS occurring after a first episode of bronchial asthma associated with enterovirus D68 infection. CASE PRESENTATION: A 5-year-old girl developed acute respiratory distress. On the fourth hospital day, both her legs became paralyzed except for slight muscle contraction in the right lower limb. Tendon reflexes in the lower limbs were diminished and there was a positive Babinski sign on the right. Sensation was normal in all modalities, and there was no uro-rectal disturbance. Spinal magnetic resonance imaging identified T2-hyperintense lesions with spinal cord edema, mainly involving the bilateral T11 to L1 anterior horns, with left side dominance extending to the left posterior horn. The neurological and neuro-radiological findings of our case were suggestive of HS; however, she had no history of bronchial asthma. An acetylcholine inhalation challenge eventually proved the presence of reversible airway hyper-responsiveness, allowing us to diagnose HS. We identified enterovirus D68 in the patient's intratracheal aspirates using a sensitive polymerase chain reaction assay. Intravenous immunoglobulin administrations at 2 g/kg2 for 5 consecutive days were repeated every month up to four times. After these treatments, the muscle strength of her right lower limb slightly improved while her left lower leg remained completely paralyzed. CONCLUSION: This case emphasizes the importance of provocation tests to reveal the presence of airway hyper-responsiveness when a child shows neurological signs mimicking HS following acute respiratory distress. Furthermore, the present case suggests a possible link between HS and acute flaccid paralysis following lower respiratory tract infection by enterovirus D68.. |
| 132. |
Hiroyuki Murai, Ken-Ichi Kaida, Yuji Nakatsuji, Hideyuki Takeuchi, Koji Yamanaka, Ryo Yamasaki, Renewal of the Editorial Board members: The dawn of a new era, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12456, 9, 2, 79-80, 2018.05. |
| 133. |
Yuri Mizuno, Koji Shinoda, Mitsuru Watanabe, Takuya Matsushita, Ryo Yamasaki, Jun-Ichi Kira, Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms in NMOSD., Neurology(R) neuroimmunology & neuroinflammation, 10.1212/NXI.0000000000000447, 5, 3, e447, 2018.05. |
| 134. |
Tomohiro Ohgomori, Ryo Yamasaki, Jun-Ichi Kira, Shozo Jinno, Upregulation of Vesicular Glutamate Transporter 2 and STAT3 Activation in the Spinal Cord of Mice Receiving 3,3'-Iminodipropionitrile., Neurotoxicity research, 10.1007/s12640-017-9822-x, 33, 4, 768-780, 2018.05, Chronic administration of 3,3'-iminodipropionitrile (IDPN) causes axonal impairment. Although controversy still remains, it has been suggested that IDPN intoxication mimics the axonopathy of amyotrophic lateral sclerosis (ALS). Interestingly, recent studies including our own showed that signal transducer and activator of transcription 3 (STAT3) in spinal α-motoneurons was activated in both IDPN-treated mice and SOD1 G93A mice, a genetic model of familial ALS. Because activation of STAT3 occurs in response to various stimuli, such as axonal injury, ischemia, and excessive glutamate, here we focused on a potential link between phosphorylated STAT3 (pSTAT3, an active form) and vesicular glutamate transporter 2 (VGluT2, a regulator of glutamate storage and release) in IDPN-treated mice and SOD1 G93A mice. Impairment of axonal transport was confirmed by western blot analysis: the expression levels of phosphorylated neurofilament H were elevated in both models. As shown in SOD1 G93A mice, the expression frequencies of VGluT2 in synaptophysin-positive (SYP)+ presynaptic terminals around spinal α-motoneurons were significantly higher in IDPN-treated mice than in vehicle controls. The coverages of spinal α-motoneurons by VGluT2+ presynaptic terminals were more elevated around pSTAT3+ cells than around pSTAT3- cells in IDPN-treated mice and SOD1 G93A mice. Considering that excessive glutamate is shown to be involved in axonal impairment and STAT3 activation, the present results suggest that IDPN-induced upregulation of VGluT2 may result in an increase in glutamate, which might cause axonopathy and induction of pSTAT3. The link between upregulation of VGluT2 and activation of STAT3 via glutamate may represent a common pathological feature of IDPN-treated mice and SOD1 G93A mice.. |
| 135. |
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, APR, 2018.04, We recently reported that deletion-type copy number variations of the T cell receptor (TCR) γ, α, and δ genes greatly enhanced susceptibility to multiple sclerosis (MS). However, the effect of abnormal TCR γδ gene rearrangement on MS pathogenesis remains unknown. In the present study, we aimed to clarify γδ 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 Vδ2+ and Vδ2+Vγ9+ cells in γδ T cells (pcorr = 0.0297 and pcorr = 0.0288, respectively) and elevated Vδ1/Vδ2 ratios compared with HCs (p = 0.0033). The percentages of interferon (IFN)-γ+Vδ2+ and interleukin (IL)-17A+IFN-γ+Vδ2+ cells in γδ T cells, as well as IFN-γ+ cells in Vδ2+ γδ T cells, were significantly lower in MS patients than in HCs (pcorr corr = 0.0135, and pcorr = 0.0054, respectively). The percentages of Vδ2+ and Vδ2+Vγ9+ cells in γδ T cells were negatively correlated with both the Expanded Disability Status Scale score (r = -0.5006, p = 0.0048; and r = -0.5040, p = 0.0045, respectively) and Multiple Sclerosis Severity Score (r = -0.4682, p = 0.0091; and r = -0.4706, p = 0.0087, respectively), but not with age at disease onset, disease duration, or annualized relapse rate. In HCs, the percentages of Vδ2+ and Vδ2+Vγ9+ cells of total CD3+ T cells had strong positive correlations with the percentage of CD25+CD127low/- cells in CD4+ T cells (r = 0.7826, p +Vγ9+ γδ T cells are associated with disability in MS. Therefore, the Vδ1/Vδ2 ratio might be a candidate biomarker for predicting disease severity in MS.. |
| 136. |
Hiroyuki Ishiura, Koichiro Doi, Jun Mitsui, Jun Yoshimura, Miho Kawabe Matsukawa, Asao Fujiyama, Yasuko Toyoshima, Akiyoshi Kakita, Hitoshi Takahashi, Yutaka Suzuki, Sumio Sugano, Wei Qu, Kazuki Ichikawa, Hideaki Yurino, Koichiro Higasa, Shota Shibata, Aki Mitsue, Masaki Tanaka, Yaeko Ichikawa, Yuji Takahashi, Hidetoshi Date, Takashi Matsukawa, Junko Kanda, Fumiko Kusunoki Nakamoto, Mana Higashihara, Koji Abe, Ryoko Koike, Mutsuo Sasagawa, Yasuko Kuroha, Naoya Hasegawa, Norio Kanesawa, Takayuki Kondo, Takefumi Hitomi, Masayoshi Tada, Hiroki Takano, Yutaka Saito, Kazuhiro Sanpei, Osamu Onodera, Masatoyo Nishizawa, Masayuki Nakamura, Takeshi Yasuda, Yoshio Sakiyama, Mieko Otsuka, Akira Ueki, Ken Ichi Kaida, Jun Shimizu, Ritsuko Hanajima, Toshihiro Hayashi, Yasuo Terao, Ryo Yamasaki, Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy, Nature Genetics, 10.1038/s41588-018-0067-2, 50, 4, 581-590, 2018.04, Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.. |
| 137. |
Ishiura H, Doi K, Mitsui J, Yoshimura J, Matsukawa MK, Fujiyama A, Toyoshima Y, Kakita A, Takahashi H, Suzuki Y, Sugano S, Qu W, Ichikawa K, Yurino H, Higasa K, Shibata S, Mitsue A, Tanaka M, Ichikawa Y, Takahashi Y, Date H, Matsukawa T, Kanda J, Nakamoto FK, Higashihara M, Abe K, Koike R, Sasagawa M, Kuroha Y, Hasegawa N, Kanesawa N, Kondo T, Hitomi T, Tada M, Takano H, Saito Y, Sanpei K, Onodera O, Nishizawa M, Nakamura M, Yasuda T, Sakiyama Y, Otsuka M, Ueki A, Kaida KI, Shimizu J, Hanajima R, Hayashi T, Terao Y, Inomata-Terada S, Hamada M, Shirota Y, Kubota A, Ugawa Y, Koh K, Takiyama Y, Ohsawa-Yoshida N, Ishiura S, Yamasaki R, Tamaoka A, Akiyama H, Otsuki T, Sano A, Ikeda A, Goto J, Morishita S, Tsuji S, Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy., Nature genetics, 10.1038/s41588-018-0067-2, 50, 4, 581-590, 2018.04. |
| 138. |
Misawa Sonoko, Kuwabara Satoshi, Sato Yasunori, Yamaguchi Nobuko, Nagashima Kengo, Katayama Kanako, Sekiguchi Yukari, Iwai Yuta, Amino Hiroshi, Suichi Tomoki, Yokota Takanori, Nishida Yoichiro, Kanouchi Tadashi, Kohara Nobuo, Kawamoto Michi, Ishii Junko, Kuwabara Motoi, Suzuki Hidekazu, Hirata Koichi, Kokubun Norito, Masuda Ray, Kaneko Juntaro, Yabe Ichiro, Sasaki Hidenao, Kaida Ken-ichi, Takazaki Hiroshi, Suzuki Norihiro, Suzuki Shigeaki, Hiroyuki Nodera, Naoko Matsui, Tsuji Shoji, Koike Haruki, Yamasaki Ryo, Kusunki Susumu, Safety and efficacy of eculizumab in Guillain-Barr? syndrome: a multicentre, double-blind, randomised phase 2 trial., The Lancet Neurology, 10.1016/S1474-4422(18)30114-5, Vol.17, No.6, 519-529, 2018.04, Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barr? syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barr? syndrome. This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barr? syndrome were aged 18 years or older and could not walk independently (Guillain-Barr? syndrome functional grade 3-5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ?2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ?2) was 61% (90% CI 42-78; n=14) in the eculizumab group, and 45% (20-73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.. |
| 139. |
Ryo Yamasaki, Connexins in health and disease, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12433, 9, 30-36, 2018.03, Gap junctions or hemichannels are expressed on all cells in our body, and have a highly significant role in homeostasis and in disease states. There are 21 connexins found in humans and they have distinct characteristics that compensate for each other. The anatomical expression pattern also differs between each connexin; some of them are expressed together and some are not. Genetically mutated connexin genes induce inheritable diseases, but acquired disorders can also be caused by primary or secondary connexin dysfunctions. In the central nervous system, glial cells are the main connexin-expressing cells. They utilize connexin gap junctions to assemble glial networks. The present review not only describes the basic structures and functions of connexins, it also examines the relationships between connexins and their role in disease pathology.. |
| 140. |
Ryo Yamasaki, Connexins in health and disease, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12433, 9, 30-36, 2018.03, Gap junctions or hemichannels are expressed on all cells in our body, and have a highly significant role in homeostasis and in disease states. There are 21 connexins found in humans and they have distinct characteristics that compensate for each other. The anatomical expression pattern also differs between each connexin
some of them are expressed together and some are not. Genetically mutated connexin genes induce inheritable diseases, but acquired disorders can also be caused by primary or secondary connexin dysfunctions. In the central nervous system, glial cells are the main connexin-expressing cells. They utilize connexin gap junctions to assemble glial networks. The present review not only describes the basic structures and functions of connexins, it also examines the relationships between connexins and their role in disease pathology.. |
| 141. |
Hidenori Ogata, Ryo Yamasaki, Anti-neurofascin 155 antibody-related neuropathy, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12444, 9, 1, 54-64, 2018.02, Chronic inflammatory demyelinating polyneuropathy (CIDP) is an intractable inflammatory disease affecting peripheral nerves. The etiology of CIDP remains to be established, but it is regarded as a mixture of heterogeneous conditions presenting a variety of clinical and electrophysiological manifestations. In recent years, autoantibodies against paranodal cell adhesion molecules, such as neurofascin 155 (NF155), contactin 1 and contactin-associated protein 1, have been detected in subsets of CIDP patients. The clinical characteristics of anti-NF155 antibody-positive CIDP have been delineated, and include a younger onset age, higher frequency of distal muscle weakness, sensory ataxia and tremor, higher cerebrospinal fluid protein levels, more conspicuous demyelination on nerve conduction studies, and nerve root hypertrophy on magnetic resonance neurography, when compared with anti-NF155 antibody-negative CIDP patients. Predominant elevation of immunoglobulin G4 subclass is also a characteristic of this disease. Sural nerve biopsy specimens of anti-NF155 antibody-positive CIDP patients show axo-glial detachment in paranodes without inflammatory cell infiltrates or onion bulb formation. While intravenous immunoglobulin is not as effective as expected against anti-NF155 antibody-positive CIDP patients, other immunotherapies, such as corticosteroids, plasmapheresis and B-cell depletion therapy, seem to be effective. Early diagnosis and treatment is important for preventing secondary axonal degeneration. The present review summarizes the emerging details of anti-NF155 antibody-related neuropathy.. |
| 142. |
Hidenori Ogata, Ryo Yamasaki, Anti-neurofascin 155 antibody-related neuropathy, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12444, 9, 1, 54-64, 2018.02, Chronic inflammatory demyelinating polyneuropathy (CIDP) is an intractable inflammatory disease affecting peripheral nerves. The etiology of CIDP remains to be established, but it is regarded as a mixture of heterogeneous conditions presenting a variety of clinical and electrophysiological manifestations. In recent years, autoantibodies against paranodal cell adhesion molecules, such as neurofascin 155 (NF155), contactin 1 and contactin-associated protein 1, have been detected in subsets of CIDP patients. The clinical characteristics of anti-NF155 antibody-positive CIDP have been delineated, and include a younger onset age, higher frequency of distal muscle weakness, sensory ataxia and tremor, higher cerebrospinal fluid protein levels, more conspicuous demyelination on nerve conduction studies, and nerve root hypertrophy on magnetic resonance neurography, when compared with anti-NF155 antibody-negative CIDP patients. Predominant elevation of immunoglobulin G4 subclass is also a characteristic of this disease. Sural nerve biopsy specimens of anti-NF155 antibody-positive CIDP patients show axo-glial detachment in paranodes without inflammatory cell infiltrates or onion bulb formation. While intravenous immunoglobulin is not as effective as expected against anti-NF155 antibody-positive CIDP patients, other immunotherapies, such as corticosteroids, plasmapheresis and B-cell depletion therapy, seem to be effective. Early diagnosis and treatment is important for preventing secondary axonal degeneration. The present review summarizes the emerging details of anti-NF155 antibody-related neuropathy.. |
| 143. |
Atsushi Fujita, Hidenori Ogata, Ryo Yamasaki, Takuya Matsushita, Jun-Ichi Kira, Parallel fluctuation of anti-neurofascin 155 antibody levels with clinico-electrophysiological findings in patients with chronic inflammatory demyelinating polyradiculoneuropathy, Journal of the Neurological Sciences, 10.1016/j.jns.2017.11.035, 384, 107-112, 2018.01, Background The long-term clinical course and closely related biomarkers in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with anti-neurofascin 155 (NF155) antibodies remain to be elucidated. Methods We retrospectively studied the longitudinal clinical courses of three Japanese male anti-NF155 antibody-positive CIDP patients. Anti-NF155 antibody levels were measured by flow cytometry using HEK293 cell lines stably expressing human NF155. Results All three patients presented with chronic progressive sensorimotor disturbance, with ages at onset of 16, 26, and 34 years old, and they were followed for 58, 31, and 38 months, respectively, from the onset. All patients had postural tremor and generalized decreased deep tendon reflexes. Peak cerebrospinal fluid protein levels were > 400 mg/dl, and nerve conduction studies (NCS) showed severe demyelination patterns. Combined immunotherapies including intravenous immunoglobulin, plasma exchange, corticosteroids, and other immunosuppressants ameliorated clinical severity and NCS abnormalities, with improvements of > 10 kg in grip strength and at least 20% in F-wave latencies. However, their symptoms exacerbated after the immunotherapies were tapered. Anti-NF155 antibody levels varied in parallel with the clinical and electrophysiological changes, or preceded them. Conclusion The patients’ clinical courses suggest that anti-NF155 antibody levels and NCS findings could be disease activity markers in anti-NF155 antibody-positive CIDP.. |
| 144. |
Ryo Yamasaki, Jun-Ichi Kira, The contribution of glial inflammation in the pathogenesis of multiple sclerosis, Neuro-Ophthalmology Japan, 10.11476/shinkeiganka.35.4, 35, 1, 4-10, 2018.01, Multiple sclerosis (MS) is one of the most prominent demyelinating disorders with a phenotype of relapsing and remitting neurological deficits. The recurrence of relapse contributes to the accumulation of neuronal damage, which leads to the transition of the disease into secondaryprogressive MS (SPMS). The mechanisms of SPMS are unknown, making the invention of new therapeutic options for SPMS difficult. In the progressive phase, "glial inflammation" is assumed to be the major player in neurodegeneration. Recently, our group and others have shown that gap junction proteins called connexins are important in the pathomechanisms of SPMS in the context of "glial inflammation". The expression of glia in connexins differs between cell types. Astroglial connexins are down regulated in the acute phase and up regulated in the chronic phase of MS, while oligodendroglial connexins are down regulated through the course of the disease. The modification and malfunction of gap junction connexins are thought to play roles in the pathomechanisms of SPMS. Further elucidation of their mechanisms may provide clues useful for the invention of new therapeutic options for SPMS.. |
| 145. |
Akio Hiwatashi, Osamu Togao, Koji Yamashita, Kazufumi Kikuchi, Daichi Momosaka, Hiroshi Nakatake, Ryo Yamasaki, Hidenori Ogata, Masami Yoneyama, Jun Ichi Kira, Hiroshi Honda, Lumbar plexus in patients with chronic inflammatory demyelinating polyradiculoneuropathy
Evaluation with simultaneous T2 mapping and neurography method with SHINKEI, British Journal of Radiology, 10.1259/bjr.20180501, 91, 1092, 2018.01, Objective: To evaluate the usefulness of simultaneous T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) in the lumbar plexus to distinguish patients with chronic inflammatory demyelinating polyneuropathy (CIDP) from healthy controls. Methods: Our institutional review boards approved this retrospective study, and written informed consent was waived. 10 patients with CIDP from 2015 to 2017 were studied along with 5 healthy controls on a 3 T scanner. The T2 relaxation time and the size of the dorsal root ganglia and nerves of the lumbar plexus at L3-S1 were measured. Statistical analyses were performed with the Mann-Whitney U test and a receiver operating characteristics analysis. Results: The T2 relaxation times of the dorsal root ganglia and the nerves of the lumbar plexus were longer in the CIDP patients (133.34 ± 41.36 and 130.40 ± 47.78 ms) compared to the healthy controls (114.69 ± 24.90 and 83.72 ± 17.51 ms, p = 0.0265 andp 2 relaxation time of the nerves was best at distinguishing the CIDP patients from the controls (Az = 0.848). Conclusion: Patients with CIDP could be distinguished from healthy controls using simultaneous T2 mapping and neurography with SHINKEI in the lumbar plexus. Advances in knowledge: Patients with CIDP could be distinguished from healthy controls using simultaneous T2 mapping and neurography with SHINKEI in the lumbar plexus.. |
| 146. |
Haruki Koike, Ryoji Nishi, Shohei Ikeda, Yuichi Kawagashira, Masahiro Iijima, Naoki Atsuta, Tomohiko Nakamura, Masaaki Hirayama, Hidenori Ogata, Ryo Yamasaki, Jun Ichi Kira, Masahisa Katsuno, Gen Sobue, Restoration of a conduction block after the long-term treatment of CIDP with anti-neurofascin 155 antibodies
Follow-up of a case over 23 years, Internal Medicine, 10.2169/internalmedicine.0455-17, 57, 14, 2061-2066, 2018.01, We herein report a woman with chronic inflammatory demyelinating polyneuropathy (CIDP) in whom positivity for anti-neurofascin 155 antibodies was revealed 23 years after the onset of neuropathy. The patient initially reported numbness in the face at 50 years of age and subsequently manifested features compatible to typical CIDP. Steroid administration initiated at 54 years of age ameliorated her neuropathic symptoms. Although the nerve conduction indices at 59 years of age deteriorated, those at 68, 72, and 73 years of age showed a gradual recovery. The deterioration and subsequent restoration of compound muscle action potential amplitudes was the most dramatic, suggesting that a conduction block can be reversed earlier than other electrophysiological indices.. |
| 147. |
Li G, Yamasaki R, Fang M, Masaki K, Ochi H, Matsushita T, Kira JI, Novel disease-modifying anti-rheumatic drug iguratimod suppresses chronic experimental autoimmune encephalomyelitis by down-regulating activation of macrophages/microglia through an NF-κB pathway., Scientific reports, 10.1038/s41598-018-20390-5, 8, 1, 1933-1933, 2018.01. |
| 148. |
Atsushi Fujita, Hidenori Ogata, Ryo Yamasaki, Takuya Matsushita, Jun-Ichi Kira, Parallel fluctuation of anti-neurofascin 155 antibody levels with clinico-electrophysiological findings in patients with chronic inflammatory demyelinating polyradiculoneuropathy., Journal of the neurological sciences, 10.1016/j.jns.2017.11.035, 384, 107-112, 2018.01, BACKGROUND: The long-term clinical course and closely related biomarkers in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with anti-neurofascin 155 (NF155) antibodies remain to be elucidated. METHODS: We retrospectively studied the longitudinal clinical courses of three Japanese male anti-NF155 antibody-positive CIDP patients. Anti-NF155 antibody levels were measured by flow cytometry using HEK293 cell lines stably expressing human NF155. RESULTS: All three patients presented with chronic progressive sensorimotor disturbance, with ages at onset of 16, 26, and 34years old, and they were followed for 58, 31, and 38months, respectively, from the onset. All patients had postural tremor and generalized decreased deep tendon reflexes. Peak cerebrospinal fluid protein levels were >400mg/dl, and nerve conduction studies (NCS) showed severe demyelination patterns. Combined immunotherapies including intravenous immunoglobulin, plasma exchange, corticosteroids, and other immunosuppressants ameliorated clinical severity and NCS abnormalities, with improvements of >10kg in grip strength and at least 20% in F-wave latencies. However, their symptoms exacerbated after the immunotherapies were tapered. Anti-NF155 antibody levels varied in parallel with the clinical and electrophysiological changes, or preceded them. CONCLUSION: The patients' clinical courses suggest that anti-NF155 antibody levels and NCS findings could be disease activity markers in anti-NF155 antibody-positive CIDP.. |
| 149. |
Yuko Yamagishi, Hidekazu Suzuki, Masahiro Sonoo, Satoshi Kuwabara, Takanori Yokota, Kyoichi Nomura, Atsuro Chiba, Ryuji Kaji, Takashi Kanda, Kenichi Kaida, Shu Ichi Ikeda, Tatsuro Mutoh, Ryo Yamasaki, Hiroshi Takashima, Makoto Matsui, Kazutoshi Nishiyama, Gen Sobue, Susumu Kusunoki, Markers for Guillain-Barré syndrome with poor prognosis
a multi-center study, Journal of the Peripheral Nervous System, 10.1111/jns.12234, 22, 4, 433-439, 2017.12, Guillain-Barré syndrome (GBS) is an acute monophasic neuropathy. Prognostic tools include the modified Erasmus GBS outcome score (mEGOS), Erasmus GBS respiratory insufficiency score (EGRIS), and the increase in serum IgG levels (ΔIgG) 2 weeks after intravenous immunoglobulin (IVIg) treatment. Given that proportions of GBS subtypes differ between Western countries and Japan, the usefulness of these tools in Japan or other countries remains unknown. We enrolled 177 Japanese patients with GBS from 15 university hospitals and retrospectively obtained mEGOS and EGRIS for all and ΔIgG status for 79 of them. High mEGOS scores on admission or on day 7 were significantly associated with poorer outcomes (unable to walk independently at 6 months). High EGRIS scores (≥5 points) were associated with an increased risk for mechanical ventilation. Patients with ΔIgG |
| 150. |
Mitsuhiko Katoh, Bao Wu, Huy Bang Nguyen, Truc Quynh Thai, Ryo Yamasaki, Haiyan Lu, Anna M. Rietsch, Musab M. Zorlu, Youichi Shinozaki, Yurika Saitoh, Sei Saitoh, Takashi Sakoh, Kazuhiro Ikenaka, Schuichi Koizumi, Richard M. Ransohoff, Nobuhiko Ohno, Polymorphic regulation of mitochondrial fission and fusion modifies phenotypes of microglia in neuroinflammation, Scientific Reports, 10.1038/s41598-017-05232-0, 7, 1, 2017.12, Microglia are the resident macrophages of the central nervous system and play complex roles in the milieu of diseases including the primary diseases of myelin. Although mitochondria are critical for cellular functions and survival in the nervous system, alterations in and the roles of mitochondrial dynamics and associated signaling in microglia are still poorly understood. In the present study, by combining immunohistochemistry and 3D ultrastructural analyses, we show that mitochondrial fission/fusion in reactive microglia is differentially regulated from that in monocyte-derived macrophages and the ramified microglia of normal white matter in myelin disease models. Mouse cerebral microglia in vitro demonstrated that stimulation of TLR4 with lipopolysaccharide, widely used to examine microglial reactions, caused the activation of the mitochondrial fission protein, dynamin-related protein 1 (Drp1) and enhanced production of reactive oxygen species (ROS). The increase in the ROS level activated 5′ adenosine monophosphate-activated protein kinase (AMPK), and facilitated elongation of mitochondria along the microtubule tracks. These results suggest that the polymorphic regulation of mitochondrial fission and fusion in reactive microglia is mediated by distinct signaling under inflammatory conditions, and modulates microglial phenotypes through the production of ROS.. |
| 151. |
Yamagishi Y, Suzuki H, Sonoo M, Kuwabara S, Yokota T, Nomura K, Chiba A, Kaji R, Kanda T, Kaida K, Ikeda SI, Mutoh T, Yamasaki R, Takashima H, Matsui M, Nishiyama K, Sobue G, Kusunoki S, Markers for Guillain-Barré syndrome with poor prognosis: a multi-center study., Journal of the peripheral nervous system : JPNS, 10.1111/jns.12234, 22, 4, 433-439, 2017.12. |
| 152. |
Ryo Yamasaki, Astroglial phagocytosis in central nervous system health and disease, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12413, 8, 4, 285-286, 2017.11, Phagocytosis by astrocytes is important in the developing brain and in central nervous system lesions. Astroglial phagocytosis usually contributes to the repair of damaged lesions, but, depending on the local milieu, astrocytes can become activated “A1” type astroglia, which release neurotoxic substances and accelerate regional damage.. |
| 153. |
Tatsuo Mano, Kenichi Nagata, Takashi Nonaka, Airi Tarutani, Tomohiro Imamura, Tadafumi Hashimoto, Taro Bannai, Kagari Koshi-Mano, Takeyuki Tsuchida, Ryo Ohtomo, Junko Takahashi-Fujigasaki, Satoshi Yamashita, Yasumasa Ohyagi, Ryo Yamasaki, Shoji Tsuji, Akira Tamaoka, Takeshi Ikeuchi, Takaomi C. Saido, Takeshi Iwatsubo, Toshikazu Ushijima, Shigeo Murayama, Masato Hasegawa, Atsushi Iwata, Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer’s disease, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1707151114, 114, 45, E9645-E9654, 2017.11, Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid β (Aβ) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aβ. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aβ burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.. |
| 154. |
Tatsuo Mano, Kenichi Nagata, Takashi Nonaka, Airi Tarutani, Tomohiro Imamura, Tadafumi Hashimoto, Taro Bannai, Kagari Koshi-Mano, Takeyuki Tsuchida, Ryo Ohtomo, Junko Takahashi-Fujigasaki, Satoshi Yamashita, Yasumasa Ohyagi, Ryo Yamasaki, Shoji Tsuji, Akira Tamaoka, Takeshi Ikeuchi, Takaomi C Saido, Takeshi Iwatsubo, Toshikazu Ushijima, Shigeo Murayama, Masato Hasegawa, Atsushi Iwata, Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease., Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1707151114, 114, 45, E9645-E9654-E9654, 2017.11, Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid β (Aβ) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aβ. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aβ burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.. |
| 155. |
Ryo Yamasaki, Astroglial phagocytosis in central nervous system health and disease, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12413, 8, 4, 285-286, 2017.11, Phagocytosis by astrocytes is important in the developing brain and in central nervous system lesions. Astroglial phagocytosis usually contributes to the repair of damaged lesions, but, depending on the local milieu, astrocytes can become activated “A1” type astroglia, which release neurotoxic substances and accelerate regional damage.. |
| 156. |
Daisuke Kondo, Koji Shinoda, kenichiro yamashita, Ryo Yamasaki, Akihiro Hashiguchi, Hiroshi Takashima, Jun-Ichi Kira, A novel mutation in FGD4 causes Charcot–Marie–Tooth disease type 4H with cranial nerve involvement, Neuromuscular Disorders, 10.1016/j.nmd.2017.07.011, 27, 10, 959-961, 2017.10, Charcot–Marie–Tooth disease type 4H (CMT4H) is a rare variant of autosomal recessive hereditary neuropathy. It is caused by FGD4 mutations and characterized by early infantile onset, slowly progressive distal muscle weakness, scoliosis, and myelin outfoldings visible in nerve biopsy samples. Here, we report a 65-year-old male born to consanguineous parents, who carries a novel homozygous FGD4 c.724C>T nonsense mutation. He developed lower limb weakness in his teens, which progressed slowly and was accompanied by diplopia, bilateral hearing loss, and erectile dysfunction from his twenties. At the age of 65, he was wheelchair-bound and had mild scoliosis, bilateral ophthalmoplegia, facial muscle weakness, inner ear hearing loss, distal-dominant weakness, and sensory disturbance, but no cognitive deterioration. Magnetic resonance imaging revealed enlarged bilateral trigeminal and facial nerves. Accordingly, we believe that this mutation causes slowly progressive sensorimotor neuropathy with apparent cranial nerve involvement, thereby further expanding the clinical spectrum of CMT4H.. |
| 157. |
Koji Tanaka, Shoji Matsumoto, Hiroyuki Murai, Ryo Yamasaki, Jun-Ichi Kira, Measurement Conditions of End-Diastolic Ratio of Common Carotid Arteries Alter Diagnostic Ability for Large Artery Intracranial Occlusive Disease, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2017.05.038, 26, 10, 2421-2426, 2017.10, Background End-diastolic ratio, calculated by the side-to-side ratio of end-diastolic flow velocities of the common carotid arteries, is an indicator for large artery intracranial occlusive disease. However, the diagnostic ability of end-diastolic ratios derived from different measurement conditions is unclear. Methods End-diastolic ratios were measured twice by single carotid duplex ultrasonography. End-diastolic ratio1st was calculated from separate end-diastolic flow velocities measured during routine assessment. End-diastolic ratio2nd was calculated almost simultaneously without head rotation. For each end-diastolic ratio, the measurement conditions and prediction ability for occlusions of the internal carotid artery or proximal portion of the middle cerebral artery using an established cutoff of 1.4 or greater were compared. Results Two hundred thirty-three patients (147 men, median 67 years) were registered, with available intracranial artery information in 158 patients (67.8%) and occlusions detected in 7 patients (4.4%). End-diastolic ratio1st was significantly higher than end-diastolic ratio2nd (median 1.21 versus 1.08, P <.001 compared with end-diastolic ratio>1st, end-diastolic ratio2nd had a significantly shorter time interval (median 709 versus 28 seconds, P <.001 and smaller pulse rate difference versus.25 beats per minute p=".004)." to predict occlusions the sensitivity specificity overall accuracy for end-diastolic ratio>1st of 1.4 or greater were 85.7%, 70.9%, and 71.5%, respectively, and for end-diastolic ratio2nd of 1.4 or greater were 85.7%, 98.0%, and 97.5%, respectively. End-diastolic ratio2nd had better specificity and overall accuracy than end-diastolic ratio1st (P <.001 conclusions end-diastolic ratio varies with measurement conditions. combined flow velocities may improve diagnostic ability for large artery intracranial occlusive disease.. id="gencho_ronbuns10059403" class="qir_handle_link"> |
| 158. |
Mitsunori Shimmura, Taira Uehara, kenichiro yamashita, Hiroshi Shigeto, Ryo Yamasaki, Kinya Ishikawa, Jun-Ichi Kira, Slowed abduction during smooth pursuit eye movement in episodic ataxia type 2 with a novel CACNA1A mutation, Journal of the Neurological Sciences, 10.1016/j.jns.2017.07.040, 381, 4-6, 2017.10. |
| 159. |
Daisuke Kondo, Koji Shinoda, Ken-Ichiro Yamashita, Ryo Yamasaki, Akihiro Hashiguchi, Hiroshi Takashima, Jun-Ichi Kira, A novel mutation in FGD4 causes Charcot-Marie-Tooth disease type 4H with cranial nerve involvement., Neuromuscular disorders : NMD, 10.1016/j.nmd.2017.07.011, 27, 10, 959-961, 2017.10, Charcot-Marie-Tooth disease type 4H (CMT4H) is a rare variant of autosomal recessive hereditary neuropathy. It is caused by FGD4 mutations and characterized by early infantile onset, slowly progressive distal muscle weakness, scoliosis, and myelin outfoldings visible in nerve biopsy samples. Here, we report a 65-year-old male born to consanguineous parents, who carries a novel homozygous FGD4 c.724C>T nonsense mutation. He developed lower limb weakness in his teens, which progressed slowly and was accompanied by diplopia, bilateral hearing loss, and erectile dysfunction from his twenties. At the age of 65, he was wheelchair-bound and had mild scoliosis, bilateral ophthalmoplegia, facial muscle weakness, inner ear hearing loss, distal-dominant weakness, and sensory disturbance, but no cognitive deterioration. Magnetic resonance imaging revealed enlarged bilateral trigeminal and facial nerves. Accordingly, we believe that this mutation causes slowly progressive sensorimotor neuropathy with apparent cranial nerve involvement, thereby further expanding the clinical spectrum of CMT4H.. |
| 160. |
Koji Tanaka, Shoji Matsumoto, Hiroyuki Murai, Ryo Yamasaki, Jun-Ichi Kira, Measurement Conditions of End-Diastolic Ratio of Common Carotid Arteries Alter Diagnostic Ability for Large Artery Intracranial Occlusive Disease., Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 10.1016/j.jstrokecerebrovasdis.2017.05.038, 26, 10, 2421-2426, 2017.10, BACKGROUND: End-diastolic ratio, calculated by the side-to-side ratio of end-diastolic flow velocities of the common carotid arteries, is an indicator for large artery intracranial occlusive disease. However, the diagnostic ability of end-diastolic ratios derived from different measurement conditions is unclear. METHODS: End-diastolic ratios were measured twice by single carotid duplex ultrasonography. End-diastolic ratio1st was calculated from separate end-diastolic flow velocities measured during routine assessment. End-diastolic ratio2nd was calculated almost simultaneously without head rotation. For each end-diastolic ratio, the measurement conditions and prediction ability for occlusions of the internal carotid artery or proximal portion of the middle cerebral artery using an established cutoff of 1.4 or greater were compared. RESULTS: Two hundred thirty-three patients (147 men, median 67 years) were registered, with available intracranial artery information in 158 patients (67.8%) and occlusions detected in 7 patients (4.4%). End-diastolic ratio1st was significantly higher than end-diastolic ratio2nd (median 1.21 versus 1.08, P |
| 161. |
Mitsunori Shimmura, Taira Uehara, Kenichiro Yamashita, Hiroshi Shigeto, Ryo Yamasaki, Kinya Ishikawa, Jun-Ichi Kira, Slowed abduction during smooth pursuit eye movement in episodic ataxia type 2 with a novel CACNA1A mutation., Journal of the neurological sciences, 10.1016/j.jns.2017.07.040, 381, 4-6, 2017.10. |
| 162. |
K. Shinoda, G. Maimaitijiang, Y. Nakamura, K. Masaki, T. Matsushita, R. Yamasaki, Y. Yoshikai, J. -I. Kira, A distinct repertoire of the gamma delta T cell population is associated with disease severity of multiple sclerosis, MULTIPLE SCLEROSIS JOURNAL, 23, 201-201, 2017.10. |
| 163. |
Takayuki Fujii, Ryo Yamasaki, Kyoko Iinuma, Daisuke Tsuchimoto, Mizuho A. Kido, Shinichi Aishima, Yusaku Nakabeppu, Jun-Ichi Kira, An Anti-Plexin D1 Autoantibody Is Associated with Immunotherapy-Responsive Neuropathic Pain, ANNALS OF NEUROLOGY, 82, S119-S119, 2017.10. |
| 164. |
Jun-Ichi Kira, Ryo Yamasaki, Hayato Une, Mei Fang, Yinan Zhao, Guanrui Li, Kyoko Iinuma, Katsuhisa Masaki, Kouji Shinoda, Hiroo Yamaguchi, Astroglial and Oligodendroglial Connexins Differentially Modulate Acute and Chronic Experimental Autoimmune Encephalomyelitis, ANNALS OF NEUROLOGY, 82, S124-S124, 2017.10. |
| 165. |
Ryo Yamasaki, Yiwen Cui, Katsuhisa Masaki, Shotaro Hayashida, Jun-ichi Kira, Establishing a Hypertrophic Pachymeningitis Model Mice and Successful Treatment with Tumor Growth Factor-beta Blockade, ANNALS OF NEUROLOGY, 82, S26-S26, 2017.10. |
| 166. |
S. Hayashida, K. Masaki, S. O. Suzuki, T. Matsushita, R. Yamasaki, T. Suenaga, K. Takahashi, T. Iwaki, J. -I. Kira, Focal cortical astrocytopathy lesions with demyelination and inflammatory cell infiltrates in neuromyelitis optica spectrum disorder: a neuropathological study of eleven autopsied cases, MULTIPLE SCLEROSIS JOURNAL, 23, 173-173, 2017.10. |
| 167. |
Lamin B1関連常染色体優性遺伝性白質脳症 コピー数多型と臨床的特徴. |
| 168. |
Koike H, Kadoya M, Kaida K. I, Nishi R, Ikeda S, Kawagashira Y, Lijima M, Kato D, Ogata H, Yamasaki R, Matsukawa N, Kira J. I, Katsuno M, Sobue G, Paranodal axo-glial detachment in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies, JOURNAL OF THE NEUROLOGICAL SCIENCES, 10.1016/j.jns.2017.08.226, 381, 59-60, 2017.10. |
| 169. |
趙 奕楠, 山崎 亮, 山口 浩雄, 宇根 隼人, 飯沼 今日子, 真崎 勝久, 篠田 紘司, 吉良 潤一, 基礎研究・実験モデル オリゴデンドログリアのコネキシン47欠失は慢性進行型実験的自己免疫性脳脊髄炎を悪化させる, 神経免疫学, 22, 1, 120-120, 2017.10. |
| 170. |
H. Ogata, A. Fujita, R. Yamasaki, T. Matsushita, J. Kira, CLINICO-ELECTROPHYSIOLOGICAL CORRELATION WITH ANTI-NEUROFASCIN155 ANTIBODY LEVELS IN THE ANTIBODY-POSITIVE CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY PATIENTS, JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, 22, 3, 348-349, 2017.09. |
| 171. |
H. Koike, M. Kadoya, K. Kaida, S. Ikeda, Y. Kawagashira, M. Iijima, D. Kato, H. Ogata, R. Yamasaki, N. Matsukawa, J. Kira, M. Katsuno, G. Sobue, PARANODAL DISSECTION IN CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY WITH ANTI-NEUROFASCIN 155 AND ANTI-CONTACTIN 1 ANTIBODIES, JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, 22, 3, 318-318, 2017.09. |
| 172. |
Tomohiro Ohgomori, Ryo Yamasaki, Hideyuki Takeuchi, Kenji Kadomatsu, Jun-Ichi Kira, Shozo Jinno, Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis, European Journal of Neuroscience, 10.1111/ejn.13650, 46, 4, 2001-2014, 2017.08, Signal transducer and activator of transcription (STAT) proteins are activated by phosphorylation in the spinal cord of patients suffering from amyotrophic lateral sclerosis (ALS). The major scope of our study is a comprehensive histological characterization of the mechanisms underlying neuronal and glial STAT3 activation in the pathogenesis of ALS using SOD1G93A mice. We calculated the fold changes (FCs, ratios vs. appropriate controls) of the numerical densities of the following phosphorylated STAT3-positive (pSTAT3)+ cells – choline acetyltransferase (ChAT)+ α-motoneurons, ionized calcium-binding adapter molecule 1 (Iba1)+ microglia, and S100β+ astrocytes in SOD1G93A mice. The FCs of pSTAT3+ microglia and pSTAT3+ astrocytes were increased from 9 to 15 weeks of age and then plateaued until 21 weeks. In contrast, the FCs of pSTAT3+ α-motoneurons peaked at 9 weeks and then decreased until 21 weeks. The immunoreactivity for nonphosphorylated neurofilament protein (SMI-32), a marker of axonal impairment, was decreased in pSTAT3+ α-motoneurons compared with pSTAT3− α-motoneurons at 9 weeks of age. We then compared the following pharmacological models – the chronic administration of 3,3′-iminodipropionitrile (IDPN), which models axonal impairment, and the acute administration of lipopolysaccharide (LPS), which is a model of neuroinflammation. The FCs of pSTAT3+ α-motoneurons were increased in IDPN-treated mice, while those of pSTAT3+ microglia were increased in LPS-treated mice. The FCs of pSTAT3+ astrocytes were higher in SOD1G93A mice at 9 weeks compared with IDPN- and LPS-treated mice. Our results indicate that axonopathy and neuroinflammation may trigger the respective activation of neuronal and glial STAT3, which is observed during ALS pathogenesis.. |
| 173. |
Tomohiro Ohgomori, Ryo Yamasaki, Hideyuki Takeuchi, Kenji Kadomatsu, Jun-Ichi Kira, Shozo Jinno, Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1(G93A) mouse model of amyotrophic lateral sclerosis, European Journal of Neuroscience, 10.1111/ejn.13650, 46, 4, 2001-2014, 2017.08, Signal transducer and activator of transcription (STAT) proteins are activated by phosphorylation in the spinal cord of patients suffering from amyotrophic lateral sclerosis (ALS). The major scope of our study is a comprehensive histological characterization of the mechanisms underlying neuronal and glial STAT3 activation in the pathogenesis of ALS using SOD1(G93A) mice. We calculated the fold changes (FCs, ratios vs. appropriate controls) of the numerical densities of the following phosphorylated STAT3-positive (pSTAT3)(+) cells - choline acetyltransferase (ChAT)(+) α-motoneurons, ionized calcium-binding adapter molecule 1 (Iba1)(+) microglia, and S100β(+) astrocytes in SOD1(G93A) mice. The FCs of pSTAT3(+) microglia and pSTAT3(+) astrocytes were increased from 9 to 15 weeks of age and then plateaued until 21 weeks. In contrast, the FCs of pSTAT3(+) α-motoneurons peaked at 9 weeks and then decreased until 21 weeks. The immunoreactivity for nonphosphorylated neurofilament protein (SMI-32), a marker of axonal impairment, was decreased in pSTAT3(+) α-motoneurons compared with pSTAT3(-) α-motoneurons at 9 weeks of age. We then compared the following pharmacological models - the chronic administration of 3,3'-iminodipropionitrile (IDPN), which models axonal impairment, and the acute administration of lipopolysaccharide (LPS), which is a model of neuroinflammation. The FCs of pSTAT3(+) α-motoneurons were increased in IDPN-treated mice, while those of pSTAT3(+) microglia were increased in LPS-treated mice. The FCs of pSTAT3(+) astrocytes were higher in SOD1(G93A) mice at 9 weeks compared with IDPN- and LPS-treated mice. Our results indicate that axonopathy and neuroinflammation may trigger the respective activation of neuronal and glial STAT3, which is observed during ALS pathogenesis.. |
| 174. |
Hiwatashi Akio, Osamu Togao, Koji Yamashita, kazufumi kikuchi, Ryotato Kamei, Daichi Momosaka, Hidenori Ogata, Ryo Yamasaki, Masami Yoneyama, Jun-Ichi Kira, Hiroshi Honda, Lumbar plexus in patients with chronic inflammatory demyelinating polyneuropathy
Evaluation with 3D nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (3D SHINKEI), European Journal of Radiology, 10.1016/j.ejrad.2017.05.031, 93, 95-99, 2017.08, Purpose To evaluate whether 3D SHINKEI in the lumbar plexus could identify patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Materials and methods Twenty-one patients with CIDP and 15 non-CIDP patients were studied in this retrospective study. The SNR, contrast-to-noise ratio (CNR), contrast ratio (CR) and the size of the lumbar ganglions and roots were measured. Statistical analyses were performed with Mann-Whitney U test and receiver operating characteristics (ROC) analysis. Results The SNRs of the ganglions and roots were larger in patients with CIDP (8.30 ± 4.87 and 8.24 ± 4.92) than in non-CIDP patients (4.95 ± 2.05 and 5.08 ± 1.97, P |
| 175. |
Yu Hashimoto, Koji Shinoda, Eizo Tanaka, Taira Uehara, Takuya Matsushita, Ryo Yamasaki, Jun-Ichi Kira, Re-emergence of a tumefactive demyelinating lesion after initiation of fingolimod therapy, Journal of the Neurological Sciences, 10.1016/j.jns.2017.06.002, 379, 167-168, 2017.08. |
| 176. |
Tomohiro Ohgomori, Ryo Yamasaki, Hideyuki Takeuchi, Kenji Kadomatsu, Jun-Ichi Kira, Shozo Jinno, Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis., The European journal of neuroscience, 10.1111/ejn.13650, 46, 4, 2001-2014, 2017.08, Signal transducer and activator of transcription (STAT) proteins are activated by phosphorylation in the spinal cord of patients suffering from amyotrophic lateral sclerosis (ALS). The major scope of our study is a comprehensive histological characterization of the mechanisms underlying neuronal and glial STAT3 activation in the pathogenesis of ALS using SOD1G93A mice. We calculated the fold changes (FCs, ratios vs. appropriate controls) of the numerical densities of the following phosphorylated STAT3-positive (pSTAT3)+ cells - choline acetyltransferase (ChAT)+ α-motoneurons, ionized calcium-binding adapter molecule 1 (Iba1)+ microglia, and S100β+ astrocytes in SOD1G93A mice. The FCs of pSTAT3+ microglia and pSTAT3+ astrocytes were increased from 9 to 15 weeks of age and then plateaued until 21 weeks. In contrast, the FCs of pSTAT3+ α-motoneurons peaked at 9 weeks and then decreased until 21 weeks. The immunoreactivity for nonphosphorylated neurofilament protein (SMI-32), a marker of axonal impairment, was decreased in pSTAT3+ α-motoneurons compared with pSTAT3- α-motoneurons at 9 weeks of age. We then compared the following pharmacological models - the chronic administration of 3,3'-iminodipropionitrile (IDPN), which models axonal impairment, and the acute administration of lipopolysaccharide (LPS), which is a model of neuroinflammation. The FCs of pSTAT3+ α-motoneurons were increased in IDPN-treated mice, while those of pSTAT3+ microglia were increased in LPS-treated mice. The FCs of pSTAT3+ astrocytes were higher in SOD1G93A mice at 9 weeks compared with IDPN- and LPS-treated mice. Our results indicate that axonopathy and neuroinflammation may trigger the respective activation of neuronal and glial STAT3, which is observed during ALS pathogenesis.. |
| 177. |
Akio Hiwatashi, Osamu Togao, Koji Yamashita, Kazufumi Kikuchi, Ryotato Kamei, Daichi Momosaka, Hidenori Ogata, Ryo Yamasaki, Masami Yoneyama, Jun-Ichi Kira, Hiroshi Honda, Lumbar plexus in patients with chronic inflammatory demyelinating polyneuropathy: Evaluation with 3D nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (3D SHINKEI)., European journal of radiology, 10.1016/j.ejrad.2017.05.031, 93, 95-99, 2017.08, PURPOSE: To evaluate whether 3D SHINKEI in the lumbar plexus could identify patients with chronic inflammatory demyelinating polyneuropathy (CIDP). MATERIALS AND METHODS: Twenty-one patients with CIDP and 15 non-CIDP patients were studied in this retrospective study. The SNR, contrast-to-noise ratio (CNR), contrast ratio (CR) and the size of the lumbar ganglions and roots were measured. Statistical analyses were performed with Mann-Whitney U test and receiver operating characteristics (ROC) analysis. RESULTS: The SNRs of the ganglions and roots were larger in patients with CIDP (8.30±4.87 and 8.24±4.92) than in non-CIDP patients (4.95±2.05 and 5.08±1.97, P |
| 178. |
Yu Hashimoto, Koji Shinoda, Eizo Tanaka, Taira Uehara, Takuya Matsushita, Ryo Yamasaki, Jun-Ichi Kira, Re-emergence of a tumefactive demyelinating lesion after initiation of fingolimod therapy., Journal of the neurological sciences, 10.1016/j.jns.2017.06.002, 379, 167-168, 2017.08. |
| 179. |
Tomohiro Ohgomori, Ryo Yamasaki, Hideyuki Takeuchi, Kenji Kadomatsu, Jun-Ichi Kira, Shozo Jinno, Differential involvement of vesicular and glial glutamate transporters around spinal α-motoneurons in the pathogenesis of SOD1G93A mouse model of amyotrophic lateral sclerosis, Neuroscience, 10.1016/j.neuroscience.2017.05.014, 356, 114-124, 2017.07, From a view point of the glutamate excitotoxicity theory, several studies have suggested that abnormal glutamate homeostasis via dysfunction of glial glutamate transporter-1 (GLT-1) may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). However, the detailed role of GLT-1 in the pathogenies of ALS remains controversial. To assess this issue, here we elucidated structural alterations associated with dysregulation of glutamate homeostasis using SOD1G93A mice, a genetic model of familial ALS. We first examined the viability of α-motoneurons in the lumbar spinal cord of SOD1G93A mice. Measurement of the soma size and density indicated that α-motoneurons might be intact at 9 weeks of age (presymptomatic stage), then soma shrinkage began at 15 weeks of age (progressive stage), and finally neuronal density declined at 21 weeks of age (end stage). Next, we carried out the line profile analysis, and found that the coverage of α-motoneurons by GLT-1-positive (GLT-1+) astrocytic processes was decreased only at 21 weeks of age, while the reduction of coverage of α-motoneurons by synaptophysin-positive (SYP+) presynaptic terminals began at 15 weeks of age. Interestingly, the coverage of α-motoneurons by VGluT2+ presynaptic terminals was transiently increased at 9 weeks of age, and then gradually decreased towards 21 weeks of age. On the other hand, there were no time-dependent alterations in the coverage of α-motoneurons by GABAergic presynaptic terminals. These findings suggest that VGluT2 and GLT-1 may be differentially involved in the pathogenesis of ALS via abnormal glutamate homeostasis at the presymptomatic stage and end stage of disease, respectively.. |
| 180. |
Ohgomori T, Yamasaki R, Takeuchi H, Kadomatsu K, Kira JI, Jinno S, Differential involvement of vesicular and glial glutamate transporters around spinal α-motoneurons in the pathogenesis of SOD1G93A mouse model of amyotrophic lateral sclerosis., Neuroscience, 10.1016/j.neuroscience.2017.05.014, 356, 114-124, 2017.07. |
| 181. |
Mitsuhiko Katoh, Bao Wu, Huy Bang Nguyen, Truc Quynh Thai, Ryo Yamasaki, Haiyan Lu, Anna M Rietsch, Musab M Zorlu, Youichi Shinozaki, Yurika Saitoh, Sei Saitoh, Takashi Sakoh, Kazuhiro Ikenaka, Schuichi Koizumi, Richard M Ransohoff, Nobuhiko Ohno, Polymorphic regulation of mitochondrial fission and fusion modifies phenotypes of microglia in neuroinflammation., Scientific reports, 10.1038/s41598-017-05232-0, 7, 1, 4942-4942, 2017.07, Microglia are the resident macrophages of the central nervous system and play complex roles in the milieu of diseases including the primary diseases of myelin. Although mitochondria are critical for cellular functions and survival in the nervous system, alterations in and the roles of mitochondrial dynamics and associated signaling in microglia are still poorly understood. In the present study, by combining immunohistochemistry and 3D ultrastructural analyses, we show that mitochondrial fission/fusion in reactive microglia is differentially regulated from that in monocyte-derived macrophages and the ramified microglia of normal white matter in myelin disease models. Mouse cerebral microglia in vitro demonstrated that stimulation of TLR4 with lipopolysaccharide, widely used to examine microglial reactions, caused the activation of the mitochondrial fission protein, dynamin-related protein 1 (Drp1) and enhanced production of reactive oxygen species (ROS). The increase in the ROS level activated 5' adenosine monophosphate-activated protein kinase (AMPK), and facilitated elongation of mitochondria along the microtubule tracks. These results suggest that the polymorphic regulation of mitochondrial fission and fusion in reactive microglia is mediated by distinct signaling under inflammatory conditions, and modulates microglial phenotypes through the production of ROS.. |
| 182. |
Ohgomori T, Yamasaki R, Takeuchi H, Kadomatsu K, Kira JI, Jinno S, Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis., Neuroscience, 10.1016/j.neuroscience.2017.05.014, 356, 114-124, 2017.07. |
| 183. |
Plexin D1は小径無髄後根神経節神経細胞を標的とした免疫介在性神経障害性疼痛の責任自己抗原である. |
| 184. |
Ryo Yamasaki, Paranodal dissection in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies., J Neurol Neurosurg Psychiatry, 2017.06. |
| 185. |
Ryo Yamasaki, Cerebral blood flow laterality derived from arterial spin labeling as a biomarker for assessing the disease severity of parkinson's disease., J Magn Reson Imaging., 2017.06. |
| 186. |
Koji Yamashita, Hiwatashi Akio, Osamu Togao, kazufumi kikuchi, hiroo yamaguchi, Yuriko Suzuki, Ryotaro Kamei, Ryo Yamasaki, Jun-Ichi Kira, Hiroshi Honda, Cerebral blood flow laterality derived from arterial spin labeling as a biomarker for assessing the disease severity of parkinson's disease, Journal of Magnetic Resonance Imaging, 10.1002/jmri.25489, 45, 6, 1821-1826, 2017.06, Purpose: To evaluate cerebral blood flow (CBF) laterality derived from arterial spin labeling (ASL) in early-stage Parkinson's disease (PD) patients compared with those with advanced stages. Materials and Methods: Thirty-eight patients with PD (21 patients in early stages, 17 patients in advanced stages) were retrospectively studied. The CBF maps derived from 3T ASL data were co-registered to the corresponding 3DT1WI using SPM 12 software. Caudate nucleus (CN), putamen (PT), globus pallidus (GP), and thalamus (TH) were manually traced on the representative axial slices of 3DT1WI. CBF of the CN, PT, GP, and TH was measured using corresponding pixels on the co-registered CBF maps. A laterality index (LI) was calculated as the ratio of the contralateral CBF to primary affected side CBF. Each LI was compared between early and advanced stages of PD using the Mann-Whitney U-test. The LIs were also compared between each stage of PD. Results: In the CN, the LIs were significantly higher in early stages (mean LI ± SD, 95% confidence interval = 1.06 ± 0.14, 1.00–1.13) than in advanced stages (0.94 ± 0.14, 0.87–1.01; P |
| 187. |
Haruki Koike, Masato Kadoya, Ken Ichi Kaida, Shohei Ikeda, Yuichi Kawagashira, Masahiro Iijima, Daisuke Kato, Hidenori Ogata, Ryo Yamasaki, Noriyuki Matsukawa, Jun-Ichi Kira, Masahisa Katsuno, Gen Sobue, Paranodal dissection in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies, Journal of Neurology, Neurosurgery and Psychiatry, 10.1136/jnnp-2016-314895, 88, 6, 465-473, 2017.06, Objective To investigate the morphological features of chronic inflammatory demyelinating polyneuropathy (CIDP) with autoantibodies directed against paranodal junctional molecules, particularly focusing on the fine structures of the paranodes. Methods We assessed sural nerve biopsy specimens obtained from 9 patients with CIDP with anti-neurofascin-155 antibodies and 1 patient with anti-contactin-1 antibodies. 13 patients with CIDP without these antibodies were also examined to compare pathological findings. Results Characteristic light and electron microscopy findings in transverse sections from patients with anti-neurofascin-155 and anti-contactin-1 antibodies indicated a slight reduction in myelinated fibre density, with scattered myelin ovoids, and the absence of macrophage-mediated demyelination or onion bulbs. Teased-fibre preparations revealed that segmental demyelination tended to be found in patients with relatively higher frequencies of axonal degeneration and was tandemly found at consecutive nodes of Ranvier in a single fibre. Assessment of longitudinal sections by electron microscopy revealed that detachment of terminal myelin loops from the axolemma was frequently found at the paranode in patients with anti-neurofascin-155 and anti-contactin-1 antibody-positive CIDP compared with patients with antibody-negative CIDP. Patients with anti-neurofascin-155 antibodies showed a positive correlation between the frequencies of axo-glial detachment at the paranode and axonal degeneration, as assessed by teased-fibre preparations (p |
| 188. |
Koji Yamashita, Akio Hiwatashi, Osamu Togao, Kazufumi Kikuchi, Hiroo Yamaguchi, Yuriko Suzuki, Ryotaro Kamei, Ryo Yamasaki, Jun-Ichi Kira, Hiroshi Honda, Cerebral blood flow laterality derived from arterial spin labeling as a biomarker for assessing the disease severity of parkinson's disease., Journal of magnetic resonance imaging : JMRI, 10.1002/jmri.25489, 45, 6, 1821-1826, 2017.06, PURPOSE: To evaluate cerebral blood flow (CBF) laterality derived from arterial spin labeling (ASL) in early-stage Parkinson's disease (PD) patients compared with those with advanced stages. MATERIALS AND METHODS: Thirty-eight patients with PD (21 patients in early stages, 17 patients in advanced stages) were retrospectively studied. The CBF maps derived from 3T ASL data were co-registered to the corresponding 3DT1WI using SPM 12 software. Caudate nucleus (CN), putamen (PT), globus pallidus (GP), and thalamus (TH) were manually traced on the representative axial slices of 3DT1WI. CBF of the CN, PT, GP, and TH was measured using corresponding pixels on the co-registered CBF maps. A laterality index (LI) was calculated as the ratio of the contralateral CBF to primary affected side CBF. Each LI was compared between early and advanced stages of PD using the Mann-Whitney U-test. The LIs were also compared between each stage of PD. RESULTS: In the CN, the LIs were significantly higher in early stages (mean LI ± SD, 95% confidence interval = 1.06 ± 0.14, 1.00-1.13) than in advanced stages (0.94 ± 0.14, 0.87-1.01; P |
| 189. |
Haruki Koike, Masato Kadoya, Ken-Ichi Kaida, Shohei Ikeda, Yuichi Kawagashira, Masahiro Iijima, Daisuke Kato, Hidenori Ogata, Ryo Yamasaki, Noriyuki Matsukawa, Jun-Ichi Kira, Masahisa Katsuno, Gen Sobue, Paranodal dissection in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies., Journal of neurology, neurosurgery, and psychiatry, 10.1136/jnnp-2016-314895, 88, 6, 465-473, 2017.06, OBJECTIVE: To investigate the morphological features of chronic inflammatory demyelinating polyneuropathy (CIDP) with autoantibodies directed against paranodal junctional molecules, particularly focusing on the fine structures of the paranodes. METHODS: We assessed sural nerve biopsy specimens obtained from 9 patients with CIDP with anti-neurofascin-155 antibodies and 1 patient with anti-contactin-1 antibodies. 13 patients with CIDP without these antibodies were also examined to compare pathological findings. RESULTS: Characteristic light and electron microscopy findings in transverse sections from patients with anti-neurofascin-155 and anti-contactin-1 antibodies indicated a slight reduction in myelinated fibre density, with scattered myelin ovoids, and the absence of macrophage-mediated demyelination or onion bulbs. Teased-fibre preparations revealed that segmental demyelination tended to be found in patients with relatively higher frequencies of axonal degeneration and was tandemly found at consecutive nodes of Ranvier in a single fibre. Assessment of longitudinal sections by electron microscopy revealed that detachment of terminal myelin loops from the axolemma was frequently found at the paranode in patients with anti-neurofascin-155 and anti-contactin-1 antibody-positive CIDP compared with patients with antibody-negative CIDP. Patients with anti-neurofascin-155 antibodies showed a positive correlation between the frequencies of axo-glial detachment at the paranode and axonal degeneration, as assessed by teased-fibre preparations (p |
| 190. |
A. Fujita, H. Yamaguchi, Y. Matsuoka, K. -I. Yamada, R. Yamasaki, J. -I. Kira, Astrocytic connexin 30 deletion leads to hypersensitivity in a MPTP mouse model of Parkinson's disease, GLIA, 65, E182-E182, 2017.06. |
| 191. |
Ryo Yamasaki, HLA-DRB1*04:05 allele is associated with intracortical lesions on three-dimensional double inversion recovery images in Japanese patients with multiple sclerosis., Mult Scler, 2017.05. |
| 192. |
Ryo Yamasaki, Early and extensive spinal white matter involvement in neuromyelitis optica., Brain Pathol, 2017.05. |
| 193. |
Ryo Yamasaki, Differential involvement of vesicular and glial glutamate transporters around spinal α-motoneurons in the pathogenesis of SOD1(G93A) mouse model of amyotrophic lateral sclerosis., Neuroscience, 2017.05. |
| 194. |
Ryo Yamasaki, Apomorphine Therapy for Neuronal Insulin Resistance in a Mouse Model of Alzheimer's Disease., J Alzheimer's disease, 2017.05. |
| 195. |
Koji Shinoda, Takuya Matsushita, Yuri Nakamura, Katsuhisa Masaki, Ryo Yamasaki, hiroo yamaguchi, Osamu Togao, Akio Hiwatashi, Jun-Ichi Kira, HLA-DRB1*04:05 allele is associated with intracortical lesions on three-dimensional double inversion recovery images in Japanese patients with multiple sclerosis, Multiple Sclerosis, 10.1177/1352458517707067, 1352458517707067, 2017.05, BACKGROUND: Cortical lesions (CLs) frequently observed in Caucasian patients with multiple sclerosis (MS) contribute to disability. However, it remains unclear whether CLs are associated with clinical features and genetic risk factors, such as HLA-DRB1*15:01 and -DRB1*04:05 in Asian MS patients.
OBJECTIVE: To elucidate the frequency of CLs and their association with HLA-DRB1 and DPB1 alleles in Japanese MS patients.
METHODS: Three-dimensional double inversion recovery imaging and clinical information were retrospectively obtained from 92 Japanese MS patients.
RESULTS: CLs of any type, intracortical lesions (ICLs), and leukocortical lesions (LCLs) were detected in 39.1%, 26.1%, and 28.3% of patients, respectively. MS patients with ICLs had a significantly higher frequency of secondary progression and greater Expanded Disability Status Scale (EDSS) scores than those without ICLs. Similar trends were observed with CLs and LCLs. The number of all three lesion types positively correlated with EDSS scores. The frequency and number of ICLs were significantly higher in HLA-DRB1*15:01 carriers than in HLA-DRB1*15:01 non-carriers, but significantly lower in HLA-DRB1*04:05 carriers than in HLA-DRB1*04:05 non-carriers. Multivariate logistic regression analysis revealed a negative association of HLA-DRB1*04:05 with ICLs.
CONCLUSION: ICLs are associated with greater disease severity in Japanese MS patients and are partly suppressed by the HLA-DRB1*04:05 allele.. |
| 196. |
Mitsuru Watanabe, Ryo Yamasaki, Jun-Ichi Kira, Relationship between Th1 cells and astrocytic connexin 43 gap junctions in multiple sclerosis, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12384, 8, 2, 101-102, 2017.05. |
| 197. |
Shotaro Hayashida, Katsuhisa Masaki, Tomomi Yonekawa, Satoshi O Suzuki, Akio Hiwatashi, Takuya Matsushita, Mitsuru Watanabe, Ryo Yamasaki, Toshihiko Suenaga, Toru Iwaki, Hiroyuki Murai, Jun-Ichi Kira, Early and extensive spinal white matter involvement in neuromyelitis optica., Brain pathology (Zurich, Switzerland), 10.1111/bpa.12386, 27, 3, 249-265, 2017.05, OBJECTIVES: Studies of longitudinally extensive spinal cord lesions (LESCLs) in neuromyelitis optica (NMO) have focused on gray matter, where the relevant antigen, aquaporin-4 (AQP4), is abundant. Because spinal white matter pathology in NMO is not well characterized, we aimed to clarify spinal white matter pathology of LESCLs in NMO. METHODS: We analyzed 50 spinal cord lesions from eleven autopsied NMO/NMO spectrum disorder (NMOSD) cases. We also evaluated LESCLs with three or fewer spinal cord attacks by 3-tesla MRI in 15 AQP4 antibody-positive NMO/NMOSD patients and in 15 AQP4 antibody-negative multiple sclerosis (MS) patients. RESULTS: Pathological analysis revealed seven cases of AQP4 loss and four predominantly demyelinating cases. Forty-four lesions from AQP4 loss cases involved significantly more frequently posterior columns (PC) and lateral columns (LC) than anterior columns (AC) (59.1%, 63.6%, and 34.1%, respectively). The posterior horn (PH), central portion (CP), and anterior horn (AH) were similarly affected (38.6%, 36.4% and 31.8%, respectively). Isolated perivascular inflammatory lesions with selective loss of astrocyte endfoot proteins, AQP4 and connexin 43, were present only in white matter and were more frequent in PC and LC than in AC (22.7%, 29.5% and 2.3%, Pcorr = 0.020, and Pcorr = 0.004, respectively). MRI indicated LESCLs more frequently affected PC and LC than AC in anti-AQP4 antibody-seropositive NMO/NMOSD (86.7%, 60.0% and 20.0%, Pcorr = 0.005, and Pcorr = 0.043, respectively) and AQP4 antibody-seronegative MS patients (86.7%, 73.3% and 33.3%, Pcorr = 0.063, and Pcorr = 0.043, respectively). PH, CP and AH were involved in 93.3%, 86.7% and 73.3% of seropositive patients, respectively, and in 53.3%, 60.0% and 40.0% of seronegative patients, respectively. CONCLUSIONS: NMO frequently and extensively affects spinal white matter in addition to central gray matter, especially in PC and LC, where isolated perivascular lesions with astrocyte endfoot protein loss may emerge. Spinal white matter involvement may also appear in early NMO, similar to cerebral white matter lesions.. |
| 198. |
Mitsuru Watanabe, Ryo Yamasaki, Jun-Ichi Kira, Relationship between Th1 cells and astrocytic connexin 43 gap junctions in multiple sclerosis, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12384, 8, 2, 101-102, 2017.05. |
| 199. |
Ryo Yamasaki, Early strong intrathecal inflammation in cerebellar type multiple system atrophy by cerebrospinal fluid cytokine/chemokine profiles: a case control study., J Neuroinflammation, 2017.04, Background: The pathology of multiple system atrophy cerebellar-type (MSA-C) includes glial inflammation; however cerebrospinal fluid (CSF) inflammatory cytokine profiles have not been investigated. In this study, we determined CSF cytokine/chemokine/growth factor profiles in MSA-C and compared them with those in hereditary spinocerebellar ataxia (SCA). Methods: We collected clinical data and CSF from 20 MSA-C patients, 12 hereditary SCA patients, and 15 patients with other non-inflammatory neurological diseases (OND), and measured 27 cytokines/chemokines/growth factors using a multiplexed fluorescent bead-based immunoassay. The size of each part of the hindbrain and hot cross bun sign (HCBS) in the pons were studied by magnetic resonance imaging.Results: Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, IL-7, IL-12, and IL-13 levels were significantly higher in MSA-C and SCA compared with OND. In MSA-C, IL-5, IL-6, IL-9, IL-12, IL-13, platelet-derived growth factor-bb, macrophage inflammatory protein (MIP)-1α, and GM-CSF levels positively correlated with anteroposterior diameters of the pontine base, vermis, or medulla oblongata. By contrast, in SCA patients, IL-12 and MIP-1α showed significant negative correlations with anteroposterior diameters of the pontine base, and unlike MSA-C, there was no cytokine with a positive correlation in SCA. IL-6 was significantly higher in MSA-C patients with the lowest grade of HCBS compared with those with the highest grade. Macrophage chemoattractant protein-1 (MCP-1) had a significant negative correlation with disease duration only in MSA-C patients. Tumor necrosis factor-alpha, IL-2, IL-15, IL-4, IL-5, IL-10, and IL-8 were all significantly lower in MSA-C and SCA compared with OND, while IL-1ra, an anti-inflammatory cytokine, was elevated only in MSA-C. IL-1β and IL-8 had positive correlations with Unified Multiple System Atrophy Rating Scale part 1 and 2, respectively, in MSA-C.Conclusions: Although CSF cytokine/chemokine/growth factor profiles were similar between MSA-C and SCA, pro-inflammatory cytokines, such as IL-6, GM-CSF, and MCP-1, correlated with the disease stage in a way higher at the beginning only in MSA-C, reflecting early stronger intrathecal inflammation.. |
| 200. |
Ryo Yamasaki, Hiroo Yamaguchi, Takuya Matsushita, Takayuki Fujii, Akio Hiwatashi, Jun ichi Kira, Early strong intrathecal inflammation in cerebellar type multiple system atrophy by cerebrospinal fluid cytokine/chemokine profiles
A case control study, Journal of neuroinflammation, 10.1186/s12974-017-0863-0, 14, 1, 2017.04, Background: The pathology of multiple system atrophy cerebellar-type (MSA-C) includes glial inflammation; however, cerebrospinal fluid (CSF) inflammatory cytokine profiles have not been investigated. In this study, we determined CSF cytokine/chemokine/growth factor profiles in MSA-C and compared them with those in hereditary spinocerebellar ataxia (SCA). Methods: We collected clinical data and CSF from 20 MSA-C patients, 12 hereditary SCA patients, and 15 patients with other non-inflammatory neurological diseases (OND), and measured 27 cytokines/chemokines/growth factors using a multiplexed fluorescent bead-based immunoassay. The size of each part of the hindbrain and hot cross bun sign (HCBS) in the pons was studied by magnetic resonance imaging. Results: Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, IL-7, IL-12, and IL-13 levels were significantly higher in MSA-C and SCA compared with OND. In MSA-C, IL-5, IL-6, IL-9, IL-12, IL-13, platelet-derived growth factor-bb, macrophage inflammatory protein (MIP)-1α, and GM-CSF levels positively correlated with anteroposterior diameters of the pontine base, vermis, or medulla oblongata. By contrast, in SCA patients, IL-12 and MIP-1α showed significant negative correlations with anteroposterior diameters of the pontine base, and unlike MSA-C, there was no cytokine with a positive correlation in SCA. IL-6 was significantly higher in MSA-C patients with the lowest grade of HCBS compared with those with the highest grade. Macrophage chemoattractant protein-1 (MCP-1) had a significant negative correlation with disease duration only in MSA-C patients. Tumor necrosis factor-alpha, IL-2, IL-15, IL-4, IL-5, IL-10, and IL-8 were all significantly lower in MSA-C and SCA compared with OND, while IL-1ra, an anti-inflammatory cytokine, was elevated only in MSA-C. IL-1β and IL-8 had positive correlations with Unified Multiple System Atrophy Rating Scale part 1 and 2, respectively, in MSA-C. Conclusions: Although CSF cytokine/chemokine/growth factor profiles were similar between MSA-C and SCA, pro-inflammatory cytokines, such as IL-6, GM-CSF, and MCP-1, correlated with the disease stage in a way higher at the beginning only in MSA-C, reflecting early stronger intrathecal inflammation.. |
| 201. |
Ryo Yamasaki, Hiroo Yamaguchi, Takuya Matsushita, Takayuki Fujii, Akio Hiwatashi, Jun-Ichi Kira, Early strong intrathecal inflammation in cerebellar type multiple system atrophy by cerebrospinal fluid cytokine/chemokine profiles: a case control study., Journal of neuroinflammation, 10.1186/s12974-017-0863-0, 14, 1, 89-89, 2017.04, BACKGROUND: The pathology of multiple system atrophy cerebellar-type (MSA-C) includes glial inflammation; however, cerebrospinal fluid (CSF) inflammatory cytokine profiles have not been investigated. In this study, we determined CSF cytokine/chemokine/growth factor profiles in MSA-C and compared them with those in hereditary spinocerebellar ataxia (SCA). METHODS: We collected clinical data and CSF from 20 MSA-C patients, 12 hereditary SCA patients, and 15 patients with other non-inflammatory neurological diseases (OND), and measured 27 cytokines/chemokines/growth factors using a multiplexed fluorescent bead-based immunoassay. The size of each part of the hindbrain and hot cross bun sign (HCBS) in the pons was studied by magnetic resonance imaging. RESULTS: Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, IL-7, IL-12, and IL-13 levels were significantly higher in MSA-C and SCA compared with OND. In MSA-C, IL-5, IL-6, IL-9, IL-12, IL-13, platelet-derived growth factor-bb, macrophage inflammatory protein (MIP)-1α, and GM-CSF levels positively correlated with anteroposterior diameters of the pontine base, vermis, or medulla oblongata. By contrast, in SCA patients, IL-12 and MIP-1α showed significant negative correlations with anteroposterior diameters of the pontine base, and unlike MSA-C, there was no cytokine with a positive correlation in SCA. IL-6 was significantly higher in MSA-C patients with the lowest grade of HCBS compared with those with the highest grade. Macrophage chemoattractant protein-1 (MCP-1) had a significant negative correlation with disease duration only in MSA-C patients. Tumor necrosis factor-alpha, IL-2, IL-15, IL-4, IL-5, IL-10, and IL-8 were all significantly lower in MSA-C and SCA compared with OND, while IL-1ra, an anti-inflammatory cytokine, was elevated only in MSA-C. IL-1β and IL-8 had positive correlations with Unified Multiple System Atrophy Rating Scale part 1 and 2, respectively, in MSA-C. CONCLUSIONS: Although CSF cytokine/chemokine/growth factor profiles were similar between MSA-C and SCA, pro-inflammatory cytokines, such as IL-6, GM-CSF, and MCP-1, correlated with the disease stage in a way higher at the beginning only in MSA-C, reflecting early stronger intrathecal inflammation.. |
| 202. |
A case of superficial siderosis ameliorated after closure of dural deficit detected by MRI-CISS (constructive interference in steady state) imaging.
A 64-year-old male developed headache, dizziness, and difficulty hearing, two years after an operation for chronic subdural hematoma due to head injury. These symptoms gradually worsened over the following 15 years. As he showed bloody cerebrospinal fluid (CSF) and marginal hypointensity on the surface of the brain and spinal cord on T2/T2*-weighted MRI, he was diagnosed with superficial siderosis (SS), although the source of the bleeding was unclear and anti-hemorrhagic drugs were ineffective. When he was admitted to our hospital, neurological examination disclosed horizontal gaze-evoked nystagmus, severe bilateral hearing loss, scanning speech, and limb and truncal ataxia. CISS (constructive interference in steady state) MRI detected a dural defect at the Th2-3 level on the anterior side of the spinal canal. On operation, a 2 mm × 6 mm size dural defect with blood clots was found at the Th2-3 level. After closure of the dural defect, bloody CSF became transparent, and his persistent headache, dizziness, and hearing impairment improved. Brain and whole spine MRI, especially CISS imaging, should be considered for detecting the source of bleeding in intractable cases of SS.. |
| 203. |
Ryo Yamasaki, Evaluation of chronic inflammatory demyelinating polyneuropathy: 3D nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (3D SHINKEI)., Eur Radiol, 2017.02. |
| 204. |
Ryo Yamasaki, Takayuki Fujii, Allergic inflammation leads to neuropathic pain through glial cell activation, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12372, 8, 1, 7-8, 2017.02. |
| 205. |
Akio Hiwatashi, Osamu Togao, Koji Yamashita, Kazufumi Kikuchi, Hidenori Ogata, Ryo Yamasaki, Masami Yoneyama, Jun ichi Kira, Hiroshi Honda, Evaluation of chronic inflammatory demyelinating polyneuropathy
3D nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (3D SHINKEI), European Radiology, 10.1007/s00330-016-4406-3, 27, 2, 447-453, 2017.02, Objective: To evaluate the usefulness of 3D nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: This institutional review board-approved retrospective study included 14 CIDP patients and nine normal subjects. The signal-to-noise ratio (SNR), contrast ratio (CR), and the size of the cervical ganglions and roots were measured by two raters. Results: The SNRs of the ganglions and roots were larger in patients with CIDP (9.55 ± 3.87 and 9.81 ± 3.64) than in normal subjects (7.21 ± 2.42 and 5.70 ± 2.14, P |
| 206. |
Akio Hiwatashi, Osamu Togao, Koji Yamashita, Kazufumi Kikuchi, Hidenori Ogata, Ryo Yamasaki, Masami Yoneyama, Jun-Ichi Kira, Hiroshi Honda, Evaluation of chronic inflammatory demyelinating polyneuropathy: 3D nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (3D SHINKEI)., European radiology, 10.1007/s00330-016-4406-3, 27, 2, 447-453, 2017.02, OBJECTIVE: To evaluate the usefulness of 3D nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: This institutional review board-approved retrospective study included 14 CIDP patients and nine normal subjects. The signal-to-noise ratio (SNR), contrast ratio (CR), and the size of the cervical ganglions and roots were measured by two raters. RESULTS: The SNRs of the ganglions and roots were larger in patients with CIDP (9.55 ± 3.87 and 9.81 ± 3.64) than in normal subjects (7.21 ± 2.42 and 5.70 ± 2.14, P |
| 207. |
Ryo Yamasaki, Takayuki Fujii, Allergic inflammation leads to neuropathic pain through glial cell activation, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12372, 8, 1, 7-8, 2017.02. |
| 208. |
Guzailiayi Maimaitijiang, Koji Shinoda, Yuri Nakamura, Katsuhisa Masaki, Takuya Matsushita, Ryo Yamasaki, Yasunobu Yoshikai, Jun-ichi Kira, Distinct Repertoires of CD4 and CD8 T Cells in Multiple Sclerosis Patients with and without Deletion-type Copy Number Variations, MULTIPLE SCLEROSIS JOURNAL, 23, 2, 315-315, 2017.02. |
| 209. |
Hayato Une, Hiroo Yamaguchi, Yinan Zhao, Koji Shinoda, Katsuhisa Masaki, Magdalena Goetz, Ryo Yamasaki, Jun-ichi Kira, Experimental Autoimmune Encephalomyelitis (EAE) is Ameliorated in Mice with Gray Matter (GM) Astrocyte-Specific Inducible Conditional Connexin 43 Knock-Out (Cx43cKO), MULTIPLE SCLEROSIS JOURNAL, 23, 2, 319-319, 2017.02. |
| 210. |
K. Shinoda, T. Matsushita, Y. Nakamura, K. Masaki, R. Yamasaki, O. Togao, A. Hiwatashi, J-I Kira, The Effects of the HLA-DRB1*04:05 Allele on Intracortical Lesions Detected by 3-Dimensional Double Inversion Recovery Imaging in Japanese Patients with Multiple Sclerosis, MULTIPLE SCLEROSIS JOURNAL, 23, 2, 313-313, 2017.02. |
| 211. |
Yuri Mizuno, Hiroo Yamaguchi, Taira Uehara, Kenichiro Yamashita, Ryo Yamasaki, Jun Ichi Kira, A case of stiff-person syndrome due to secondary adrenal insufficiency, Clinical Neurology, 10.5692/clinicalneurol.cn-001008, 57, 6, 298-302, 2017.01, We report a case of flexion contractures in a patient's legs secondary to postpartum hypopituitarism. A 56-year-old woman presented with a 3-year history of worsening flexion contractures of the hips and knees. On admission, her hips and knees could not be extended, and she had muscle stiffness and tenderness to palpation of the lower extremities. We first suspected stiff-person syndrome or Isaacs' syndrome because of her muscle stiffness. However, multiple hormones did not respond to stimulation tests, and an MRI of the brain showed atrophy of the pituitary gland with an empty sella. A subsequent interview revealed that she had suffered a severe hemorrhage while delivering her third child. She was diagnosed with panhypopituitarism and started on cortisol replacement therapy. After 1 week of treatment with hydrocortisone (10 mg/day), her symptoms quickly improved. We then added 75 μg/day of thyroid hormone. During the course of her treatment, autoantibodies against VGKC complex were found to be weakly positive. However, we considered the antibodies to be unrelated to her disease, because her symptoms improved markedly with low-dose steroid treatment. There are a few reports describing flexion contractures of the legs in patients with primary and secondary adrenal insufficiency. As these symptoms are similar to those seen in stiff-person syndrome, adrenal and pituitary insufficiency should be taken into account to achieve the correct diagnosis and treatment in patients with flexion contractures and muscle stiffness.. |
| 212. |
Ayako Sakoda, Ken Ichiro Yamashita, Mitsumasa Hayashida, Yukihide Iwamoto, Ryo Yamasaki, Jun Ichi Kira, A case of superficial siderosis ameliorated after closure of dural deficit detected by MRI-CISS (constructive interference in steady state) imaging, Clinical Neurology, 10.5692/clinicalneurol.cn-000960, 57, 4, 180-183, 2017.01, A 64-year-old male developed headache, dizziness, and difficulty hearing, two years after an operation for chronic subdural hematoma due to head injury. These symptoms gradually worsened over the following 15 years. As he showed bloody cerebrospinal fluid (CSF) and marginal hypointensity on the surface of the brain and spinal cord on T2/T2∗-weighted MRI, he was diagnosed with superficial siderosis (SS), although the source of the bleeding was unclear and anti-hemorrhagic drugs were ineffective. When he was admitted to our hospital, neurological examination disclosed horizontal gaze-evoked nystagmus, severe bilateral hearing loss, scanning speech, and limb and truncal ataxia. CISS (constructive interference in steady state) MRI detected a dural defect at the Th2-3 level on the anterior side of the spinal canal. On operation, a 2 mm × 6 mm size dural defect with blood clots was found at the Th2-3 level. After closure of the dural defect, bloody CSF became transparent, and his persistent headache, dizziness, and hearing impairment improved. Brain and whole spine MRI, especially CISS imaging, should be considered for detecting the source of bleeding in intractable cases of SS.. |
| 213. |
Norimichi Nakamura, Yasumasa Ohyagi, Tomohiro Imamura, Yuki T. Yanagihara, Kyoko M. Iinuma, Naoko Soejima, Hiroyuki Murai, Ryo Yamasaki, Jun Ichi Kira, Apomorphine Therapy for Neuronal Insulin Resistance in a Mouse Model of Alzheimer's Disease, Journal of Alzheimer's Disease, 10.3233/JAD-160344, 58, 4, 1151-1161, 2017.01, Apomorphine (APO) promotes intraneuronal amyloid-β (Aβ) degradation and improves memory function in an Alzheimer's disease (AD) model, 3xTg-AD mice. Since insulin resistance is increased in AD neurons, we investigated the effects of APO on brain insulin resistance in 3xTg-AD mice at early and late stages. After 1-month subcutaneous injection of Apokyn® to 3xTg-AD mice at 6 or 12 months of age, memory function was significantly improved in both age groups. Protein levels of insulin-degrading enzyme (IDE), which is linked to insulin signaling and degrades Aβ, significantly increased in the 3xTg-AD mice brain compared with non-transgenic mice, and were further increased by APO. Protein levels of two types of serine-phosphorylated insulin receptor substrate-1 (IRS-1), pS616 and pS636/639, significantly decreased following APO treatment in the 13-month-old 3xTg-AD mice brain, suggesting improved brain insulin resistance. Immunostaining of the IDE, pS616 and pS636/639 IRS-1 demonstrated similar changes due to APO treatment. Thus, brain insulin resistance is considered an important therapeutic target in AD, and APO may provide improved neuronal insulin resistance.. |
| 214. |
Ryo Yamasaki, Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation., Sci Rep, 2016.12. |
| 215. |
Ryo Yamasaki, Autoantibodies in chronic inflammatory neuropathies, Brain and Nerve, 68, 12, 1415-1421, 2016.12, Autoantibodies in chronic demyelinating neuropathies have been explored for several years. Recently, the peptides in the nodes of Ranvier have been the focus of attention in finding targets of autoantibodies. Until now, the most popular autoantibodies have been contactin-1 and neurofascin-155 for chronic demyelinating polyradiculoneuropathy (CIDP), GM1-ganglioside for multifocal motor neuropathy, and myelin-associated glycoprotein for polyneuropathy associated with monoclonal gammopathy of unknown significance. IgG is restricted to the lgG4 subtype in CIDP, indicating anti-inflammatory mechanisms related to the functional modification of the nodes of Ranvier. The clinical characteristics are also correlated with the presence of each of the autoantibodies, indicating the importance of auto-antibody screening in the development of suitable therapeutic strategies for each patient.. |
| 216. |
Masato Kadoya, Kenichi Kaida, Haruki Koike, Hiroshi Takazaki, Hidenori Ogata, Kota Moriguchi, Jun Shimizu, Eiichiro Nagata, Shunya Takizawa, Atsuro Chiba, Ryo Yamasaki, Jun ichi Kira, Gen Sobue, Katsunori Ikewaki, IgG4 anti-neurofascin155 antibodies in chronic inflammatory demyelinating polyradiculoneuropathy
Clinical significance and diagnostic utility of a conventional assay, Journal of Neuroimmunology, 10.1016/j.jneuroim.2016.10.013, 301, 16-22, 2016.12, We aimed to validate the diagnostic utility of enzyme-linked immunosorbent assay (ELISA) for the detection of anti-neurofascin (NF) 155 antibody in 191 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Human NF155-based ELISA clearly distinguished between anti-NF155 antibody-positive and -negative sera. Fifteen CIDP patients (8%) were IgG4 anti-human NF155 antibody-positive, which were confirmed by western blot, cell-based assay and immunohistochemical study. None of disease controls or healthy subjects had positive results. Clinical presentation of IgG4 anti-NF155 antibody-positive patients was consistent with those in previous reports. This ELISA combined with determination of the IgG4 subclass is useful in screening for anti-NF155 antibodies.. |
| 217. |
K. Shinoda, T. Iwata, Y. Nakamura, K. Masaki, T. Matsushita, R. Yamasaki, J. I. Kira, Minocycline-induced human herpesvirus 6 encephalomyelitis with drastically disseminated contrast-enhanced lesions, European Journal of Neurology, 10.1111/ene.13190, 23, 12, e76-e77, 2016.12. |
| 218. |
Mitsuru Watanabe, Katsuhisa Masaki, Ryo Yamasaki, Jun Kawanokuchi, Hideyuki Takeuchi, Takuya Matsushita, Akio Suzumura, Jun Ichi Kira, Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation, Scientific reports, 10.1038/srep38387, 6, 2016.12, We previously reported early and extensive loss of astrocytic connexin 43 (Cx43) in acute demyelinating lesions of multiple sclerosis (MS) patients. Because it is widely accepted that autoimmune T cells initiate MS lesions, we hypothesized that infiltrating T cells affect Cx43 expression in astrocytes, which contributes to MS lesion formation. Primary mixed glial cell cultures were prepared from newborn mouse brains, and microglia were isolated by anti-CD11b antibody-conjugated magnetic beads. Next, we prepared astrocyte-rich cultures and astrocyte/microglia-mixed cultures. Treatment of primary mixed glial cell cultures with interferon (IFN) γ, interleukin (IL)-4, or IL-17 showed that only IFNβ or IL-17 at high concentrations reduced Cx43 protein levels. Upon treatment of astrocyte-rich cultures and astrocyte/microglia-mixed cultures with IFNγ;, Cx43 mRNA/protein levels and the function of gap junctions were reduced only in astrocyte/microglia-mixed cultures. IFNγ-treated microglia-conditioned media and IL-1β, which was markedly increased in IFNγ-treated microglia-conditioned media, reduced Cx43 protein levels in astrocyte-rich cultures. Finally, we confirmed that Th1 cell-conditioned medium decreased Cx43 protein levels in mixed glial cell cultures. These findings suggest that Th1 cell-derived IFNγ activates microglia to release IL-1β that reduces Cx43 gap junctions in astrocytes. Thus, Th1-dominant inflammatory states disrupt astrocytic intercellular communication and may exacerbate MS.. |
| 219. |
Masato Kadoya, Kenichi Kaida, Haruki Koike, Hiroshi Takazaki, Hidenori Ogata, Kota Moriguchi, Jun Shimizu, Eiichiro Nagata, Shunya Takizawa, Atsuro Chiba, Ryo Yamasaki, Jun-Ichi Kira, Gen Sobue, Katsunori Ikewaki, IgG4 anti-neurofascin155 antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: Clinical significance and diagnostic utility of a conventional assay., Journal of neuroimmunology, 10.1016/j.jneuroim.2016.10.013, 301, 16-22, 2016.12, We aimed to validate the diagnostic utility of enzyme-linked immunosorbent assay (ELISA) for the detection of anti-neurofascin (NF) 155 antibody in 191 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Human NF155-based ELISA clearly distinguished between anti-NF155 antibody-positive and -negative sera. Fifteen CIDP patients (8%) were IgG4 anti-human NF155 antibody-positive, which were confirmed by western blot, cell-based assay and immunohistochemical study. None of disease controls or healthy subjects had positive results. Clinical presentation of IgG4 anti-NF155 antibody-positive patients was consistent with those in previous reports. This ELISA combined with determination of the IgG4 subclass is useful in screening for anti-NF155 antibodies.. |
| 220. |
Mitsuru Watanabe, Katsuhisa Masaki, Ryo Yamasaki, Jun Kawanokuchi, Hideyuki Takeuchi, Takuya Matsushita, Akio Suzumura, Jun-Ichi Kira, Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation., Scientific reports, 10.1038/srep38387, 6, 38387-38387, 2016.12, We previously reported early and extensive loss of astrocytic connexin 43 (Cx43) in acute demyelinating lesions of multiple sclerosis (MS) patients. Because it is widely accepted that autoimmune T cells initiate MS lesions, we hypothesized that infiltrating T cells affect Cx43 expression in astrocytes, which contributes to MS lesion formation. Primary mixed glial cell cultures were prepared from newborn mouse brains, and microglia were isolated by anti-CD11b antibody-conjugated magnetic beads. Next, we prepared astrocyte-rich cultures and astrocyte/microglia-mixed cultures. Treatment of primary mixed glial cell cultures with interferon (IFN) γ, interleukin (IL)-4, or IL-17 showed that only IFNγ or IL-17 at high concentrations reduced Cx43 protein levels. Upon treatment of astrocyte-rich cultures and astrocyte/microglia-mixed cultures with IFNγ, Cx43 mRNA/protein levels and the function of gap junctions were reduced only in astrocyte/microglia-mixed cultures. IFNγ-treated microglia-conditioned media and IL-1β, which was markedly increased in IFNγ-treated microglia-conditioned media, reduced Cx43 protein levels in astrocyte-rich cultures. Finally, we confirmed that Th1 cell-conditioned medium decreased Cx43 protein levels in mixed glial cell cultures. These findings suggest that Th1 cell-derived IFNγ activates microglia to release IL-1β that reduces Cx43 gap junctions in astrocytes. Thus, Th1-dominant inflammatory states disrupt astrocytic intercellular communication and may exacerbate MS.. |
| 221. |
K. Shinoda, T. Iwata, Y. Nakamura, K. Masaki, T. Matsushita, R. Yamasaki, J. -I. Kira, Minocycline-induced human herpesvirus 6 encephalomyelitis with drastically disseminated contrast-enhanced lesions, EUROPEAN JOURNAL OF NEUROLOGY, 10.1111/ene.13190, 23, 12, E76-E77, 2016.12. |
| 222. |
Ryo Yamasaki, Recurrent Hemorrhagic Venous Infarctions Caused by Thrombosis of a Pontine Developmental Venous Anomaly and Protein S Mutation., Cerebrovasc Dis, 2016.11. |
| 223. |
Ryo Yamasaki, Allergic Inflammation Leads to Neuropathic Pain via Glial Cell Activation., J Neurosci, 2016.11, Allergic and atopic disorders have increased over the past few decades and have been associated with neuropsychiatric conditions, such as autism spectrum disorder and asthmatic amyotrophy. Myelitis presenting with neuropathic pain can occur in patients with atopic disorder; however, the relationship between allergic inflammation and neuropathic pain, and the underlying mechanism, remains to be established. We studied whether allergic inflammation affects the spinal nociceptive system. We found that mice with asthma, atopic dermatitis, or atopic diathesis had widespread and significantly more activated microglia and astroglia in the spinal cord than those without atopy, and displayed tactile allodynia. Microarray analysis of isolated microglia revealed a dysregulated phenotype showing upregulation of M1 macrophage markers and downregulation of M2 markers in atopic mice. Among the cell surface protein genes, endothelin receptor type B (EDNRB) was most upregulated. Immunohistochemical analysis revealed that EDNRB expression was en- hanced in microglia and astroglia, whereas endothelin-1, an EDNRB ligand, was increased in serum, lungs, and epidermis of atopic mice. No EDNRA expression was found in the spinal cord. Expression of FBJ murine osteosarcoma viral oncogene homolog B was significantly higher in the dorsal horn neurons of asthma mice than nonatopic mice. The EDNRB antagonist BQ788 abolished glial and neural activation and allodynia. We found increased serum endothelin-1 in atopic patients with myelitis and neuropathic pain, and activation of spinal microglia and astroglia with EDNRB upregulation in an autopsied case. These results suggest that allergic inflammation induces diffuse glial activation, influencing the nociceptive system via the EDNRB pathway.. |
| 224. |
Ryo Yamasaki, IgG4 anti-neurofascin155 antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: Clinical significance and diagnostic utility of a conventional assay., J Neuroimmunol, 2016.11. |
| 225. |
Ryo Yamasaki, Takayuki Fujii, Bing Wang, Katsuhisa Masaki, Mizuho A. Kido, Mari Yoshida, Takuya Matsushita, Jun Ichi Kira, Allergic inflammation leads to neuropathic pain via glial cell activation, Journal of Neuroscience, 10.1523/JNEUROSCI.1981-16.2016, 36, 47, 11929-11945, 2016.11, Allergic and atopic disorders have increased over the past few decades and have been associated with neuropsychiatric conditions, such as autism spectrum disorder and asthmatic amyotrophy. Myelitis presenting with neuropathic pain can occur in patients with atopic disorder; however, the relationship between allergic inflammation and neuropathic pain, and the underlying mechanism, remains to be established. We studied whether allergic inflammation affects the spinal nociceptive system. We found that mice with asthma, atopic dermatitis, or atopic diathesis had widespread and significantly more activated microglia and astroglia in the spinal cord than those without atopy, and displayed tactile allodynia. Microarray analysis of isolated microglia revealed a dysregulated phenotype showing upregulation of M1 macrophage markers and downregulation of M2 markers in atopic mice. Among the cell surface protein genes, endothelin receptor type B (EDNRB) was most upregulated. Immunohistochemical analysis revealed that EDNRB expression was enhanced in microglia and astroglia, whereas endothelin-1, an EDNRB ligand, was increased in serum, lungs, and epidermis of atopic mice. No EDNRA expression was found in the spinal cord. Expression of FBJ murine osteosarcoma viral oncogene homolog B was significantly higher in the dorsal horn neurons of asthma mice than nonatopic mice. The EDNRB antagonist BQ788 abolished glial and neural activation and allodynia.Wefound increased serum endothelin-1 in atopic patients with myelitis and neuropathic pain, and activation of spinal microglia and astroglia with EDNRB upregulation in an autopsied case. These results suggest that allergic inflammation induces diffuse glial activation, influencing the nociceptive system via the EDNRB pathway.. |
| 226. |
Satoshi Nagata, Koji Shinoda, Taira Uehara, Takuya Matsushita, Ryo Yamasaki, Jun Ichi Kira, Clear detection of lower medullary lesions by three-dimensional double inversion recovery imaging in a patient with neuromyelitis optica spectrum disorder, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12330, 7, 4, 355-356, 2016.11. |
| 227. |
Zi Ye Song, Yuri Nakamura, Ryo Yamasaki, Yuji Kawano, Koji Shinoda, Maimaitijiang Guzailiayi, Katsuhisa Masaki, Hiroo Yamaguchi, Takuya Matsushita, Jun Ichi Kira, Peripheral blood T cell subset characteristics of multiple sclerosis in remission phase correlate with annualized relapse rates, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12321, 7, 4, 346-352, 2016.11, Objective: A large number of disease-modifying drugs are available for multiple sclerosis (MS); however, there is no established biomarker to predict long-term disease severity and future relapses in MS. We aimed to clarify the alterations in peripheral blood T cell subsets that are associated with MS relapse and disease severity, according to cytokine production profiles in the remission phase. Methods: Blood samples collected from 29 relapsing–remitting MS patients in the remission phase and 21 healthy controls (HC) were analyzed for various cytokine-producing T cell subsets by flow cytometry. Results: MS patients in the remission phase had significantly higher percentages of interleukin (IL)-17+CD4+ T cells, IL-4+CD4+ T cells, IL-9+CD4+ T cells, interferon-γ+CD8+ T cells and IL-4+CD8+ T cells than HC (P = 0.047, P = 0.007, P = 0.026, P = 0.015 and P = 0.007, respectively). In MS, the percentages of IL-9+CD4+ T cells, IL-9+CD8+ T cells and IFN-γ+IL-17+CD8+ T cells showed a significant positive correlation with annualized relapse rates (ARR) (P = 0.011, r = 0.47, P = 0.007, r = 0.49 and P = 0.044, r = 0.38, respectively). Conclusions: In the remission phase of MS, both anti-inflammatory cytokine-producing T cells and pro-inflammatory cytokine-producing T cells are increased; however, only the percentages of pro-inflammatory cytokine-producing T cells, such as IL-9-producing CD4+ T cells, IL-9-producing CD8+ T cells and IFN-γ- and IL-17-producing CD8+ T cells, correlate with ARR. These pro-inflammatory cytokine-producing T cells in the remission phase might be candidate biomarkers for future relapses in MS patients.. |
| 228. |
Yuri Nakamura, Kei ichiro Takase, Takuya Matsushita, Satoshi Yoshimura, Ryo Yamasaki, Hiroyuki Murai, Kazufumi Kikuchi, Jun ichi Kira, Recurrent Hemorrhagic Venous Infarctions Caused by Thrombosis of a Pontine Developmental Venous Anomaly and Protein S Mutation, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2016.08.040, 25, 11, e216-e217, 2016.11, A 34-year-old man presented with an acute onset of upbeat nystagmus, slurred speech, and limb and truncal ataxias. The patient had a history of limb ataxia and gait disturbance previously treated as brainstem encephalitis with corticosteroids 3 years previously. Brain magnetic resonance imaging showed pontine developmental venous anomaly (DVA) and hemorrhagic infarction within the drainage territory of the DVA. Three months later, the patient exhibited recurrent limb ataxia, double vision, and numbness of the left side of the body. The brain magnetic resonance imaging revealed recurrent hemorrhagic venous infarction within the same territory of the pontine DVA. Laboratory tests disclosed a hypercoagulable state owing to a decrease of protein S activity despite the normal antigen level. Genetic testing indicated that the patient was a homozygous carrier of protein S Tokushima. The patient's severe disability remained unchanged in spite of treatment with anticoagulation therapy using warfarin. We propose that further research on hereditary coagulopathy be carried out in patients with recurrent episodes of DVA-related infarction.. |
| 229. |
Ryo Yamasaki, Takayuki Fujii, Bing Wang, Katsuhisa Masaki, Mizuho A Kido, Mari Yoshida, Takuya Matsushita, Jun-Ichi Kira, Allergic Inflammation Leads to Neuropathic Pain via Glial Cell Activation., The Journal of neuroscience : the official journal of the Society for Neuroscience, 10.1523/JNEUROSCI.1981-16.2016, 36, 47, 11929-11945, 2016.11, Allergic and atopic disorders have increased over the past few decades and have been associated with neuropsychiatric conditions, such as autism spectrum disorder and asthmatic amyotrophy. Myelitis presenting with neuropathic pain can occur in patients with atopic disorder; however, the relationship between allergic inflammation and neuropathic pain, and the underlying mechanism, remains to be established. We studied whether allergic inflammation affects the spinal nociceptive system. We found that mice with asthma, atopic dermatitis, or atopic diathesis had widespread and significantly more activated microglia and astroglia in the spinal cord than those without atopy, and displayed tactile allodynia. Microarray analysis of isolated microglia revealed a dysregulated phenotype showing upregulation of M1 macrophage markers and downregulation of M2 markers in atopic mice. Among the cell surface protein genes, endothelin receptor type B (EDNRB) was most upregulated. Immunohistochemical analysis revealed that EDNRB expression was enhanced in microglia and astroglia, whereas endothelin-1, an EDNRB ligand, was increased in serum, lungs, and epidermis of atopic mice. No EDNRA expression was found in the spinal cord. Expression of FBJ murine osteosarcoma viral oncogene homolog B was significantly higher in the dorsal horn neurons of asthma mice than nonatopic mice. The EDNRB antagonist BQ788 abolished glial and neural activation and allodynia. We found increased serum endothelin-1 in atopic patients with myelitis and neuropathic pain, and activation of spinal microglia and astroglia with EDNRB upregulation in an autopsied case. These results suggest that allergic inflammation induces diffuse glial activation, influencing the nociceptive system via the EDNRB pathway. SIGNIFICANCE STATEMENT: The prevalence of allergic disorders has markedly increased over the past few decades. Allergic disorders are associated with neuropsychiatric conditions; however, the relationship between allergic inflammation and CNS complications is unknown. A peculiar myelitis presenting with persistent neuropathic pain has been reported in patients with allergic disorders. We studied how atopy exerts substantial influence on the nociceptive system. We found that mice with allergic disorders had severe allodynia with activated astroglia and microglia, and showed marked upregulation of endothelin-1 (ET-1) receptor type B (EDNRB) in the spinal cord. A selective EDNRB antagonist prevented allodynia and glial activation. Our findings suggest a novel mechanism whereby atopy induces glial activation and neuropathic pain via an ET-1/EDNRB pathway.. |
| 230. |
Satoshi Nagata, Koji Shinoda, Taira Uehara, Takuya Matsushita, Ryo Yamasaki, Jun-Ichi Kira, Clear detection of lower medullary lesions by three-dimensional double inversion recovery imaging in a patient with neuromyelitis optica spectrum disorder, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12330, 7, 4, 355-356, 2016.11. |
| 231. |
Zi-Ye Song, Yuri Nakamura, Ryo Yamasaki, Yuji Kawano, Koji Shinoda, Maimaitijiang Guzailiayi, Katsuhisa Masaki, Hiroo Yamaguchi, Takuya Matsushita, Jun-Ichi Kira, Peripheral blood T cell subset characteristics of multiple sclerosis in remission phase correlate with annualized relapse rates, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12321, 7, 4, 346-352, 2016.11, Objective: A large number of disease-modifying drugs are available for multiple sclerosis (MS)
however, there is no established biomarker to predict long-term disease severity and future relapses in MS. We aimed to clarify the alterations in peripheral blood T cell subsets that are associated with MS relapse and disease severity, according to cytokine production profiles in the remission phase. Methods: Blood samples collected from 29 relapsing–remitting MS patients in the remission phase and 21 healthy controls (HC) were analyzed for various cytokine-producing T cell subsets by flow cytometry. Results: MS patients in the remission phase had significantly higher percentages of interleukin (IL)-17+CD4+ T cells, IL-4+CD4+ T cells, IL-9+CD4+ T cells, interferon-γ+CD8+ T cells and IL-4+CD8+ T cells than HC (P = 0.047, P = 0.007, P = 0.026, P = 0.015 and P = 0.007, respectively). In MS, the percentages of IL-9+CD4+ T cells, IL-9+CD8+ T cells and IFN-γ+IL-17+CD8+ T cells showed a significant positive correlation with annualized relapse rates (ARR) (P = 0.011, r = 0.47, P = 0.007, r = 0.49 and P = 0.044, r = 0.38, respectively). Conclusions: In the remission phase of MS, both anti-inflammatory cytokine-producing T cells and pro-inflammatory cytokine-producing T cells are increased
however, only the percentages of pro-inflammatory cytokine-producing T cells, such as IL-9-producing CD4+ T cells, IL-9-producing CD8+ T cells and IFN-γ- and IL-17-producing CD8+ T cells, correlate with ARR. These pro-inflammatory cytokine-producing T cells in the remission phase might be candidate biomarkers for future relapses in MS patients.. |
| 232. |
Yuri Nakamura, Kei-Ichiro Takase, Takuya Matsushita, Satoshi Yoshimura, Ryo Yamasaki, Hiroyuki Murai, Kazufumi Kikuchi, Jun-Ichi Kira, Recurrent Hemorrhagic Venous Infarctions Caused by Thrombosis of a Pontine Developmental Venous Anomaly and Protein S Mutation., Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 10.1016/j.jstrokecerebrovasdis.2016.08.040, 25, 11, e216-e217-e217, 2016.11, A 34-year-old man presented with an acute onset of upbeat nystagmus, slurred speech, and limb and truncal ataxias. The patient had a history of limb ataxia and gait disturbance previously treated as brainstem encephalitis with corticosteroids 3 years previously. Brain magnetic resonance imaging showed pontine developmental venous anomaly (DVA) and hemorrhagic infarction within the drainage territory of the DVA. Three months later, the patient exhibited recurrent limb ataxia, double vision, and numbness of the left side of the body. The brain magnetic resonance imaging revealed recurrent hemorrhagic venous infarction within the same territory of the pontine DVA. Laboratory tests disclosed a hypercoagulable state owing to a decrease of protein S activity despite the normal antigen level. Genetic testing indicated that the patient was a homozygous carrier of protein S Tokushima. The patient's severe disability remained unchanged in spite of treatment with anticoagulation therapy using warfarin. We propose that further research on hereditary coagulopathy be carried out in patients with recurrent episodes of DVA-related infarction.. |
| 233. |
Kenji Kayashima, Ryo Yamasaki, Ultrasonographic Identification of the Thyrocervical Trunk and Vertebral Artery in Adults to Decrease Complications., Turkish journal of anaesthesiology and reanimation, 44, 5, 275-275, 2016.10. |
| 234. |
Ryo Yamasaki, Mei Fang, Hiroo Yamaguchi, Jun-Ichi Kira, Functional Analysis of Cx30 in Experimental Autoimmune Encephalomyelitis, ANNALS OF NEUROLOGY, 80, S175-S176, 2016.10. |
| 235. |
Katsuhisa Masaki, Satoshi O. Suzuki, Shotaro Hayashida, Mitsuru Watanabe, Takuya Matsushita, Ryo Yamasaki, Makiko Suzuki, Toshihiko Suenaga, Toru Iwaki, Jun-ichi Kira, Immunopathological Study of Glucose and Lactate Transporters in White and Gray Matter Lesions of Multiple Sclerosis and Neuromyelitis Optica, ANNALS OF NEUROLOGY, 80, S80-S80, 2016.10. |
| 236. |
Kenji Kayashima, Ryo Yamasaki, Ultrasonographic identification of the thyrocervical trunk and vertebral artery in adults to decrease complications, Turk Anesteziyoloji ve Reanimasyon Dernegi Dergisi, 10.5152/TJAR.2016.02679, 44, 5, 275, 2016.10. |
| 237. |
Ryo Yamasaki, Efficacy of intravenous methylprednisolone pulse therapy in patients with multiple sclerosis and neuromyelitis optica., Mult Scler, 2016.09. |
| 238. |
Ryo Yamasaki, Takuya Matsushita, Toshiyuki Fukazawa, Kazumasa Yokoyama, Kazuo Fujihara, Mieko Ogino, Takanori Yokota, Katsuichi Miyamoto, Masaaki Niino, Kyoichi Nomura, Ryo Tomioka, Masami Tanaka, Izumi Kawachi, Takashi Ohashi, Ken Ichi Kaida, Makoto Matsui, Yuji Nakatsuji, Hirofumi Ochi, Hikoaki Fukaura, Takashi Kanda, Akiko Nagaishi, Kanae Togo, Hidehiro Mizusawa, Hiroyuki Murai, Jun Ichi Kira, Efficacy of intravenous methylprednisolone pulse therapy in patients with multiple sclerosis and neuromyelitis optica, Multiple Sclerosis, 10.1177/1352458515617248, 22, 10, 1337-1348, 2016.09, Background: No large-scale studies have compared the efficacy of intravenous methylprednisolone pulse therapy (IVMP) for multiple sclerosis (MS) and neuromyelitis optica (NMO). Objective: To explain differences in treatment responses of MS and NMO patients to IVMP. Methods: Changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of IVMP completion were obtained in 2010 at 28 institutions, and retrospectively collated from 271 MS (478 courses) and 73 NMO (118 courses) cases. Results: In MS patients, decreased EDSS score was significant after the first (-0.8 ± 0.9), second (-0.7 ± 0.9), and third (-0.7 ± 0.8) courses (p |
| 239. |
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-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis
A cross-sectional study, Journal of neuroinflammation, 10.1186/s12974-016-0695-3, 13, 1, 2016.09, Background: Higher latitude and human leukocyte antigen (HLA)-DRB1*04:05 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-DRB1*04:05 and DRB1*15:01 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 |
| 240. |
Ryo Yamasaki, Takuya Matsushita, Toshiyuki Fukazawa, Kazumasa Yokoyama, Kazuo Fujihara, Mieko Ogino, Takanori Yokota, Katsuichi Miyamoto, Masaaki Niino, Kyoichi Nomura, Ryo Tomioka, Masami Tanaka, Izumi Kawachi, Takashi Ohashi, Ken-Ichi Kaida, Makoto Matsui, Yuji Nakatsuji, Hirofumi Ochi, Hikoaki Fukaura, Takashi Kanda, Akiko Nagaishi, Kanae Togo, Hidehiro Mizusawa, Hiroyuki Murai, Jun-Ichi Kira, Efficacy of intravenous methylprednisolone pulse therapy in patients with multiple sclerosis and neuromyelitis optica., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458515617248, 22, 10, 1337-48, 2016.09, BACKGROUND: No large-scale studies have compared the efficacy of intravenous methylprednisolone pulse therapy (IVMP) for multiple sclerosis (MS) and neuromyelitis optica (NMO). OBJECTIVE: To explain differences in treatment responses of MS and NMO patients to IVMP. METHODS: Changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of IVMP completion were obtained in 2010 at 28 institutions, and retrospectively collated from 271 MS (478 courses) and 73 NMO (118 courses) cases. RESULTS: In MS patients, decreased EDSS score was significant after the first (-0.8 ± 0.9), second (-0.7 ± 0.9), and third (-0.7 ± 0.8) courses (p |
| 241. |
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-DRB1*04:05 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)-DRB1*04:05 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-DRB1*04:05 and DRB1*15:01 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 |
| 242. |
M. Watanabe, K. Masaki, R. Yamasaki, J. Kawanokuchi, H. Takeuchi, A. Suzumura, J. -I. Kira, IFN gamma reduces expression of connexin43 in astrocytes via activation of microglia, MULTIPLE SCLEROSIS JOURNAL, 22, 159-159, 2016.09. |
| 243. |
H. Ogata, R. Yamasaki, N. Oka, M. Kuwahara, H. Suzuki, S. Kusunoki, Y. Yagi, T. Matsushita, T. Yokota, J. Kira, VALUABLE OBJECTIVE MARKERS FOR PREDICTING ANTI-NEUROFASCIN 155 ANTIBODY STATUS AMONG CIDP PATIENTS, JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, 21, 3, 196-196, 2016.09. |
| 244. |
方 梅, 山崎 亮, 山口 浩雄, 真崎 勝久, 李 広瑞, 篠田 紘司, 吉良 潤一, 実験的自己免疫性脳脊髄炎における大グリア細胞コネキシン30の新規の役割(Novel roles of astroglial connexin30 in experimental autoimmune encephalomyelitis), 神経免疫学, 21, 1, 151-151, 2016.09. |
| 245. |
Ban Yu Saitoh, Shintaro Hayashi, Katsuya Ogata, Taira Uehara, Hikaru Doi, Osamu Watanabe, Ryo Yamasaki, Hiroyuki Murai, Jun Ichi Kira, Immune-mediated spastic paraparesis accompanied with high titres of voltage-gated potassium channel complex antibodies and myokymia/fasciculation, Journal of the Neurological Sciences, 10.1016/j.jns.2016.03.028, 364, 133-135, 2016.05. |
| 246. |
Ban-Yu Saitoh, Shintaro Hayashi, Katsuya Ogata, Taira Uehara, Hikaru Doi, Osamu Watanabe, Ryo Yamasaki, Hiroyuki Murai, Jun-Ichi Kira, Immune-mediated spastic paraparesis accompanied with high titres of voltage-gated potassium channel complex antibodies and myokymia/fasciculation., Journal of the neurological sciences, 10.1016/j.jns.2016.03.028, 364, 133-5, 2016.05. |
| 247. |
Ryo Yamasaki, Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2., Ann Neurol., 2016.04. |
| 248. |
Ryo Yamasaki, Early and Extensive Spinal White Matter Involvement in Neuromyelitis Optica., Brain Pathol, 10.1111/bpa.12386, 2016.04. |
| 249. |
Ryo Yamasaki, Evaluation of chronic inflammatory demyelinating polyneuropathy: 3D nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (3D SHINKEI)., Eur Radiol. , 2016.04. |
| 250. |
Yujiro Higuchi, Akihiro Hashiguchi, Junhui Yuan, Akiko Yoshimura, Jun Mitsui, Hiroyuki Ishiura, Masaki Tanaka, Satoshi Ishihara, Hajime Tanabe, Satoshi Nozuma, Yuji Okamoto, Eiji Matsuura, Ryuichi Ohkubo, Saeko Inamizu, Wataru Shiraishi, Ryo Yamasaki, Yasumasa Ohyagi, Jun Ichi Kira, Yasushi Oya, Hayato Yabe, Noriko Nishikawa, Shinsuke Tobisawa, Nozomu Matsuda, Masayuki Masuda, Chiharu Kugimoto, Kazuhiro Fukushima, Satoshi Yano, Jun Yoshimura, Koichiro Doi, Masanori Nakagawa, Shinichi Morishita, Shoji Tsuji, Hiroshi Takashima, Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2, Annals of Neurology, 10.1002/ana.24612, 79, 4, 659-672, 2016.04, Objective The objective of this study was to identify new causes of Charcot-Marie-Tooth (CMT) disease in patients with autosomal-recessive (AR) CMT. Methods To efficiently identify novel causative genes for AR-CMT, we analyzed 303 unrelated Japanese patients with CMT using whole-exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation. Results We identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta-amyloid (Aβ)-degrading enzymes. All patients had a similar phenotype consistent with late-onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss-of-function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aβ in Pittsburgh compound-B positron emission tomography imaging. Interpretation Our results indicate that loss-of-function MME mutations are the most frequent cause of adult-onset AR-CMT2 in Japan, and we propose that this new disease should be termed AR-CMT2T. A loss-of-function MME mutation did not cause early-onset Alzheimer's disease. Identifying the MME mutation responsible for AR-CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT.. |
| 251. |
Yujiro Higuchi, Akihiro Hashiguchi, Junhui Yuan, Akiko Yoshimura, Jun Mitsui, Hiroyuki Ishiura, Masaki Tanaka, Satoshi Ishihara, Hajime Tanabe, Satoshi Nozuma, Yuji Okamoto, Eiji Matsuura, Ryuichi Ohkubo, Saeko Inamizu, Wataru Shiraishi, Ryo Yamasaki, Yasumasa Ohyagi, Jun-ichi Kira, Yasushi Oya, Hayato Yabe, Noriko Nishikawa, Shinsuke Tobisawa, Nozomu Matsuda, Masayuki Masuda, Chiharu Kugimoto, Kazuhiro Fukushima, Satoshi Yano, Jun Yoshimura, Koichiro Doi, Masanori Nakagawa, Shinichi Morishita, Shoji Tsuji, Hiroshi Takashima, Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2., Annals of neurology, 10.1002/ana.24612, 79, 4, 659-72, 2016.04, OBJECTIVE: The objective of this study was to identify new causes of Charcot-Marie-Tooth (CMT) disease in patients with autosomal-recessive (AR) CMT. METHODS: To efficiently identify novel causative genes for AR-CMT, we analyzed 303 unrelated Japanese patients with CMT using whole-exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation. RESULTS: We identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta-amyloid (Aβ)-degrading enzymes. All patients had a similar phenotype consistent with late-onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss-of-function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aβ in Pittsburgh compound-B positron emission tomography imaging. INTERPRETATION: Our results indicate that loss-of-function MME mutations are the most frequent cause of adult-onset AR-CMT2 in Japan, and we propose that this new disease should be termed AR-CMT2T. A loss-of-function MME mutation did not cause early-onset Alzheimer's disease. Identifying the MME mutation responsible for AR-CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT.. |
| 252. |
Sudarshini Ramanathan, Shinya Sato, Takuya Matsushita, Katsuhisa Masaki, Ryo Yamasaki, Russell Dale, Jun-ichi Kira, Fabienne Brilot, The Low Frequency of Antibodies to Myelin Oligodendrocyte Glycoprotein in Japanese Opticospinal Multiple Sclerosis, NEUROLOGY, 86, 2016.04. |
| 253. |
Sudarshini Ramanathan, Shinya Sato, Takuya Matsushita, Katsuhisa Masaki, Ryo Yamasaki, Russell Dale, Jun-ichi Kira, Fabienne Brilot, The Low Frequency of Antibodies to Myelin Oligodendrocyte Glycoprotein in Japanese Opticospinal Multiple Sclerosis, NEUROLOGY, 86, 2016.04. |
| 254. |
Ryo Yamasaki, Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2., Ann Neurol, 2016.03. |
| 255. |
Hidenori Ogata, Dai Matsuse, Ryo Yamasaki, Nobutoshi Kawamura, Takuya Matsushita, Tomomi Yonekawa, Makoto Hirotani, Hiroyuki Murai, Jun Ichi Kira, A nationwide survey of combined central and peripheral demyelination in Japan, Journal of Neurology, Neurosurgery and Psychiatry, 10.1136/jnnp-2014-309831, 87, 1, 29-36, 2016.01, Objectives To clarify the clinical features of combined central and peripheral demyelination (CCPD) via a nationwide survey. Methods The following characteristics were used to define CCPD: T2 high-signal intensity lesions in the brain, optic nerves or spinal cord on MRI, or abnormalities on visual-evoked potentials; conduction delay, conduction block, temporal dispersion or F-wave abnormalities suggesting demyelinating neuropathy based on nerve conduction studies; exclusion of secondary demyelination. We conducted a nationwide survey in 2012, sending questionnaires to 1332 adult and paediatric neurology institutions in Japan. Results We collated 40 CCPD cases, including 29 women. Age at onset was 31.7±14.1 years (mean±SD). Sensory disturbance (94.9%), motor weakness (92.5%) and gait disturbance (79.5%) were common. Although cerebrospinal fluid protein levels were increased in 82.5%, oligoclonal IgG bands and elevated IgG indices were detected in 7.4% and 18.5% of cases, respectively. Fifteen of 21 patients (71.4%) had abnormal visual-evoked potentials. Antineurofascin 155 antibodies were positive in 5/11 (45.5%). Corticosteroids, intravenous immunoglobulins and plasmapheresis resulted in an 83.3%, 66.7% and 87.5% improvement, respectively, whereas interferon-β was effective in only 10% of cases. CCPD cases with simultaneous onset of central nervous system (CNS) and peripheral nervous system (PNS) involvement exhibited greater disability, but less recurrence and more frequent extensive cerebral and spinal cord MRI lesions compared to those with temporarily separated onset, whereas optic nerve involvement was more common in the latter. Conclusions CCPD shows different characteristics from classical demyelinating diseases, and distinctive features exist between cases with simultaneous and temporarily separated onset of CNS and PNS involvement.. |
| 256. |
Sudarshini Ramanathan, Shinya Sato, Takuya Matsushita, Katsuhisa Masaki, Ryo Yamasaki, Russell C. Dale, Jun Ichi Kira, Fabienne Brilot, Antibodies to myelin oligodendrocyte glycoprotein are uncommon in Japanese opticospinal multiple sclerosis, Multiple Sclerosis, 10.1177/1352458515586089, 22, 1, 127-128, 2016.01. |
| 257. |
Sudarshini Ramanathan, Shinya Sato, Takuya Matsushita, Katsuhisa Masaki, Ryo Yamasaki, Russell C. Dale, Jun Ichi Kira, Fabienne Brilot, Antibodies to myelin oligodendrocyte glycoprotein are uncommon in Japanese opticospinal multiple sclerosis, Multiple Sclerosis, 10.1177/1352458515586089, 22, 1, 127-128, 2016.01. |
| 258. |
Hidenori Ogata, Dai Matsuse, Ryo Yamasaki, Nobutoshi Kawamura, Takuya Matsushita, Tomomi Yonekawa, Makoto Hirotani, Hiroyuki Murai, Jun-ichi Kira, A nationwide survey of combined central and peripheral demyelination in Japan., Journal of neurology, neurosurgery, and psychiatry, 10.1136/jnnp-2014-309831, 87, 1, 29-36, 2016.01, OBJECTIVES: To clarify the clinical features of combined central and peripheral demyelination (CCPD) via a nationwide survey. METHODS: The following characteristics were used to define CCPD: T2 high-signal intensity lesions in the brain, optic nerves or spinal cord on MRI, or abnormalities on visual-evoked potentials; conduction delay, conduction block, temporal dispersion or F-wave abnormalities suggesting demyelinating neuropathy based on nerve conduction studies; exclusion of secondary demyelination. We conducted a nationwide survey in 2012, sending questionnaires to 1332 adult and paediatric neurology institutions in Japan. RESULTS: We collated 40 CCPD cases, including 29 women. Age at onset was 31.7±14.1 years (mean±SD). Sensory disturbance (94.9%), motor weakness (92.5%) and gait disturbance (79.5%) were common. Although cerebrospinal fluid protein levels were increased in 82.5%, oligoclonal IgG bands and elevated IgG indices were detected in 7.4% and 18.5% of cases, respectively. Fifteen of 21 patients (71.4%) had abnormal visual-evoked potentials. Antineurofascin 155 antibodies were positive in 5/11 (45.5%). Corticosteroids, intravenous immunoglobulins and plasmapheresis resulted in an 83.3%, 66.7% and 87.5% improvement, respectively, whereas interferon-β was effective in only 10% of cases. CCPD cases with simultaneous onset of central nervous system (CNS) and peripheral nervous system (PNS) involvement exhibited greater disability, but less recurrence and more frequent extensive cerebral and spinal cord MRI lesions compared to those with temporarily separated onset, whereas optic nerve involvement was more common in the latter. CONCLUSIONS: CCPD shows different characteristics from classical demyelinating diseases, and distinctive features exist between cases with simultaneous and temporarily separated onset of CNS and PNS involvement.. |
| 259. |
Sudarshini Ramanathan, Shinya Sato, Takuya Matsushita, Katsuhisa Masaki, Ryo Yamasaki, Russell C Dale, Jun-Ichi Kira, Fabienne Brilot, Antibodies to myelin oligodendrocyte glycoprotein are uncommon in Japanese opticospinal multiple sclerosis., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458515586089, 22, 1, 127-8, 2016.01. |
| 260. |
Shotaro Hayashida, Katsuhisa Masaki, Takuya Matsushita, Mitsuru Watanabe, Ryo Yamasaki, Hiroyuki Murai, Jun Ichi Kira, Holocord involvement with sparing of the peripheral white matter rim in longitudinally extensive spinal cord lesions of neuromyelitis optica, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12274, 6, 78-79, 2015.12. |
| 261. |
Shotaro Hayashida, Katsuhisa Masaki, Takuya Matsushita, Mitsuru Watanabe, Ryo Yamasaki, Hiroyuki Murai, Jun-Ichi Kira, Holocord involvement with sparing of the peripheral white matter rim in longitudinally extensive spinal cord lesions of neuromyelitis optica, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12274, 6, 78-79, 2015.12. |
| 262. |
Ryo Yamasaki, Copy number variations in multiple sclerosis and neuromyelitis optica, ANNALS OF NEUROLOGY, 10.1002/ana.24511, 78, 5, 762-774, 2015.11. |
| 263. |
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.. |
| 264. |
Ryo Yamasaki, Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy., Ann Clin Transl Neurol., S79-S79, 2015.10. |
| 265. |
Hidenori Ogata, Ryo Yamasaki, Akio Hiwatashi, Nobuyuki Oka, Nobutoshi Kawamura, Dai Matsuse, Motoi Kuwahara, Hidekazu Suzuki, Susumu Kusunoki, Yuichi Fujimoto, Koji Ikezoe, Hitaru Kishida, Fumiaki Tanaka, Takuya Matsushita, Hiroyuki Murai, Jun Ichi Kira, Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy, Annals of Clinical and Translational Neurology, 10.1002/acn3.248, 2, 10, 960-971, 2015.10, Objective: To investigate anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: Sera from 50 consecutive CIDP patients diagnosed in our clinic, 32 patients with multiple sclerosis, 40 patients with other neuropathies including 26 with Guillain–Barré syndrome (GBS)/Fisher syndrome, and 30 healthy controls were measured for anti-NF antibodies by flow cytometry using HEK293 cell lines stably expressing human NF155 or NF186. Four additional CIDP patients with anti-NF155 antibodies referred from other clinics were enrolled for clinical characterization. Results: The positivity rate for anti-NF155 antibodies in CIDP patients was 18% (9/50), who all showed a predominance of IgG4 subclass. No other subjects were positive, except one GBS patient harboring IgG1 anti-NF155 antibodies. No anti-NF155 antibody carriers had anti-NF186 antibodies. Anti-NF155 antibody-positive CIDP patients had a significantly younger onset age, higher frequency of drop foot, gait disturbance, tremor and distal acquired demyelinating symmetric phenotype, greater cervical root diameter on magnetic resonance imaging neurography, higher cerebrospinal fluid protein levels, and longer distal and F-wave latencies than anti-NF155 antibody-negative patients. Marked symmetric hypertrophy of cervical and lumbosacral roots/plexuses was present in all anti-NF155 antibody-positive CIDP patients examined by neurography. Biopsied sural nerves from two patients with anti-NF155 antibodies demonstrated subperineurial edema and occasional paranodal demyelination, but no vasculitis, inflammatory cell infiltrates, or onion bulbs. Among anti-NF155 antibody-positive patients, treatment responders more frequently had daily oral corticosteroids and/or immunosuppressants in addition to intravenous immunoglobulins than nonresponders did. Interpretation: Anti-NF155 antibodies occur in a subset of CIDP patients with distal-dominant involvement and symmetric nerve hypertrophy.. |
| 266. |
Hidenori Ogata, Ryo Yamasaki, Akio Hiwatashi, Nobuyuki Oka, Nobutoshi Kawamura, Dai Matsuse, Motoi Kuwahara, Hidekazu Suzuki, Susumu Kusunoki, Yuichi Fujimoto, Koji Ikezoe, Hitaru Kishida, Fumiaki Tanaka, Takuya Matsushita, Hiroyuki Murai, Jun-Ichi Kira, Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy., Annals of clinical and translational neurology, 10.1002/acn3.248, 2, 10, 960-71, 2015.10, OBJECTIVE: To investigate anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Sera from 50 consecutive CIDP patients diagnosed in our clinic, 32 patients with multiple sclerosis, 40 patients with other neuropathies including 26 with Guillain-Barré syndrome (GBS)/Fisher syndrome, and 30 healthy controls were measured for anti-NF antibodies by flow cytometry using HEK293 cell lines stably expressing human NF155 or NF186. Four additional CIDP patients with anti-NF155 antibodies referred from other clinics were enrolled for clinical characterization. RESULTS: The positivity rate for anti-NF155 antibodies in CIDP patients was 18% (9/50), who all showed a predominance of IgG4 subclass. No other subjects were positive, except one GBS patient harboring IgG1 anti-NF155 antibodies. No anti-NF155 antibody carriers had anti-NF186 antibodies. Anti-NF155 antibody-positive CIDP patients had a significantly younger onset age, higher frequency of drop foot, gait disturbance, tremor and distal acquired demyelinating symmetric phenotype, greater cervical root diameter on magnetic resonance imaging neurography, higher cerebrospinal fluid protein levels, and longer distal and F-wave latencies than anti-NF155 antibody-negative patients. Marked symmetric hypertrophy of cervical and lumbosacral roots/plexuses was present in all anti-NF155 antibody-positive CIDP patients examined by neurography. Biopsied sural nerves from two patients with anti-NF155 antibodies demonstrated subperineurial edema and occasional paranodal demyelination, but no vasculitis, inflammatory cell infiltrates, or onion bulbs. Among anti-NF155 antibody-positive patients, treatment responders more frequently had daily oral corticosteroids and/or immunosuppressants in addition to intravenous immunoglobulins than nonresponders did. INTERPRETATION: Anti-NF155 antibodies occur in a subset of CIDP patients with distal-dominant involvement and symmetric nerve hypertrophy.. |
| 267. |
Hidenori Ogata, Ryo Yamasaki, Akio Hiwatashi, Nobuyuki Oka, Nobutoshi Kawamura, Dai Matsuse, Motoi Kuwahara, Hidekazu Suzuki, Susumu Kusunoki, Yuichi Fujimoto, Koji Ikezoe, Hitaru Kishida, Fumiaki Tanaka, Takuya Matsushita, Hiroyuki Murai, Jun-ichi Kira, IgG4 Neurofascin 155 Antibody-Positive Hypertrophic Demyelinating Polyneuropathy, ANNALS OF NEUROLOGY, 78, S79-S79, 2015.10. |
| 268. |
Takayuki Fujii, Ryo Yamasaki, Bing Wang, Mei Fang, Mizuho Kido, Katsuhisa Masaki, Jun-ichi Kira, Peripheral Allergy/Atopy Induces Glial Activation Leading to Allodynia and Exacerbation of Autoimmune Central Nervous System Inflammation Via Endothelin-1, ANNALS OF NEUROLOGY, 78, S75-S75, 2015.10. |
| 269. |
K. Masaki, S. O. Suzuki, S. Hayashida, M. Watanabe, T. Matsushita, R. Yamasaki, M. Suzuki, T. Iwaki, J. -I. Kira, Extensive loss of astrocytic monocarboxylate transporter 4 in active lesions of multiple sclerosis and neuromyelitis optica, MULTIPLE SCLEROSIS JOURNAL, 21, 69-70, 2015.09. |
| 270. |
M. Watanabe, K. Masaki, R. Yamasaki, J. Kawanokuchi, H. Takeuchi, A. Suzumura, J. -I. Kira, Th1 cells inhibit the expression of connexins in astrocytes, MULTIPLE SCLEROSIS JOURNAL, 21, 135-135, 2015.09. |
| 271. |
Hidenori Ogata, Ryo Yamasaki, Jun Ichi Kira, Nationwide Japanese survey shows the characteristic features of combined central and peripheral demyelination, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12224, 6, 3, 214-215, 2015.08. |
| 272. |
Hidenori Ogata, Ryo Yamasaki, Jun-Ichi Kira, Nationwide Japanese survey shows the characteristic features of combined central and peripheral demyelination, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12224, 6, 3, 214-215, 2015.08. |
| 273. |
R. Yamasaki, J-I. Kira, A mouse model of atopic diathesis displaying tactile allodynia with glial inflammation in the spinal cord, GLIA, 63, E356-E356, 2015.08. |
| 274. |
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.. |
| 275. |
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.. |
| 276. |
T. Fujii, R. Yamasaki, B. Wang, M. Kido, K. Masaki, J. Kira, Peripheral Atopic Diathesis Induces Neuropathic Pain and Activation of Astrocytes in The Posterior Horns of The Spinal Cord, MULTIPLE SCLEROSIS JOURNAL, 21, 6, 830-831, 2015.05. |
| 277. |
Z. Y. Song, Y. Kawano, S. Sato, M. Watanabe, S. Imamura, T. Yonekawa, K. Masaki, T. Matsushita, R. Yamasaki, J. Kira, Peripheral Blood T Cell Alterations in Myelitis with Various Causes, MULTIPLE SCLEROSIS JOURNAL, 21, 6, 829-829, 2015.05. |
| 278. |
Zi Ye Song, Ryo Yamasaki, Yuji Kawano, Shinya Sato, Katsuhisa Masaki, Satoshi Yoshimura, Dai Matsuse, Hiroyuki Murai, Takuya Matsushita, Jun Ichi Kira, Peripheral blood T cell dynamics predict relapse in multiple sclerosis patients on fingolimod, PloS one, 10.1371/journal.pone.0124923, 10, 4, 2015.04, Background: Fingolimod efficiently reduces multiple sclerosis (MS) relapse by inhibiting lymphocyte egress from lymph nodes through down-modulation of sphingosine 1-phosphate (S1P) receptors. We aimed to clarify the alterations in peripheral blood T cell subsets associated with MS relapse on fingolimod. Methods/Principal Findings: Blood samples successively collected from 23 relapsing-remitting MS patients before and during fingolimod therapy (0.5 mg/day) for 12 months and 18 healthy controls (HCs) were analysed for T cell subsets by flow cytometry. In MS patients, the percentages of central memory T (CCR7+CD45RO+) cells (TCM) and naïve T (CCR7+CD45RO-) cells decreased significantly, while those of effector memory T (CCR7-CD45RA-) and suppressor precursor T (CD28-) cells increased in both CD4+T and CD8+T cells from 2 weeks to 12 months during fingolimod therapy. The percentages of regulatory T (CD4+CD25highCD127low) cells in CD4+T cells and CCR7-CD45RA+T cells in CD8+T cells also increased significantly. Eight relapsed patients demonstrated greater percentages of CD4+TCM than 15 non-relapsed patients at 3 and 6 months (p=0.0051 and p=0.0088, respectively). The IL17-, IL9-, and IL4-producing CD4+T cell percentages were significantly higher at pre-treatment in MS patients compared with HCs (p+T cell percentages tended to show a transient increase at 2 weeks of fingolimod therapy (pcorr=0.0834). Conclusions: The CD4+TCM percentages at 2 weeks to 12 months during fingolimod therapy are related to relapse.. |
| 279. |
Ryo Yamasaki, A nationwide survey of combined central and peripheral demyelination in Japan., J Neurol Neurosurg Psychiatry (in press)., 2015.03. |
| 280. |
Ryo Yamasaki, Decreased serum vitamin D levels in Japanese patients with multiple sclerosis, JOURNAL OF NEUROIMMUNOLOGY, 10.1016/j.jneuroim.2015.01.007, 279, 40-45, 2015.02. |
| 281. |
Masaaki Niino, Shinya Sato, Toshiyuki Fukazawa, Katsuhisa Masaki, Yusei Miyazaki, Dai Matsuse, Ryo Yamasaki, Eri Takahashi, Seiji Kikuchi, Jun-ichi Kira, Decreased serum vitamin D levels in Japanese patients with multiple sclerosis., Journal of neuroimmunology, 10.1016/j.jneuroim.2015.01.007, 279, 40-5, 2015.02, Data regarding vitamin D in multiple sclerosis (MS) in Asia are limited. We investigated whether Japanese MS patients show decreased serum 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and vitamin D-binding protein (DBP) during winter. Mean serum 25(OH)D and 1,25(OH)2D levels were significantly lower in MS patients than in controls. There were no significant differences in serum 25(OH)D, 1,25(OH)2D, and DBP levels between patients or between controls from northern Japan (Hokkaido) and southern Japan (Kyushu). Serum vitamin D levels were low in Japanese MS patients but did not differ in patients from northern and southern Japan.. |
| 282. |
Ryo Yamasaki, Distinct roles of microglia and monocytes in central nervous system inflammation and degeneration, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12162, 5, s1, 41-48, 2014.12, Monocytes and microglia both originate from myeloid precursor cells and share common characteristics even after differentiation. Recent studies have shown functional differences between these cell types, indicating their unique roles in lesion formation in neurodegenerative diseases. The present review summarizes the functional characteristics of these "similar but different" macrophages in both health and disease.. |
| 283. |
Ryo Yamasaki, Distinct roles of microglia and monocytes in central nervous system inflammation and degeneration, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12162, 5, 1, 41-48, 2014.12, Monocytes and microglia both originate from myeloid precursor cells and share common characteristics even after differentiation. Recent studies have shown functional differences between these cell types, indicating their unique roles in lesion formation in neurodegenerative diseases. The present review summarizes the functional characteristics of these "similar but different" macrophages in both health and disease.. |
| 284. |
Hikaru Doi, Zi Ye Song, Satoshi Yoshimura, Takahisa Tateishi, Tomomi Yonekawa, Ryo Yamasaki, Hiroyuki Murai, Takuya Matsushita, Jun Ichi Kira, Distinct cytokine and T helper cell profiles between patients with multiple sclerosis who had or had not received interferon-beta, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12138, 5, 3, 321-327, 2014.10, Objectives Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, and is generally considered to be mediated by T helper (Th) 1/Th17 cells. Interferon-β (IFNβ) is widely used as a disease-modifying MS drug, but its effects on Th17 cells are still disputed. Furthermore, the effects of IFNβ on Th9 cells have not been elucidated. The present study aimed to clarify the effects of IFNβ on cytokines/growth factors in cerebrospinal fluid (CSF) and cytokine-producing Th cells in peripheral blood.
Methods First, the frequency of IFNγ, interleukin (IL)-17A, IL-9, and IL-4-producing Th cells in peripheral blood lymphocytes was analyzed by flow cytometry in 34 MS patients and 15 healthy volunteers enrolled in the cytokine-producing Th cell study. Second, levels of 27 cytokines/growth factors in the CSF were measured using a multiple fluorescence bead-based immunoassay in 34 MS patients enrolled in the cytokines/growth factors study.
Results We found a significantly higher frequency of IL-4-IL-9+CD4+ T cells and lower frequency of IFNγ+IL-17A-CD4+ cells in peripheral blood lymphocytes in the 10 MS patients who had received IFNβ than in the 24 MS patients who had not received IFNβ or the 15 healthy controls (P Conclusions The present results suggest the suppression of IL-17A production in the central nervous system and augmentation of Th9 cells in the peripheral blood by IFNβ in MS patients.. |
| 285. |
Hajime Arahata, Yasumasa Ohyagi, Kyoko M. Iinuma, Masahito Tanaka, Takahisa Tateishi, Ryo Yamasaki, Takuya Matsushita, Jun Ichi Kira, Early inhibition of tumor necrosis factor-α and interleukin-6 in muscle tissue as a therapy for dystrophinopathy in mdx mice, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12111, 5, 3, 371-377, 2014.10, Objective Pro-inflammatory cytokines can exacerbate muscle fiber damage in dystrophinopathy. The aim of the present study was to identify cytokine/chemokine alterations in the muscle tissues of mdx mice, a model of dystrophinopathy, and the beneficial effects of anti-proinflammatory cytokine therapy. Methods A total of 23 cytokines and chemokines were quantitatively measured in muscle tissues from mdx mice by fluorescent bead-based immunoassay. The mdx mice were treated with anti-tumor necrosis factor-α (TNF-α) and anti-interleukin-6 (IL-6) drugs, and their physical condition was evaluated by Rotarod and muscle damage by histopathological analysis. Results Levels of TNF-α and IL-6 were elevated at 14 days (P14), before a transient increase of macrophage and neutrophil-activating pro-inflammatory cytokines/chemokines, such as C-C motif ligand 2 (CCL2), CCL4 and KC (mouse C-X-C motif ligand 8 homolog), at P20. Administration of an anti-TNF-α drug (etanercept) and an anti-IL-6 receptor antibody (MR16-1) from P7 improved physical performance, and reduced both the area of basophilic fibers that indicated degenerating/regenerating fibers and CD68-positive macrophage infiltration. Initiating therapy at P7 inhibited the elevation of CCL2, CCL4 and KC more effectively than at P13. Conclusions The early administration of anti-TNF-α and anti-IL-6 drugs attenuated muscle fiber degeneration in a mouse model of dystrophinopathy.. |
| 286. |
Hikaru Doi, Zi-Ye Song, Satoshi Yoshimura, Takahisa Tateishi, Tomomi Yonekawa, Ryo Yamasaki, Hiroyuki Murai, Takuya Matsushita, Jun-Ichi Kira, Distinct cytokine and T helper cell profiles between patients with multiple sclerosis who had or had not received interferon-beta, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12138, 5, 3, 321-327, 2014.10, Objectives Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, and is generally considered to be mediated by T helper (Th) 1/Th17 cells. Interferon-β (IFNβ) is widely used as a disease-modifying MS drug, but its effects on Th17 cells are still disputed. Furthermore, the effects of IFNβ on Th9 cells have not been elucidated. The present study aimed to clarify the effects of IFNβ on cytokines/growth factors in cerebrospinal fluid (CSF) and cytokine-producing Th cells in peripheral blood.
Methods First, the frequency of IFNγ, interleukin (IL)-17A, IL-9, and IL-4-producing Th cells in peripheral blood lymphocytes was analyzed by flow cytometry in 34 MS patients and 15 healthy volunteers enrolled in the cytokine-producing Th cell study. Second, levels of 27 cytokines/growth factors in the CSF were measured using a multiple fluorescence bead-based immunoassay in 34 MS patients enrolled in the cytokines/growth factors study.
Results We found a significantly higher frequency of IL-4-IL-9+CD4+ T cells and lower frequency of IFNγ+IL-17A-CD4+ cells in peripheral blood lymphocytes in the 10 MS patients who had received IFNβ than in the 24 MS patients who had not received IFNβ or the 15 healthy controls (P <
0.05). The seven MS patients who received IFNβ showed significantly lower IL-17A levels in CSF than did the 27 MS patients who had not received IFNβ (P <
0.05).
Conclusions The present results suggest the suppression of IL-17A production in the central nervous system and augmentation of Th9 cells in the peripheral blood by IFNβ in MS patients.. |
| 287. |
Hajime Arahata, Yasumasa Ohyagi, Kyoko M. Iinuma, Masahito Tanaka, Takahisa Tateishi, Ryo Yamasaki, Takuya Matsushita, Jun-Ichi Kira, Early inhibition of tumor necrosis factor-α and interleukin-6 in muscle tissue as a therapy for dystrophinopathy in mdx mice, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12111, 5, 3, 371-377, 2014.10, Objective Pro-inflammatory cytokines can exacerbate muscle fiber damage in dystrophinopathy. The aim of the present study was to identify cytokine/chemokine alterations in the muscle tissues of mdx mice, a model of dystrophinopathy, and the beneficial effects of anti-proinflammatory cytokine therapy. Methods A total of 23 cytokines and chemokines were quantitatively measured in muscle tissues from mdx mice by fluorescent bead-based immunoassay. The mdx mice were treated with anti-tumor necrosis factor-α (TNF-α) and anti-interleukin-6 (IL-6) drugs, and their physical condition was evaluated by Rotarod and muscle damage by histopathological analysis. Results Levels of TNF-α and IL-6 were elevated at 14 days (P14), before a transient increase of macrophage and neutrophil-activating pro-inflammatory cytokines/chemokines, such as C-C motif ligand 2 (CCL2), CCL4 and KC (mouse C-X-C motif ligand 8 homolog), at P20. Administration of an anti-TNF-α drug (etanercept) and an anti-IL-6 receptor antibody (MR16-1) from P7 improved physical performance, and reduced both the area of basophilic fibers that indicated degenerating/regenerating fibers and CD68-positive macrophage infiltration. Initiating therapy at P7 inhibited the elevation of CCL2, CCL4 and KC more effectively than at P13. Conclusions The early administration of anti-TNF-α and anti-IL-6 drugs attenuated muscle fiber degeneration in a mouse model of dystrophinopathy.. |
| 288. |
Shinya Sato, Ken Yamamoto, Takuya Matsushita, Noriko Isobe, Yuji Kawano, Kyoko Iinuma, Tomomi Yonekawa, Katsuhisa Masaki, Satoshi Yoshimura, Ryo Yamasaki, Jun-ichi Kira, Copy number variations in T cell receptor loci are associated with susceptibility to multiple sclerosis and neuromyelitis optica, JOURNAL OF NEUROIMMUNOLOGY, 10.1016/j.jneuroim.2014.08.140, 275, 1-2, 53-53, 2014.10. |
| 289. |
Shinya Sato, Ken Yamamoto, Takuya Matsushita, Noriko Isobe, Yuji Kawano, Kyoko Iinuma, Tomomi Yonekawa, Katsuhisa Masaki, Satoshi Yoshimura, Ryo Yamasaki, Junichi Kira, Deletion-Type Copy Number Variations at T Cell Receptor Genes Confer Susceptibility to Multiple Sclerosis and Neuromyelitis Optica, ANNALS OF NEUROLOGY, 76, S110-S111, 2014.10. |
| 290. |
Ryo Yamasaki, Takuya Matsushita, Yasumasa Ohyagi, Akio Hiwatashi, Takashi Yoshiura, Jun-ichi Kira, Distinct Value of Cerebrospinal Fluid Cytokines in Patients with Multiple System Atrophy and Spinocerebellar Degenerations, ANNALS OF NEUROLOGY, 76, S50-S51, 2014.10. |
| 291. |
S. Sato, K. Yamamoto, T. Matsushita, N. Isobe, Y. Kawano, K. Iinuma, T. Yonekawa, K. Masaki, S. Yoshimura, R. Yamasaki, J-I Kira, A genome-wide copy number variation study identified T-cell receptor as a susceptibility gene for multiple sclerosis and neuromyelitis optica, MULTIPLE SCLEROSIS JOURNAL, 20, 251-252, 2014.09. |
| 292. |
方 梅, 山崎 亮, 王 冰, 城戸 瑞穗, 吉良 潤一, アトピー体質の動物モデルにおけるEAEの調節(Modulation of EAE in an animal model of atopic diathesis), 神経免疫学, 19, 1, 152-152, 2014.09. |
| 293. |
李 広瑞, 山崎 亮, 吉良 潤一, マウスの実験的自己免疫性脳脊髄炎(EAE)におけるNotch4の機能解析(Functional analysis of Notch4 in mouse experimental autoimmune encephalomyelitis (EAE)), 神経免疫学, 19, 1, 121-121, 2014.09. |
| 294. |
方 梅, 山崎 亮, 王 冰, 城戸 瑞穂, 吉良 潤一, アトピー素因を持つモデル動物におけるEAEの調節(Modulation of EAE in an animal model of atopic diathesis), NEUROINFECTION, 19, 2, 216-216, 2014.08. |
| 295. |
Ryo Yamasaki, Richard Ransohoff, Differential roles of microglia and monocytes in the inflamed central nervous system., J Exp Med, 2014.07. |
| 296. |
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, 732-739, 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.. |
| 297. |
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.. |
| 298. |
Ryo Yamasaki, Haiyan Lu, Oleg Butovsky, Nobuhiko Ohno, Anna M Rietsch, Ron Cialic, Pauline M Wu, Camille E Doykan, Jessica Lin, Anne C Cotleur, Grahame Kidd, Musab M Zorlu, Nathan Sun, Weiwei Hu, LiPing Liu, Jar-Chi Lee, Sarah E Taylor, Lindsey Uehlein, Debra Dixon, Jinyu Gu, Crina M Floruta, Min Zhu, Israel F Charo, Howard L Weiner, Richard M Ransohoff, Differential roles of microglia and monocytes in the inflamed central nervous system., The Journal of experimental medicine, 10.1084/jem.20132477, 211, 8, 1533-49, 2014.07, In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.. |
| 299. |
Y. Kawano, M. Watanabe, T. Yonekawa, K. Masaki, S. Sato, R. Yamasaki, S. Imamura, J. Kira, Anti-KIR4.1 Antibody in Japanese Patients with Multiple Sclerosis and Other Neurological Diseases, MULTIPLE SCLEROSIS JOURNAL, 20, 7, 921-922, 2014.06. |
| 300. |
H. Ogata, R. Yamasaki, D. Matsuse, N. Kawamura, T. Yonekawa, T. Matsushita, S. Imamura, S. Kusunoki, S. Nagayama, Y. Fukuda, H. Murai, J. Kira, Combined Central And Peripheral Demyelination: Diagnostic Value Of Anti-Neurofascin Antibody And First Nationwide Survey In Japan, MULTIPLE SCLEROSIS JOURNAL, 20, 7, 909-909, 2014.06. |
| 301. |
Yi Wen Cui, Yuji Kawano, Nan Shi, Katsuhisa Masaki, Noriko Isobe, Tomomi Yonekawa, Takuya Matsushita, Takahisa Tateishi, Ryo Yamasaki, Jun-ichi Kira, Cytokine Receptor Expression in Monocyte Subsets in Multiple Sclerosis, Neuromyelitis Optica, and Amyotrophic Lateral Sclerosis, MULTIPLE SCLEROSIS JOURNAL, 20, 7, 944-944, 2014.06. |
| 302. |
G. Ainiding, Y. Kawano, S. Sato, N. Isobe, T. Matsushita, S. Yoshimura, T. Yonekawa, R. Yamasaki, J. Kira, Interleukin 2 Receptor Alpha Chain Gene Polymorphisms and Risk of Multiple Sclerosis and Neuromyelitis Optica, MULTIPLE SCLEROSIS JOURNAL, 20, 7, 923-923, 2014.06. |
| 303. |
Kunihiro Yoshida, Ryo Yamasaki, Primary microgliopathy mimics primary progressive MS, MULTIPLE SCLEROSIS JOURNAL, 20, 7, 904-904, 2014.06. |
| 304. |
Z. Y. Song, Y. Kawano, S. Yoshimura, M. Watanabe, S. Imamura, T. Yonekawa, K. Masaki, T. Matsushita, R. Yamasaki, J. Kira, The Peripheral Blood T-cell Subset Dynamics Of Oral Fingolimod (FTY720)-Treated Multiple Sclerosis Patients, MULTIPLE SCLEROSIS JOURNAL, 20, 7, 930-930, 2014.06. |
| 305. |
Ryo Yamasaki, Masaki Katsuhisa, HAYASHI SHINTARO, Satoshi O Suzuki, Jun-ichi Kira, Extensive dysregulations of oligodendrocytic and astrocytic connexins are associated with disease progression in an amyotrophic lateral sclerosis mouse model., J Neuroinflammation, 2014.03, Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which glial cells play significant roles in disease progression. Connexins (Cxs) form homotypic or heterotypic gap junctions (GJs) and allow direct intercellular communications among nervous tissue cells. The role of Cxs in motor neuron disease has never been investigated; therefore, we aimed to evaluate alterations of Cxs in mSOD1-transgenic (mSOD1-Tg) mice in comparison with their non-transgenic (non-Tg) littermates at the same ages.
METHODS:
We pathologically evaluated temporal changes to astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 immunoreactivities at presymptomatic, disease-progressive, and end stages, relative to aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-2 (EAAT2), myelin-oligodendrocyte glycoprotein (MOG), and Nogo-A immunoreactivities, and observed neuronal loss by NeuN and neurofilament immunostaining, and microglial response by Iba-1 immunostaining. We also performed quantitative immunoblotting and real-time PCR analyses for Cxs.
RESULTS:
The mSOD1-Tg mice showed neuronal and axonal loss in the anterior horns of the lumbar spinal cord accompanied by increased activation of microglia compared with non-Tg mice at the disease-progressive and end stages. Expression patterns of Cxs were not different between mSOD1-Tg and non-Tg mice at the presymptomatic stage, but immunoreactivities for GFAP, Cx43, Cx30 and AQP4 were increased in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. By contrast, Cx47 and Cx32 immunoreactivities were markedly diminished in Nogo-A-positive oligodendrocytes in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages, especially in oligodendrocytes showing SOD1 accumulation. EAAT2 immunoreactivity was also diminished in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. Quantitative immunoblotting revealed a significant reduction in Cx47 and Cx32 protein levels in mSOD1-Tg mice at the disease-progressive and end stages. The levels of Cx47 and Cx32 mRNAs were also decreased at these stages.
CONCLUSIONS:
Our findings indicate that oligodendrocytic and astrocytic GJ proteins in the anterior horns of spinal cord in mSOD1-Tg mice are profoundly affected at the disease-progressive and end stages, where disruption of GJs among glial cells may exacerbate motor neuronal death.. |
| 306. |
Yiwen Cui, Katsuhisa Masaki, Ryo Yamasaki, Shihoko Imamura, Satoshi O. Suzuki, Shintaro Hayashi, Shinya Sato, Yuko Nagara, Mami F. Kawamura, Jun ichi Kira, Extensive dysregulations of oligodendrocytic and astrocytic connexins are associated with disease progression in an amyotrophic lateral sclerosis mouse model, Journal of neuroinflammation, 10.1186/1742-2094-11-42, 11, 2014.03, Background: Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which glial cells play significant roles in disease progression. Connexins (Cxs) form homotypic or heterotypic gap junctions (GJs) and allow direct intercellular communications among nervous tissue cells. The role of Cxs in motor neuron disease has never been investigated; therefore, we aimed to evaluate alterations of Cxs in mSOD1-transgenic (mSOD1-Tg) mice in comparison with their non-transgenic (non-Tg) littermates at the same ages.Methods: We pathologically evaluated temporal changes to astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 immunoreactivities at presymptomatic, disease-progressive, and end stages, relative to aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-2 (EAAT2), myelin-oligodendrocyte glycoprotein (MOG), and Nogo-A immunoreactivities, and observed neuronal loss by NeuN and neurofilament immunostaining, and microglial response by Iba-1 immunostaining. We also performed quantitative immunoblotting and real-time PCR analyses for Cxs.Results: The mSOD1-Tg mice showed neuronal and axonal loss in the anterior horns of the lumbar spinal cord accompanied by increased activation of microglia compared with non-Tg mice at the disease-progressive and end stages. Expression patterns of Cxs were not different between mSOD1-Tg and non-Tg mice at the presymptomatic stage, but immunoreactivities for GFAP, Cx43, Cx30 and AQP4 were increased in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. By contrast, Cx47 and Cx32 immunoreactivities were markedly diminished in Nogo-A-positive oligodendrocytes in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages, especially in oligodendrocytes showing SOD1 accumulation. EAAT2 immunoreactivity was also diminished in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. Quantitative immunoblotting revealed a significant reduction in Cx47 and Cx32 protein levels in mSOD1-Tg mice at the disease-progressive and end stages. The levels of Cx47 and Cx32 mRNAs were also decreased at these stages.Conclusions: Our findings indicate that oligodendrocytic and astrocytic GJ proteins in the anterior horns of spinal cord in mSOD1-Tg mice are profoundly affected at the disease-progressive and end stages, where disruption of GJs among glial cells may exacerbate motor neuronal death.. |
| 307. |
Yiwen Cui, Katsuhisa Masaki, Ryo Yamasaki, Shihoko Imamura, Satoshi O Suzuki, Shintaro Hayashi, Shinya Sato, Yuko Nagara, Mami F Kawamura, Jun-ichi Kira, Extensive dysregulations of oligodendrocytic and astrocytic connexins are associated with disease progression in an amyotrophic lateral sclerosis mouse model., Journal of neuroinflammation, 10.1186/1742-2094-11-42, 11, 42-42, 2014.03, BACKGROUND: Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which glial cells play significant roles in disease progression. Connexins (Cxs) form homotypic or heterotypic gap junctions (GJs) and allow direct intercellular communications among nervous tissue cells. The role of Cxs in motor neuron disease has never been investigated; therefore, we aimed to evaluate alterations of Cxs in mSOD1-transgenic (mSOD1-Tg) mice in comparison with their non-transgenic (non-Tg) littermates at the same ages. METHODS: We pathologically evaluated temporal changes to astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 immunoreactivities at presymptomatic, disease-progressive, and end stages, relative to aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-2 (EAAT2), myelin-oligodendrocyte glycoprotein (MOG), and Nogo-A immunoreactivities, and observed neuronal loss by NeuN and neurofilament immunostaining, and microglial response by Iba-1 immunostaining. We also performed quantitative immunoblotting and real-time PCR analyses for Cxs. RESULTS: The mSOD1-Tg mice showed neuronal and axonal loss in the anterior horns of the lumbar spinal cord accompanied by increased activation of microglia compared with non-Tg mice at the disease-progressive and end stages. Expression patterns of Cxs were not different between mSOD1-Tg and non-Tg mice at the presymptomatic stage, but immunoreactivities for GFAP, Cx43, Cx30 and AQP4 were increased in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. By contrast, Cx47 and Cx32 immunoreactivities were markedly diminished in Nogo-A-positive oligodendrocytes in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages, especially in oligodendrocytes showing SOD1 accumulation. EAAT2 immunoreactivity was also diminished in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. Quantitative immunoblotting revealed a significant reduction in Cx47 and Cx32 protein levels in mSOD1-Tg mice at the disease-progressive and end stages. The levels of Cx47 and Cx32 mRNAs were also decreased at these stages. CONCLUSIONS: Our findings indicate that oligodendrocytic and astrocytic GJ proteins in the anterior horns of spinal cord in mSOD1-Tg mice are profoundly affected at the disease-progressive and end stages, where disruption of GJs among glial cells may exacerbate motor neuronal death.. |
| 308. |
Ryo Yamasaki, Yuji Kawano, Takuya Matsushita, Yoshimura Satoshi, Hiroyuki Murai, Jun-ichi Kira, Interleukin 2 receptor α chain gene polymorphisms and risks of multiple sclerosis and neuromyelitis optica in southern Japanese., J Neurol Sci, 2014.02, 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.. |
| 309. |
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, 10.1177/1352458513513057, 20, 2, 258-260, 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.. |
| 310. |
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, 147-150, 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.. |
| 311. |
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.. |
| 312. |
Ainiding G, Kawano Y, Sato S, Isobe N, Matsushita T, Yoshimura S, Yonekawa T, Yamasaki R, Murai H, Kira J, South Japan Multiple Sclerosis Genetics Consortium, 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. |
| 313. |
Yi Wen Cui, Yuji Kawano, Ryo Yamasaki, Nan Shi, Katsuhisa Masaki, Noriko Isobe, Tomomi Yonekawa, Takuya Matsushita, Takahisa Tateishi, Shintaro Hayashi, Jun-Ichi Kira, Decreased CCR2 and CD62L expressions on peripheral blood classical monocytes in amyotrophic lateral sclerosis, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12088, 5, 1, 92-96, 2014.01, Objective Recent evidence has suggested the importance of an aberrantly activated monocyte system in amyotrophic lateral sclerosis (ALS) pathogenesis. However, the roles of each monocyte subset, namely CD14+CD16-classical monocytes, CD14dimCD16+ non-classical monocytes and CD14+CD16+ intermediate monocytes, in ALS remain unknown. We aimed to clarify the alterations in the monocyte subset proportions and the surface marker expressions on each monocyte subset in ALS. Methods Blood samples were collected from 19 ALS patients and 28 healthy controls (HC). The surface expressions of CCR2, CX3CR1, CD64 and CD62L were measured in the three monocyte subsets (classical, non-classical and intermediate) by flow cytometry. Results The percentages of CCR2 and CD62L on CD14+CD16-classical monocytes were significantly lower in ALS patients than in HC (P = 0.0012 and P = 0.0296, respectively). No differences were found in CX3CR1 and CD64 on each monocyte subset. The percentage of intermediate monocytes showed a significant negative correlation with the revised ALS functional rating scale score (r =-0.631, P = 0.0038). Conclusions Reductions in chemotaxis-and adhesion-related molecules on classical inflammatory monocytes are present in ALS, further suggesting the involvement of an aberrant innate immune system in ALS pathogenesis.. |
| 314. |
Ryo Yamasaki, Microglia in vivo and in vitro, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12120, 5, 2, 114-116, 2014.01, Unlike in vivo microglia, isolated microglia are already primed and activated, and have exaggerated responses to additional stimulation. In the present Commentary, the differences between in vivo and in vitro microglia are discussed.. |
| 315. |
Ryo Yamasaki, The role of microglia in inflammatory demyelination lesion in the central nervous system, Clinical Neurology, 10.5692/clinicalneurol.54.981, 54, 12, 981-983, 2014.01, In the lesion of experimental autoimmune encephalomyelitis (EAE), two different kinds of macrophages are activated: microglia derived macrophages (MiDM) and monocytes derived macrophages (MDM). These macrophages elicit different functions in the development of demyelination lesions in EAE. MDMs are infiltrated in the acute phase of EAE, and initiate demyelination at the nodes of Ranvier. On the other hands, MiDM always activated at the peak and the chronic stage of the disease. These macrophages express totally different cytokines at different time course of the disease: MDM are activated in the early stage of the disease and express genes that are mainly related to inflammation, while MiDM are activated at the peak and recovery stage and express genes that are related to homeostasis. Our findings provide the idea to develop new therapeutic strategy not only for demyelinating disease but also other neurological diseases with neuro-inflammation.. |
| 316. |
Ryo Yamasaki, Haiyan Lu, Oleg Butovsky, Nobuhiko Ohno, Anna M. Rietsch, Ron Cialic, Pauline M. Wu, Camille E. Doykan, Jessica Lin, Anne C. Cotleur, Grahame Kidd, Musab M. Zorlu, Nathan Sun, Weiwei Hu, Li Ping Liu, Jar Chi Lee, Sarah E. Taylor, Lindsey Uehlein, Debra Dixon, Jinyu Gu, Crina M. Floruta, Min Zhu, Israel F. Charo, Howard L. Weiner, Richard M. Ransohoff, Differential roles of microglia and monocytes in the inflamed central nervous system, Journal of Experimental Medicine, 10.1084/jem.20132477, 211, 8, 1533-1549, 2014, In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocytederived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.. |
| 317. |
Ryo Yamasaki, Nobutoshi Kawamura, Anti-neurofascin antibodies in patients with combined central and peripheral demyelination, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12073, 4, 3, 257-258, 2013.12. |
| 318. |
Jun Ichi Kira, Ryo Yamasaki, Satoshi Yoshimura, Toshiyuki Fukazawa, Kazumasa Yokoyama, Kazuo Fujihara, Mieko Ogino, Takanori Yokota, Katsuichi Miyamoto, Masaaki Niino, Kyoichi Nomura, Ryo Tomioka, Masami Tanaka, Izumi Kawachi, Takashi Ohashi, Kenichi Kaida, Makoto Matsui, Yuji Nakatsuji, Hirofumi Ochi, Hikoaki Fukaura, Takashi Kanda, Akiko Nagaishi, Kanae Togo, Hidehiro Mizusawa, Yuji Kawano, Efficacy of methylprednisolone pulse therapy for acute relapse in Japanese patients with multiple sclerosis and neuromyelitis optica
A multicenter retrospective analysis - 1. Whole group analysis, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12071, 4, 3, 305-317, 2013.12, Objectives There has been no large-scale study of methylprednisolone pulse therapy in Asian patients with multiple sclerosis (MS) or neuromyelitis optica (NMO), despite it being widely used for acute relapse. We aimed to clarify treatment response of MS and NMO patients to methylprednisolone pulse therapy and post-pulse oral corticosteroids in real clinical practice in a multicenter study in Japan. Methods Investigators at 28 institutions collected changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of completion of methylprednisolone pulse therapy carried out in 2010, and after post-pulse oral corticosteroids therapy, by retrospective review of medical records. Results In 345 patients (95.1% of all registered patients), 457 series of methylprednisolone pulse therapy were carried out for treatment of acute relapse. EDSS scores improved by 0.8 ± 1.1 (mean ± SD) after the first course. The second and third courses also produced sufficient improvements (by 0.7 and 0.6, respectively), but much smaller improvements were observed thereafter. The target neurological symptoms and signs improved in 79.5% of patients. Improvement rates were 5-20% lower after a course of pulse therapy than after a series of pulse therapy. A half dose (500 mg/day) produced less improvement than a standard dose (1000 mg/day; 65.9 vs 79.5%). During post-pulse oral corticosteroid therapy, EDSS scores decreased by 0.6 ± 0.9. No significant adverse effects were observed. Conclusions Methylprednisolone pulse therapy is beneficial in nearly 80% of Japanese MS and NMO patients, and EDSS score improvements after therapy are compatible with those in Western MS patients.. |
| 319. |
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.. |
| 320. |
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.. |
| 321. |
Ryo Yamasaki, Nobutoshi Kawamura, Anti-neurofascin antibodies in patients with combined central and peripheral demyelination, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12073, 4, 3, 257-258, 2013.12. |
| 322. |
Jun-Ichi Kira, Ryo Yamasaki, Satoshi Yoshimura, Toshiyuki Fukazawa, Kazumasa Yokoyama, Kazuo Fujihara, Mieko Ogino, Takanori Yokota, Katsuichi Miyamoto, Masaaki Niino, Kyoichi Nomura, Ryo Tomioka, Masami Tanaka, Izumi Kawachi, Takashi Ohashi, Kenichi Kaida, Makoto Matsui, Yuji Nakatsuji, Hirofumi Ochi, Hikoaki Fukaura, Takashi Kanda, Akiko Nagaishi, Kanae Togo, Hidehiro Mizusawa, Yuji Kawano, Efficacy of methylprednisolone pulse therapy for acute relapse in Japanese patients with multiple sclerosis and neuromyelitis optica: A multicenter retrospective analysis - 1. Whole group analysis, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12071, 4, 3, 305-317, 2013.12, Objectives There has been no large-scale study of methylprednisolone pulse therapy in Asian patients with multiple sclerosis (MS) or neuromyelitis optica (NMO), despite it being widely used for acute relapse. We aimed to clarify treatment response of MS and NMO patients to methylprednisolone pulse therapy and post-pulse oral corticosteroids in real clinical practice in a multicenter study in Japan. Methods Investigators at 28 institutions collected changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of completion of methylprednisolone pulse therapy carried out in 2010, and after post-pulse oral corticosteroids therapy, by retrospective review of medical records. Results In 345 patients (95.1% of all registered patients), 457 series of methylprednisolone pulse therapy were carried out for treatment of acute relapse. EDSS scores improved by 0.8 ± 1.1 (mean ± SD) after the first course. The second and third courses also produced sufficient improvements (by 0.7 and 0.6, respectively), but much smaller improvements were observed thereafter. The target neurological symptoms and signs improved in 79.5% of patients. Improvement rates were 5-20% lower after a course of pulse therapy than after a series of pulse therapy. A half dose (500 mg/day) produced less improvement than a standard dose (1000 mg/day
65.9 vs 79.5%). During post-pulse oral corticosteroid therapy, EDSS scores decreased by 0.6 ± 0.9. No significant adverse effects were observed. Conclusions Methylprednisolone pulse therapy is beneficial in nearly 80% of Japanese MS and NMO patients, and EDSS score improvements after therapy are compatible with those in Western MS patients. © 2013 Japanese Society for Neuroimmunology.. |
| 323. |
Ryo Yamasaki, Tomomi Yonekawa, Hiroyuki Murai, Takuya Matsushita, Masaki Katsuhisa, Noriko Isobe, Jun-ichi Kira, A nationwide survey of hypertrophic pachymeningitis in Japan., J Neurol Neurosurg Psychiatry, 2013.11, 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.. |
| 324. |
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 Journal, 10.1177/1352458513482512, 19, 13, 1696-1703, 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 |
| 325. |
Naoko Soejima, Yasumasa Ohyagi, Norimichi Nakamura, Eri Himeno, Kyoko M. Iinuma, Nobutaka Sakae, Ryo Yamasaki, Takeshi Tabira, Kazuma Murakami, Kazuhiro Irie, Noriaki Kinoshita, Frank M. LaFerla, Yutaka Kiyohara, Toru Iwaki, Jun ichi Kira, Intracellular accumulation of toxic turn amyloid-β is associated with endoplasmic reticulum stress in Alzheimer's disease, Current Alzheimer Research, 10, 1, 11-20, 2013.11, Amyloid-β3 protein (Aβ3) accumulates in the neurons of Alzheimer's disease (AD) patients at an early stage of the disease. Recently, we found that Aβ3 with a toxic turn at positions 22 and 23 accumulates in neurons in AD brain. Here, we studied the accumulation of Aβ3, toxic turn Aβ3 and high-molecular-weight Aβ3 oligomers in presenilin 1 (PS1) gene-transfected SH-SY5Y cells as well as in the brains of 3xTg-AD mice and AD patients. Immunostaining revealed that accumulation of toxic turn Aβ3 was promoted in G384A- and I143T-mutant PS1-transfected cells and further enhanced by co-transfection of cells with the Aβ3-precursor protein (Aβ3PP) gene. In contrast, accumulation of high-molecular-weight Aβ3 oligomers was promoted in mutant PS1 cells but attenuated by co-transfection of cells with the Aβ3PP gene. Toxic turn Aβ3 was detected in the neurons of 3xTg-AD mice aged 2 months, when the mice were cognitively unimpaired. In contrast, high-molecular-weight Aβ3 oligomers were detected in the neurons of 7-month-old mice, when memory dysfunction is apparent. Furthermore, immunostaining and western blotting for Rab4, Rab6 and GRP78 revealed increased levels of these proteins in mutant PS1 cells and their accumulation in the neurons of 3xTg-AD mice. Remarkably, GRP78 immunoreactivity was increased at 2 months of age. Double-label immunostaining of AD brain revealed an apparent association between toxic turn Aβ3 and GRP78, an endoplasmic reticulum (ER) stress marker. Intraneuronal accumulation of toxic turn Aβ3 may be associated with ER stress in the brains of AD model mice and AD patients at an early stage.. |
| 326. |
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 |
| 327. |
Ban Yu Saitoh, Ryo Yamasaki, Shintaro Hayashi, Satoshi Yoshimura, Takahisa Tateishi, Yasumasa Ohyagi, Hiroyuki Murai, Toru Iwaki, Kunihiro Yoshida, Jun Ichi Kira, A case of hereditary diffuse leukoencephalopathy with axonal spheroids caused by a de novo mutation in CSF1R masquerading as primary progressive multiple sclerosis, Multiple Sclerosis Journal, 10.1177/1352458513489854, 19, 10, 1367-1370, 2013.09, We report a sporadic case of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) confirmed by biopsy and colony-stimulating factor 1 receptor (CSF1R) sequencing. A 28-year-old woman developed progressive spastic gait and dysarthria. Brain T2/FLAIR-weighted magnetic resonance imaging showed bilateral high signal intensity lesions in the parietal deep white matter, which subsequently extended anteriorly. Biopsied brain specimens demonstrated demyelinated white matter tissue with axonal spheroids infiltrated with foamy macrophages, and CD8+ and CD4+ T cells. She had a heterozygous mutation, c.2381T>C (p.782 Ile>Thr), in CSF1R. This is the first genetically proven case of HDLS mimicking primary progressive multiple sclerosis.. |
| 328. |
Yuko Nagara, Takahisa Tateishi, Ryo Yamasaki, Shintaro Hayashi, Mami Kawamura, Hitoshi Kikuchi, Kyoko Motomura Iinuma, Masahito Tanaka, Toru Iwaki, Takuya Matsushita, Yasumasa Ohyagi, Jun Ichi Kira, Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1α in amyotrophic lateral sclerosis, Brain Pathology, 10.1111/bpa.12040, 23, 5, 534-546, 2013.09, We investigated the mechanisms underlying abnormal vascular endothelial growth factor (VEGF) production in amyotrophic lateral sclerosis (ALS). We immunohistochemically studied VEGF, its receptors VEGFR1 and 2, and hypoxia-inducible factor-1α (HIF-1α) in autopsied ALS spinal cords. We also chronologically assessed the expression of HIF-1α, karyopherin β1, karyopherin β-cargo protein complex inhibitors and nuclear pore complex proteins in G93A mutant superoxide dismutase 1 (mSOD1) transgenic mice at presymptomatic, symptomatic and end stages. In ALS patients, compared with controls, HIF-1α immunoreactivity in the cytoplasm of anterior horn cells (AHCs) was significantly increased, while immunoreactivities for VEGF and VEGFRs were significantly decreased. Similar changes in HIF-1α and VEGF levels were observed in mSOD1 transgenic mice. HIF-1α co-localized with karyopherin β1 in the cytoplasm of AHCs and karyopherin β1 co-localized with nucleoporin 62 (Nup62) on the nuclear envelope. From the presymptomatic stage of mSOD1 transgenic mice, karyopherin β1 immunoreactivity in AHC nuclei significantly decreased and morphological irregularities of the Nup62-immunostained nuclear envelope became more pronounced with disease progression. Thus, in AHCs from mSOD1 transgenic mice, transport of cytoplasmic HIF-1α to the nuclear envelope and into the nucleus is impaired from the presymptomatic stage, suggesting that impaired cytoplasmic-nuclear transport of HIF-1α through the nuclear pore might precede motor neuron degeneration.. |
| 329. |
Keita Sonoda, Kensuke Sasaki, Takahisa Tateishi, Ryo Yamasaki, Shintaro Hayashi, Nobutaka Sakae, Yasumasa Ohyagi, Toru Iwaki, Jun Ichi Kira, TAR DNA-binding protein 43 pathology in a case clinically diagnosed with facial-onset sensory and motor neuronopathy syndrome
An autopsied case report and a review of the literature, Journal of the Neurological Sciences, 10.1016/j.jns.2013.06.027, 332, 1-2, 148-153, 2013.09, We report an autopsy case of a 48-year-old female clinically diagnosed with facial-onset sensory and motor neuronopathy (FOSMN) syndrome with TAR DNA-binding protein 43 (TDP-43) pathology. She developed paresthesia involving her whole face, right upper extremity and the right side of her upper trunk, followed by dysphagia, dysarthria, muscle atrophy and weakness with fasciculation in both upper extremities. Her symptoms showed a marked cranial and right-sided dominancy. She had anti-sulfoglucuronyl paragloboside (SGPG) IgG and anti-myelin-associated glycoprotein (MAG) IgG, and repeatedly showed limited response to immunotherapies. Her disease was essentially progressive, culminating in death due to respiratory failure three and a half years after onset. The autopsy revealed severe degeneration of the nuclei of the right trigeminal nerve and right facial nerve and widespread TDP-43-positive glial inclusions in the brainstem tegmentum. Neurons in the hypoglossal nerve nuclei were also shrunken and lost, with TDP-43-positive neuronal inclusions. Neuronal loss and gliosis in the anterior horn, predominantly in the cervical cord, were prominent with TDP-43-positive skein-like inclusions. Bilateral ventral roots were obviously atrophic. Spinal tract degeneration was also prominent in the ventral columns, essentially sparing the anterior corticospinal tracts at the cervical cord level. Additionally there was severe myelin pallor in the right spinal trigeminal tract and right fasciculus cuneatus of the cervical cord. The right spinal root ganglion showed numerous Nageotte's nodules and focal lymphocytic infiltration. The present case manifested FOSMN syndrome clinically, while the pathological findings suggested a motor neuron disease like TDP-43 proteinopathy and a possible involvement of immune-mediated neuropathy.. |
| 330. |
Ban-yu Saitoh, Ryo Yamasaki, Shintaro Hayashi, Satoshi Yoshimura, Takahisa Tateishi, Yasumasa Ohyagi, Hiroyuki Murai, Toru Iwaki, Kunihiro Yoshida, Jun-ichi Kira, A case of hereditary diffuse leukoencephalopathy with axonal spheroids caused by a de novo mutation in CSF1R masquerading as primary progressive multiple sclerosis., Multiple sclerosis (Houndmills, Basingstoke, England), 10.1177/1352458513489854, 19, 10, 1367-70, 2013.09, We report a sporadic case of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) confirmed by biopsy and colony-stimulating factor 1 receptor (CSF1R) sequencing. A 28-year-old woman developed progressive spastic gait and dysarthria. Brain T2/FLAIR-weighted magnetic resonance imaging showed bilateral high signal intensity lesions in the parietal deep white matter, which subsequently extended anteriorly. Biopsied brain specimens demonstrated demyelinated white matter tissue with axonal spheroids infiltrated with foamy macrophages, and CD8(+) and CD4(+) T cells. She had a heterozygous mutation, c.2381T>C (p.782 Ile>Thr), in CSF1R. This is the first genetically proven case of HDLS mimicking primary progressive multiple sclerosis.. |
| 331. |
Nagara Y, Tateishi T, Yamasaki R, Hayashi S, Kawamura M, Kikuchi H, Iinuma KM, Tanaka M, Iwaki T, Matsushita T, Ohyagi Y, Kira J, Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1α in amyotrophic lateral sclerosis., Brain pathology (Zurich, Switzerland), 10.1111/bpa.12040, 23, 5, 534-46, 2013.09. |
| 332. |
Keita Sonoda, Kensuke Sasaki, Takahisa Tateishi, Ryo Yamasaki, Shintaro Hayashi, Nobutaka Sakae, Yasumasa Ohyagi, Toru Iwaki, Jun-ichi Kira, TAR DNA-binding protein 43 pathology in a case clinically diagnosed with facial-onset sensory and motor neuronopathy syndrome: an autopsied case report and a review of the literature., Journal of the neurological sciences, 10.1016/j.jns.2013.06.027, 332, 1-2, 148-53, 2013.09, We report an autopsy case of a 48-year-old female clinically diagnosed with facial-onset sensory and motor neuronopathy (FOSMN) syndrome with TAR DNA-binding protein 43 (TDP-43) pathology. She developed paresthesia involving her whole face, right upper extremity and the right side of her upper trunk, followed by dysphagia, dysarthria, muscle atrophy and weakness with fasciculation in both upper extremities. Her symptoms showed a marked cranial and right-sided dominancy. She had anti-sulfoglucuronyl paragloboside (SGPG) IgG and anti-myelin-associated glycoprotein (MAG) IgG, and repeatedly showed limited response to immunotherapies. Her disease was essentially progressive, culminating in death due to respiratory failure three and a half years after onset. The autopsy revealed severe degeneration of the nuclei of the right trigeminal nerve and right facial nerve and widespread TDP-43-positive glial inclusions in the brainstem tegmentum. Neurons in the hypoglossal nerve nuclei were also shrunken and lost, with TDP-43-positive neuronal inclusions. Neuronal loss and gliosis in the anterior horn, predominantly in the cervical cord, were prominent with TDP-43-positive skein-like inclusions. Bilateral ventral roots were obviously atrophic. Spinal tract degeneration was also prominent in the ventral columns, essentially sparing the anterior corticospinal tracts at the cervical cord level. Additionally there was severe myelin pallor in the right spinal trigeminal tract and right fasciculus cuneatus of the cervical cord. The right spinal root ganglion showed numerous Nageotte's nodules and focal lymphocytic infiltration. The present case manifested FOSMN syndrome clinically, while the pathological findings suggested a motor neuron disease like TDP-43 proteinopathy and a possible involvement of immune-mediated neuropathy.. |
| 333. |
Ryo Yamasaki, Masaki Katsuhisa, Satoshi O Suzuki, Takuya Matsushita, 松岡 健, Toru Iwaki, Jun-ichi Kira, Connexin 43 astrocytopathy linked to rapidly progressive multiple sclerosis and neuromyelitis optica, PLoS One, 10.1371/journal.pone.0072919., 8, 8, e72919, 2013.08. |
| 334. |
Ryo Yamasaki, Nobutoshi Kawamura, Takuya Matsushita, Matsuse Dai, Hiroyuki Murai, Jun-ichi Kira, Anti-neurofascin antibody in patients with combined central and peripheral demyelination., Neurology, 2013.08, We aimed to identify the target antigens for combined central and peripheral demyelination (CCPD).
METHODS:
We screened target antigens by immunohistochemistry and immunoblotting using peripheral nerve tissues to identify target antigens recognized by serum antibodies from selected CCPD and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cases. We then measured the level of antibody to the relevant antigen in 7 patients with CCPD, 16 patients with CIDP, 20 patients with multiple sclerosis, 20 patients with Guillain-Barré syndrome, 21 patients with other neuropathies, and 23 healthy controls (HC) by ELISA and cell-based assays using HEK293 cells.
RESULTS:
At the initial screening, sera from 2 patients with CCPD showed cross-like binding to sciatic nerve sections at fixed intervals, with nearly perfect colocalization with neurofascin immunostaining at the node and paranode. ELISA with recombinant neurofascin revealed significantly higher mean optical density values in the CCPD group than in other disease groups and HC. Anti-neurofascin antibody positivity rates were 86% in patients with CCPD, 10% in patients with multiple sclerosis, 25% in patients with CIDP, 15% in patients with Guillain-Barré syndrome, and 0% in patients with other neuropathies and HC. The cell-based assay detected serum anti-neurofascin antibody in 5 of 7 patients with CCPD; all others were negative. CSF samples examined from 2 patients with CCPD were both positive. In anti-neurofascin antibody-positive CCPD patients, including those with a limited response to corticosteroids, IV immunoglobulin or plasma exchange alleviated the symptoms.
CONCLUSION:
Anti-neurofascin antibody is frequently present in patients with CCPD. Recognition of this antibody may be important, because patients with CCPD who are antibody positive respond well to IV immunoglobulin or plasma exchange.. |
| 335. |
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.. |
| 336. |
Mitsuru Watanabe, Ryo Yamasaki, Yuji Kawano, Shihoko Imamura, Jun Ichi Kira, Anti-KIR4.1 antibodies in Japanese patients with idiopathic central nervous system demyelinating diseases, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12029, 4, 2, 241-242, 2013.08. |
| 337. |
Nobutoshi Kawamura, Ryo Yamasaki, Tomomi Yonekawa, Takuya Matsushita, Susumu Kusunoki, Shigemi Nagayama, Yasuo Fukuda, Hidenori Ogata, Dai Matsuse, Hiroyuki Murai, Jun Ichi Kira, Anti-neurofascin antibody in patients with combined central and peripheral demyelination, Neurology, 10.1212/WNL.0b013e3182a1aa9c, 81, 8, 714-722, 2013.08, Objectives: We aimed to identify the target antigens for combined central and peripheral demyelination (CCPD). Methods: We screened target antigens by immunohistochemistry and immunoblotting using peripheral nerve tissues to identify target antigens recognized by serum antibodies from selected CCPD and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cases. We then measured the level of antibody to the relevant antigen in 7 patients with CCPD, 16 patients with CIDP, 20 patients with multiple sclerosis, 20 patients with Guillain-Barré syndrome, 21 patients with other neuropathies, and 23 healthy controls (HC) by ELISA and cell-based assays using HEK293 cells. Results: At the initial screening, sera from 2 patients with CCPD showed cross-like binding to sciatic nerve sections at fixed intervals, with nearly perfect colocalization with neurofascin immunostaining at the node and paranode. ELISA with recombinant neurofascin revealed significantly higher mean optical density values in the CCPD group than in other disease groups and HC. Anti-neurofascin antibody positivity rates were 86% in patients with CCPD, 10% in patients with multiple sclerosis, 25% in patients with CIDP, 15% in patients with Guillain-Barré syndrome, and 0% in patients with other neuropathies and HC. The cell-based assay detected serum anti-neurofascin antibody in 5 of 7 patients with CCPD; all others were negative. CSF samples examined from 2 patients with CCPD were both positive. In anti-neurofascin antibody- positive CCPD patients, including those with a limited response to corticosteroids, IV immunoglobulin or plasma exchange alleviated the symptoms. Conclusion: Anti-neurofascin antibody is frequently present in patients with CCPD. Recognition of this antibody may be important, because patients with CCPD who are antibody positive respond well to IV immunoglobulin or plasma exchange.. |
| 338. |
Katsuhisa Masaki, Satoshi O. Suzuki, Takuya Matsushita, Takeshi Matsuoka, Shihoko Imamura, Ryo Yamasaki, Makiko Suzuki, Toshihiko Suenaga, Toru Iwaki, Jun Ichi Kira, Connexin 43 Astrocytopathy Linked to Rapidly Progressive Multiple Sclerosis and Neuromyelitis Optica, PloS one, 10.1371/journal.pone.0072919, 8, 8, 2013.08, Background:Multiple sclerosis (MS) and neuromyelitis optica (NMO) occasionally have an extremely aggressive and debilitating disease course; however, its molecular basis is unknown. This study aimed to determine a relationship between connexin (Cx) pathology and disease aggressiveness in Asian patients with MS and NMO.Methods/Principal Findings:Samples included 11 autopsied cases with NMO and NMO spectrum disorder (NMOSD), six with MS, and 20 with other neurological diseases (OND). Methods of analysis included immunohistochemical expression of astrocytic Cx43/Cx30, oligodendrocytic Cx47/Cx32 relative to AQP4 and other astrocytic and oligodendrocytic proteins, extent of demyelination, the vasculocentric deposition of complement and immunoglobulin, and lesion staging by CD68 staining for macrophages. Lesions were classified as actively demyelinating (n=59), chronic active (n=58) and chronic inactive (n=23). Sera from 120 subjects including 30 MS, 30 NMO, 40 OND and 20 healthy controls were examined for anti-Cx43 antibody by cell-based assay. Six NMO/NMOSD and three MS cases showed preferential loss of astrocytic Cx43 beyond the demyelinated areas in actively demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte oligodendrocyte gap junctions were extensively lost. Cx43 loss was significantly associated with a rapidly progressive disease course as six of nine cases with Cx43 loss, but none of eight cases without Cx43 loss regardless of disease phenotype, died within two years after disease onset (66.7% vs. 0%, P=0.0090). Overall, five of nine cases with Cx43 loss and none of eight cases without Cx43 loss had distal oligodendrogliopathy characterized by selective myelin associated glycoprotein loss (55.6% vs. 0.0%, P=0.0296). Loss of oligodendrocytic Cx32 and Cx47 expression was observed in most active and chronic lesions from all MS and NMO/NMOSD cases. Cx43-specific antibodies were absent in NMO/NMOSD and MS patients.Conclusions:These findings suggest that autoantibody-independent astrocytic Cx43 loss may relate to disease aggressiveness and distal oligodendrogliopathy in both MS and NMO.. |
| 339. |
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 DRB1*0405 was significantly higher in the Barkhof brain lesion-negative group, that of DPB1*0301 was significantly higher in the Barkhof brain lesion-positive group, and those of DRB1*0901 and DPB1*0401 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.. |
| 340. |
Jun Ichi Kira, Ryo Yamasaki, Katsuhisa Masaki, Neuro2013, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12042, 4, 2, 243-245, 2013.08. |
| 341. |
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.. |
| 342. |
Nobutoshi Kawamura, Ryo Yamasaki, Tomomi Yonekawa, Takuya Matsushita, Susumu Kusunoki, Shigemi Nagayama, Yasuo Fukuda, Hidenori Ogata, Dai Matsuse, Hiroyuki Murai, Jun-Ichi Kira, Anti-neurofascin antibody in patients with combined central and peripheral demyelination., Neurology, 10.1212/WNL.0b013e3182a1aa9c, 81, 8, 714-22, 2013.08, OBJECTIVES: We aimed to identify the target antigens for combined central and peripheral demyelination (CCPD). METHODS: We screened target antigens by immunohistochemistry and immunoblotting using peripheral nerve tissues to identify target antigens recognized by serum antibodies from selected CCPD and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cases. We then measured the level of antibody to the relevant antigen in 7 patients with CCPD, 16 patients with CIDP, 20 patients with multiple sclerosis, 20 patients with Guillain-Barré syndrome, 21 patients with other neuropathies, and 23 healthy controls (HC) by ELISA and cell-based assays using HEK293 cells. RESULTS: At the initial screening, sera from 2 patients with CCPD showed cross-like binding to sciatic nerve sections at fixed intervals, with nearly perfect colocalization with neurofascin immunostaining at the node and paranode. ELISA with recombinant neurofascin revealed significantly higher mean optical density values in the CCPD group than in other disease groups and HC. Anti-neurofascin antibody positivity rates were 86% in patients with CCPD, 10% in patients with multiple sclerosis, 25% in patients with CIDP, 15% in patients with Guillain-Barré syndrome, and 0% in patients with other neuropathies and HC. The cell-based assay detected serum anti-neurofascin antibody in 5 of 7 patients with CCPD; all others were negative. CSF samples examined from 2 patients with CCPD were both positive. In anti-neurofascin antibody-positive CCPD patients, including those with a limited response to corticosteroids, IV immunoglobulin or plasma exchange alleviated the symptoms. CONCLUSION: Anti-neurofascin antibody is frequently present in patients with CCPD. Recognition of this antibody may be important, because patients with CCPD who are antibody positive respond well to IV immunoglobulin or plasma exchange.. |
| 343. |
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 DRB1*0405 was significantly higher in the Barkhof brain lesion-negative group, that of DPB1*0301 was significantly higher in the Barkhof brain lesion-positive group, and those of DRB1*0901 and DPB1*0401 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.. |
| 344. |
Mitsuru Watanabe, Ryo Yamasaki, Yuji Kawano, Shihoko Imamura, Jun-Ichi Kira, Anti-KIR4.1 antibodies in Japanese patients with idiopathic central nervous system demyelinating diseases, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12029, 4, 2, 241-242, 2013.08. |
| 345. |
Kazutaka Sonoda, Ryo Yamasaki, Takuya Matsushita, Takeo Yoshimura, Hiroyuki Murai, Jun-Ichi Kira, Case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids showing features common to multiple sclerosis, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12028, 4, 1, 104-106, 2013.06. |
| 346. |
Yuji Kanamori, Noriko Isobe, Tomomi Yonekawa, Takuya Matsushita, Hiroshi Shigeto, Nobutoshi Kawamura, Ryo Yamasaki, Hiroyuki Murai, Shozo Tobimatsu, Jun Ichi Kira, Multimodality evoked potentials for discrimination of atopic myelitis and multiple sclerosis, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12018, 4, 1, 29-35, 2013.06, Objectives: To clarify the differences in multimodality evoked potential findings between patients with atopic myelitis (AM) and those with multiple sclerosis (MS). Methods: A retrospective chart review of 70 consecutive AM patients and 93 MS patients was carried out. All patients were negative for serum antiaquaporin- 4 antibody. Visual- (VEP), somatosensory- (SEP) and motor-evoked potentials (MEP) recorded at first examination, and magnetic resonance imaging (MRI) findings from the first examination were compared between AM and MS patients. Results: Compared with MS patients, AM patients showed male preponderance, lower the Expanded Disability Status Scale scores and less frequent spinal cord MRI lesions. Visual impairment and muscle weakness were also less severe in AM patients. Frequencies of abnormal VEP and prolonged central conduction time on lower limb MEP were significantly lower in AM patients than in MS patients (AM vs MS: 9.5% vs 55.6%, and 28.2% vs 54.4%, respectively), whereas frequencies of peripheral nerve involvement in upper and lower limb MEP and upper limb SEP were significantly higher in AM than in MS patients (AM vs MS: 12.8% vs 2.9%, 17.9% vs 2.9% and 33.3% vs 4.4%, respectively). When patients whose EP were examined within 5 years of disease onset were compared, lower frequencies of abnormal VEP and higher peripheral nerve involvement detected by MEP and SEP were observed in AM patients. Conclusions: AM patients have distinct physiological features compared with MS patients, even at the first examination of evoked potentials, which might suggest distinct immunological mechanisms between the two conditions. Multimodality evoked potentials might contribute to the early discrimination of these two disorders.. |
| 347. |
Kazutaka Sonoda, Ryo Yamasaki, Takuya Matsushita, Takeo Yoshimura, Hiroyuki Murai, Jun-Ichi Kira, Case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids showing features common to multiple sclerosis, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12028, 4, 1, 104-106, 2013.06. |
| 348. |
Yuji Kanamori, Noriko Isobe, Tomomi Yonekawa, Takuya Matsushita, Hiroshi Shigeto, Nobutoshi Kawamura, Ryo Yamasaki, Hiroyuki Murai, Shozo Tobimatsu, Jun-Ichi Kira, Multimodality evoked potentials for discrimination of atopic myelitis and multiple sclerosis, Clinical and Experimental Neuroimmunology, 10.1111/cen3.12018, 4, 1, 29-35, 2013.06, Objectives: To clarify the differences in multimodality evoked potential findings between patients with atopic myelitis (AM) and those with multiple sclerosis (MS). Methods: A retrospective chart review of 70 consecutive AM patients and 93 MS patients was carried out. All patients were negative for serum antiaquaporin- 4 antibody. Visual- (VEP), somatosensory- (SEP) and motor-evoked potentials (MEP) recorded at first examination, and magnetic resonance imaging (MRI) findings from the first examination were compared between AM and MS patients. Results: Compared with MS patients, AM patients showed male preponderance, lower the Expanded Disability Status Scale scores and less frequent spinal cord MRI lesions. Visual impairment and muscle weakness were also less severe in AM patients. Frequencies of abnormal VEP and prolonged central conduction time on lower limb MEP were significantly lower in AM patients than in MS patients (AM vs MS: 9.5% vs 55.6%, and 28.2% vs 54.4%, respectively), whereas frequencies of peripheral nerve involvement in upper and lower limb MEP and upper limb SEP were significantly higher in AM than in MS patients (AM vs MS: 12.8% vs 2.9%, 17.9% vs 2.9% and 33.3% vs 4.4%, respectively). When patients whose EP were examined within 5 years of disease onset were compared, lower frequencies of abnormal VEP and higher peripheral nerve involvement detected by MEP and SEP were observed in AM patients. Conclusions: AM patients have distinct physiological features compared with MS patients, even at the first examination of evoked potentials, which might suggest distinct immunological mechanisms between the two conditions. Multimodality evoked potentials might contribute to the early discrimination of these two disorders. © 2013 Japanese Society for Neuroimmunology.. |
| 349. |
Saitoh BY, Ryo Yamasaki, Hayashi S, Yoshimura S, Tateishi T, Ohyagi Y, Murai H, Iwaki T, Yoshida K, Kira JI, A case of hereditary diffuse leukoencephalopathy with axonal spheroids caused by a de novo mutation in CSF1R masquerading as primary progressive multiple sclerosis., Mult Scler., 2013.05. |
| 350. |
Huang J, Yoshimura S, Isobe N, Matsushita T, Yonekawa T, Sato S, Ryo Yamasaki, Kira JI, A NOTCH4 missense mutation confers resistance to multiple sclerosis in Japanese., Mult Scler., 2013.04. |
| 351. |
Matsushita T, Tateishi T, Isobe N, Yonekawa T, Ryo Yamasaki, Matsuse D, Murai H, Kira J, Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis., PLoS One, 2013.04. |
| 352. |
Takuya Matsushita, Takahisa Tateishi, Noriko Isobe, Tomomi Yonekawa, Ryo Yamasaki, Dai Matsuse, Hiroyuki Murai, Jun Ichi Kira, Characteristic Cerebrospinal Fluid Cytokine/Chemokine Profiles in Neuromyelitis Optica, Relapsing Remitting or Primary Progressive Multiple Sclerosis, PloS one, 10.1371/journal.pone.0061835, 8, 4, 2013.04, Background: Differences in cytokine/chemokine profiles among patients with neuromyelitis optica (NMO), relapsing remitting multiple sclerosis (RRMS), and primary progressive MS (PPMS), and the relationships of these profiles with clinical and neuroimaging features are unclear. A greater understanding of these profiles may help in differential diagnosis. Methods/Principal Findings: We measured 27 cytokines/chemokines and growth factors in CSF collected from 20 patients with NMO, 26 with RRMS, nine with PPMS, and 18 with other non-inflammatory neurological diseases (OND) by multiplexed fluorescent bead-based immunoassay. Interleukin (IL)-17A, IL-6, CXCL8 and CXCL10 levels were significantly higher in NMO patients than in OND and RRMS patients at relapse, while granulocyte-colony stimulating factor (G-CSF) and CCL4 levels were significantly higher in NMO patients than in OND patients. In NMO patients, IL-6 and CXCL8 levels were positively correlated with disability and CSF protein concentration while IL-6, CXCL8, G-CSF, granulocyte-macrophage colonystimulating factor (GM-CSF) and IFN-c were positively correlated with CSF neutrophil counts at the time of sample collection. In RRMS patients, IL-6 levels were significantly higher than in OND patients at the relapse phase while CSF cell counts were negatively correlated with the levels of CCL2. Correlation coefficients of cytokines/chemokines in the relapse phase were significantly different in three combinations, IL-6 and GM-CSF, G-CSF and GM-CSF, and GM-CSF and IFN-c, between RRMS and NMO/NMOSD patients. In PPMS patients, CCL4 and CXCL10 levels were significantly higher than in OND patients. Conclusions: Our findings suggest distinct cytokine/chemokine alterations in CSF exist among NMO, RRMS and PPMS. In NMO, over-expression of a cluster of Th17- and Th1-related proinflammatory cytokines/chemokines is characteristic, while in PPMS, increased CCL4 and CXCL10 levels may reflect on-going low grade T cell and macrophage/microglia inflammation in the central nervous system. In RRMS, only a mild elevation of proinflammatory cytokines/chemokines was detectable at relapse.. |
| 353. |
Y. W. Cui, K. Masaki, R. Yamasaki, N. Shi, T. Tateishi, T. Matsushita, T. Yonekawa, J. Kira, Dysregulation of Surface Marker Expressions on Peripheral Blood Monocytes in Multiple Sclerosis, MULTIPLE SCLEROSIS JOURNAL, 19, 5, 675-676, 2013.04. |
| 354. |
Soejima N, Yasumasa Ohyagi, Nakamura N, Himeno E, Iinuma KM, Sakae N, Tabira T, Ryo Yamasaki, Murakami K, Irie K, Kinoshita N, LaFeria FM, Kiyohara Y, Iwaki T, Kira J, Intracellular accumulation of toxic turn amyloid-β is associated with endoplasmic reticulum stress in Alzheimer's disease., Curr Alzheimer Res, 2013.01. |
| 355. |
Nagara Y, Tateishi T, Ryo Yamasaki, Hayashi S, kawamura M, Kikuchi H, Iinuma KM, Tanaka M, Iwaki T, Matsushita T, Ohyagi Y, Kira JI, Impaired Cytoplasmic-Nuclear Transport of Hypoxia-Inducible Factor-1α in Amyotrophic Lateral Sclerosis., Brain Pathol, 2013.01. |
| 356. |
Soejima N, Ohyagi Y, Nakamura N, Himeno E, Iinuma KM, Sakae N, Yamasaki R, Tabira T, Murakami K, Irie K, Kinoshita N, LaFerla FM, Kiyohara Y, Iwaki T, Kira J, Intracellular accumulation of toxic turn amyloid-β is associated with endoplasmic reticulum stress in Alzheimer's disease., Current Alzheimer research, 10, 1, 11-20, 2013.01. |
| 357. |
Y. Nagara, T. Tateishi, S. Hayashi, R. Yamasaki, M. Kawamura, H. Kikuchi, K. M. Iinuma, Y. Ohoyagi, J. -I. Kira, Impaired cytoplasmic-nuclear transport (intranuclear changes and nuclear envelope alterations) occurs at the early pre-symptomatic stage of amyotrophic lateral sclerosis, EUROPEAN JOURNAL OF NEUROLOGY, 19, 276-276, 2012.09. |
| 358. |
Schafer DP, Lehman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B, Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner., Neuron, 2012.05. |
| 359. |
Dorothy P. Schafer, Emily K. Lehrman, Amanda G. Kautzman, Ryuta Koyama, Alan R. Mardinly, Ryo Yamasaki, Richard M. Ransohoff, Michael E. Greenberg, Ben A. Barres, Beth Stevens, Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner, Neuron, 10.1016/j.neuron.2012.03.026, 74, 4, 691-705, 2012.05, Microglia are the resident CNS immune cells and active surveyors of the extracellular environment. While past work has focused on the role of these cells during disease, recent imaging studies reveal dynamic interactions between microglia and synaptic elements in the healthy brain. Despite these intriguing observations, the precise function of microglia at remodeling synapses and the mechanisms that underlie microglia-synapse interactions remain elusive. In the current study, we demonstrate a role for microglia in activity-dependent synaptic pruning in the postnatal retinogeniculate system. We show that microglia engulf presynaptic inputs during peak retinogeniculate pruning and that engulfment is dependent upon neural activity and the microglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3. Furthermore, disrupting microglia-specific CR3/C3 signaling resulted in sustained deficits in synaptic connectivity. These results define a role for microglia during postnatal development and identify underlying mechanisms by which microglia engulf and remodel developing synapses.. |
| 360. |
Dorothy P Schafer, Emily K Lehrman, Amanda G Kautzman, Ryuta Koyama, Alan R Mardinly, Ryo Yamasaki, Richard M Ransohoff, Michael E Greenberg, Ben A Barres, Beth Stevens, Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner., Neuron, 10.1016/j.neuron.2012.03.026, 74, 4, 691-705, 2012.05, Microglia are the resident CNS immune cells and active surveyors of the extracellular environment. While past work has focused on the role of these cells during disease, recent imaging studies reveal dynamic interactions between microglia and synaptic elements in the healthy brain. Despite these intriguing observations, the precise function of microglia at remodeling synapses and the mechanisms that underlie microglia-synapse interactions remain elusive. In the current study, we demonstrate a role for microglia in activity-dependent synaptic pruning in the postnatal retinogeniculate system. We show that microglia engulf presynaptic inputs during peak retinogeniculate pruning and that engulfment is dependent upon neural activity and the microglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3. Furthermore, disrupting microglia-specific CR3/C3 signaling resulted in sustained deficits in synaptic connectivity. These results define a role for microglia during postnatal development and identify underlying mechanisms by which microglia engulf and remodel developing synapses.. |
| 361. |
Kawamura MF, Yamasaki R, Kawamura N, Tateishi T, Nagara Y, Matsushita T, Ohyagi Y, Kira J, Impaired recruitment of neuroprotective microglia and T cells during acute neuronal injury coincides with increased neuronal vulnerability in an amyotrophic lateral sclerosis model., Journal of experimental neurology, 2012.04. |
| 362. |
Mami Fukunaga Kawamura, Ryo Yamasaki, Nobutoshi Kawamura, Takahisa Tateishi, Yuko Nagara, Takuya Matsushita, Yasumasa Ohyagi, Jun ichi Kira, Impaired recruitment of neuroprotective microglia and T cells during acute neuronal injury coincides with increased neuronal vulnerability in an amyotrophic lateral sclerosis model, Experimental Neurology, 10.1016/j.expneurol.2012.01.015, 234, 2, 437-445, 2012.04, Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which microglia and T cells play significant roles in disease progression. However, it remains unknown whether these cells are toxic or protective. The present study aimed to clarify the developmental age-related alterations of neuronal, glial and T cell responses to acute neuron injury in non-transgenic (N-Tg) mice, and the in vivo effects of mSOD1 on these changes by studying N-Tg and mSOD1-Tg mice subjected to unilateral hypoglossal nerve axotomy at young (8. weeks) and adult (17. weeks) ages. Adult N-Tg mice showed increased neuronal viability on day 21 after axotomy and trends toward increased numbers of recruited microglia on day 3 and T cells on day 7, in the hypoglossal nucleus, compared with young N-Tg mice. Quantitative comparisons between mSOD1-Tg and N-Tg mice at the same ages, on day 3 after axotomy, showed that microglial recruitment was significantly lower in mSOD1-Tg mice than in 17-week-old N-Tg mice (the disease progression stage), but the same difference was not seen in 8-week-old mice (the presymptomatic stage), despite good preservation of hypoglossal neurons. Infiltration of CD3-positive T cells, mostly CD4-positive, on day 7 and the viability rate of hypoglossal neurons on the operated side compared with the contralateral side on day 21 were significantly decreased in mSOD1-Tg mice compared with N-Tg mice aged 17. weeks, but the same difference was not seen in mice aged 8. weeks. On day 3 after axotomy, expression levels of IGF-1 mRNA in the operated hypoglossal nucleus were significantly lower in mSOD1-Tg mice than N-Tg mice at 17. weeks of age. The observation that depressed microglial and T cell responses and expression of neurotrophic factors coincided with reduced neuronal viability in adult mSOD1-Tg mice suggests that diminished neuroprotective functions of mSOD1 microglia and T cells may contribute to exaggerated neuronal death.. |
| 363. |
Mami Fukunaga Kawamura, Ryo Yamasaki, Nobutoshi Kawamura, Takahisa Tateishi, Yuko Nagara, Takuya Matsushita, Yasumasa Ohyagi, Jun-ichi Kira, Impaired recruitment of neuroprotective microglia and T cells during acute neuronal injury coincides with increased neuronal vulnerability in an amyotrophic lateral sclerosis model., Experimental neurology, 10.1016/j.expneurol.2012.01.015, 234, 2, 437-45, 2012.04, Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which microglia and T cells play significant roles in disease progression. However, it remains unknown whether these cells are toxic or protective. The present study aimed to clarify the developmental age-related alterations of neuronal, glial and T cell responses to acute neuron injury in non-transgenic (N-Tg) mice, and the in vivo effects of mSOD1 on these changes by studying N-Tg and mSOD1-Tg mice subjected to unilateral hypoglossal nerve axotomy at young (8 weeks) and adult (17 weeks) ages. Adult N-Tg mice showed increased neuronal viability on day 21 after axotomy and trends toward increased numbers of recruited microglia on day 3 and T cells on day 7, in the hypoglossal nucleus, compared with young N-Tg mice. Quantitative comparisons between mSOD1-Tg and N-Tg mice at the same ages, on day 3 after axotomy, showed that microglial recruitment was significantly lower in mSOD1-Tg mice than in 17-week-old N-Tg mice (the disease progression stage), but the same difference was not seen in 8-week-old mice (the presymptomatic stage), despite good preservation of hypoglossal neurons. Infiltration of CD3-positive T cells, mostly CD4-positive, on day 7 and the viability rate of hypoglossal neurons on the operated side compared with the contralateral side on day 21 were significantly decreased in mSOD1-Tg mice compared with N-Tg mice aged 17 weeks, but the same difference was not seen in mice aged 8 weeks. On day 3 after axotomy, expression levels of IGF-1 mRNA in the operated hypoglossal nucleus were significantly lower in mSOD1-Tg mice than N-Tg mice at 17 weeks of age. The observation that depressed microglial and T cell responses and expression of neurotrophic factors coincided with reduced neuronal viability in adult mSOD1-Tg mice suggests that diminished neuroprotective functions of mSOD1 microglia and T cells may contribute to exaggerated neuronal death.. |
| 364. |
Ryo Yamasaki, Liping Liu, Jessica Lin, Richard M. Ransohoff, Role of CCR2 in immunobiology and neurobiology, Clinical and Experimental Neuroimmunology, 10.1111/j.1759-1961.2011.00024.x, 3, 1, 16-29, 2012.01, Chemokines and their receptors play crucial roles in the trafficking of leukocytes and are of particular interest in the context of the unique inflammatory responses elicited in the central nervous system (CNS). The chemokine receptor CCR2 and its ligand CCL2 have been implicated in a wide range of immunobiological processes and neuropathologies, including recruitment of monocytes and regulation of bone marrow homeostasis, as well as multiple sclerosis, HIV-associated dementia, Alzheimer's disease and neuropathic pain. Recently, powerful biological tools (CCR2-red fluorescent protein [RFP] knock-in mice) have been developed to analyze the functions of CCR2 in different cell populations, and intriguing results have emerged from those mice. The present review emphasizes CCR2/CCL2 as a key chemokine/chemokine receptor pair that controls the recruitment or retention of a key subset of mononuclear phagocytes in inflammation associated with host defense or disease.. |
| 365. |
Taira Uehara, Hiroyuki Murai, Ryo Yamasaki, Hitoshi Kikuchi, Hiroshi Shigeto, Yasumasa Ohyagi, Jun Ichi Kira, Thymoma-associated progressive encephalomyelitis with rigidity and myoclonus successfully treated with thymectomy and intravenous immunoglobulin, European Neurology, 10.1159/000332033, 66, 6, 328-330, 2011.12. |
| 366. |
Uehara T, Murai H, Ryo Yamasaki, Kikuchi H, Shigeto H, Ohyagi Y, Kira J, Thymoma-associated progressive encephalomyelitis with rigidity and myoclonus successfully treated with thymectomy and intravenous immunoglobulin., Eur Neurol., 2011.11. |
| 367. |
Pineda AA, Minohara M, Kawamura N, Matsushita T, Ryo Yamasaki, Sun X, Piao H, Shimokara H, Kira J, Preventive and therapeutic effects of the selective Rho-kinase inhibitor fasudil on experimental autoimmune neuritis., J Neurol Sci., 2011.07. |
| 368. |
Arnold Angelo M. Pineda, Motozumi Minohara, Nobutoshi Kawamura, Takuya Matsushita, Ryo Yamasaki, Xiaojia Sun, Hua Piao, Hiroaki Shimokawa, Jun Ichi Kira, Preventive and therapeutic effects of the selective Rho-kinase inhibitor fasudil on experimental autoimmune neuritis, Journal of the Neurological Sciences, 10.1016/j.jns.2011.03.031, 306, 1-2, 115-120, 2011.07, We studied the effects of fasudil, a selective Rho-kinase inhibitor, on experimental autoimmune neuritis (EAN). Continuous parenteral administration of fasudil prevented the development of EAN induced by P0 peptide 180-199 in Lewis rats while it also reduced EAN severity when administered after disease onset. Immunohistochemical examination disclosed a marked decrease in the amount of inflammatory cell infiltration and attenuation of demyelination and axonal degeneration. Specific proliferation of lymphocytes from fasudil-treated rats in response to P0 peptide was significantly reduced as compared with those from phosphate-buffered saline (PBS)-treated rats. Fasudil treatment was associated with a significant reduction in secretion of IFN-γ; by contrast, secretion of IL-4 was almost the same in the fasudil- and PBS-treated groups. As a result, the IFN-γ/IL-4 ratio in the supernatant was significantly deceased in fasudil-treated rats compared with PBS-treated ones. Therefore, our results indicate a beneficial effect of selective blockade of Rho-kinase in animals with autoimmune inflammation of the peripheral nerves, and may provide a rationale for the selective blockade of Rho-kinase as a new therapy for Guillain-Barré syndrome.. |
| 369. |
Arnold Angelo M Pineda, Motozumi Minohara, Nobutoshi Kawamura, Takuya Matsushita, Ryo Yamasaki, Xiaojia Sun, Hua Piao, Hiroaki Shimokawa, Jun-ichi Kira, Preventive and therapeutic effects of the selective Rho-kinase inhibitor fasudil on experimental autoimmune neuritis., Journal of the neurological sciences, 10.1016/j.jns.2011.03.031, 306, 1-2, 115-20, 2011.07, We studied the effects of fasudil, a selective Rho-kinase inhibitor, on experimental autoimmune neuritis (EAN). Continuous parenteral administration of fasudil prevented the development of EAN induced by P0 peptide 180-199 in Lewis rats while it also reduced EAN severity when administered after disease onset. Immunohistochemical examination disclosed a marked decrease in the amount of inflammatory cell infiltration and attenuation of demyelination and axonal degeneration. Specific proliferation of lymphocytes from fasudil-treated rats in response to P0 peptide was significantly reduced as compared with those from phosphate-buffered saline (PBS)-treated rats. Fasudil treatment was associated with a significant reduction in secretion of IFN-γ; by contrast, secretion of IL-4 was almost the same in the fasudil- and PBS-treated groups. As a result, the IFN-γ/IL-4 ratio in the supernatant was significantly deceased in fasudil-treated rats compared with PBS-treated ones. Therefore, our results indicate a beneficial effect of selective blockade of Rho-kinase in animals with autoimmune inflammation of the peripheral nerves, and may provide a rationale for the selective blockade of Rho-kinase as a new therapy for Guillain-Barré syndrome.. |
| 370. |
Ma L, Ohyagi Y, Nakamura N, Iinuma KM, Miyoshi K, Himeno E, Soejima N, Yanagihara YT, Sakae N, Ryo Yamasaki, Kira J, Activation of glutathione peroxidase and inhibition of p53-related apoptosis by apomorphine., J Alzheimers Dis, 2011.06. |
| 371. |
Meiko Inaba, Takako Torii, Koji Shinoda, Ryo Yamasaki, Yasumasa Ohyagi, Jun-Ichi Kira, Peripheral neuropathy, myelopathy, cerebellar ataxia, and subclinical optic neuropathy associated with copper deficiency occurring 23 years after total gastrectomy, Clinical Neurology, 10.5692/clinicalneurol.51.412, 51, 6, 412-416, 2011.06, We report a 61-year-old man with slowly progressive gait disturbance and paresthesia in the lower extremities following a total gastrectomy for gastric cancer 23 years previously. The patient presented with hyperreflexia, peripheral sensory neuropathy, and cerebellar ataxia. Magnetic resonance imaging showed atrophy of the cerebellum, and electrophysiological findings suggested the presence of disorder in both sides of the pyramidal tract, dorsal column, peripheral nerves, and optic nerve. Laboratory findings revealed anemia, neutropenia, and a remarkably low serum copper level (10 μg/dl; normal: 68-128). His serum vitamin E was slightly low and his serum vitamin B 12 was within the normal limits. After administering an oral copper supplement, his symptoms improved with normalization of the serum copper level. We need to pay attention to myeloneuropathy caused by copper deficiency if the patient has a past history of total gastrectomy.. |
| 372. |
Hagiwara K, Tominaga K, Okada Y, Kido M, Ryo Yamasaki, Shida N, Yamashita Y, Post-streptococcal chorea in an adult with bilateral striatal encephalitis., J Clin Neurosci., 2011.05. |
| 373. |
Koichi Hagiwara, Kayo Tominaga, Yoko Okada, Miwako Kido, Ryo Yamasaki, Norihiko Shida, Yoriaki Yamashita, Post-streptococcal chorea in an adult with bilateral striatal encephalitis, Journal of Clinical Neuroscience, 10.1016/j.jocn.2010.08.024, 18, 5, 708-709, 2011.05, We present distinctive MRI findings in an adult female patient with possible Sydenham's chorea. T2-weighted MRI showed bilaterally symmetric, diffusely homogenous, and clearly demarcated hyperintensities selectively involving the entire striatum with swelling of the bilateral caudate heads. The MRI features may reflect the pathogenetic mechanisms of Sydenham's chorea associated with a specific autoimmune response to the basal ganglia.. |
| 374. |
Koichi Hagiwara, Kayo Tominaga, Yoko Okada, Miwako Kido, Ryo Yamasaki, Norihiko Shida, Yoriaki Yamashita, Post-streptococcal chorea in an adult with bilateral striatal encephalitis., Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 10.1016/j.jocn.2010.08.024, 18, 5, 708-9, 2011.05, We present distinctive MRI findings in an adult female patient with possible Sydenham's chorea. T2-weighted MRI showed bilaterally symmetric, diffusely homogenous, and clearly demarcated hyperintensities selectively involving the entire striatum with swelling of the bilateral caudate heads. The MRI features may reflect the pathogenetic mechanisms of Sydenham's chorea associated with a specific autoimmune response to the basal ganglia.. |
| 375. |
Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N, Motomura K, Soejima N, Ryo Yamasaki, Hashimoto T, Tabira T, LaFeria FM, Kira J, Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation., Ann Neurol., 2011.02. |
| 376. |
Eri Himeno, Yasumasa Ohyagi, Linqing Ma, Norimichi Nakamura, Katsue Miyoshi, Nobutaka Sakae, Kyoko Motomura, Naoko Soejima, Ryo Yamasaki, Tetsuya Hashimoto, Takeshi Tabira, Frank M. Laferla, Jun Ichi Kira, Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation, Annals of Neurology, 10.1002/ana.22319, 69, 2, 248-256, 2011.02, Objective: Intracellular amyloid β-protein (Aβ) contributes to neurodegeneration in Alzheimer disease (AD). Apomorphine (APO) is a dopamine receptor agonist for Parkinson disease and also protects against oxidative stress. Efficacy of APO for an AD mouse model and effects of APO on cell cultures are studied. Methods: The triple transgenic AD mouse model (3xTg-AD) has 2 familial AD-related gene mutations (APPKM670/671NL/PS1 M146V) and a tau gene mutation (TauP301L). Six-month-old 3xTg-AD mice were treated with subcutaneous injections of APO once a week for 1 month. Memory function was evaluated by Morris water maze before and after the treatment. Brain tissues were examined by immunohistochemical staining and Western blotting. Effects of APO on intracellular Aβ degradation, activity of Aβ-degrading enzymes, and protection against oxidative stress were studied in cultured SH-SY5Y cells. Results: After APO treatment, short-term memory function was dramatically improved. Significant decreases in the levels of intraneuronal Aβ, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 proteins were observed. Moreover, APO promoted degradation of intracellular Aβ, increased activity of proteasome and insulin-degrading enzyme, protected against H2O2 toxicity, and decreased p53 protein levels in the cultured cells. Interpretation: 3xTg-AD mice show intraneuronal Aβ accumulation and memory disturbances before extracellular Aβ deposition. Our data demonstrating improvement of memory function of 3xTg-AD mice with decreases in intraneuronal Aβ and p-tau levels by APO treatment strongly suggest that intraneuronal Aβ is an important therapeutic target and APO will be a novel drug for AD.. |
| 377. |
Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N, Motomura K, Soejima N, Yamasaki R, Hashimoto T, Tabira T, LaFerla FM, Kira J, Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation., Annals of neurology, 10.1002/ana.22319, 69, 2, 248-56, 2011.02. |
| 378. |
Ryo Yamasaki, Piao H, Minohara M, Kawamura N, Li W, Matsushita T, Mizunoe Y, Kira J, Tissue binding patterns and in vitro effects of Campylobacter jejuni DNA-binding protein from starved cells., Neurochem Res, 2011.01. |
| 379. |
Linqing Ma, Yasumasa Ohyagi, Norimichi Nakamura, Kyoko M. Iinuma, Katsue Miyoshi, Eri Himeno, Naoko Soejima, Yuki T. Yanagihara, Nobutaka Sakae, Ryo Yamasaki, Jun-Ichi Kira, Activation of glutathione peroxidase and inhibition of p53-related apoptosis by apomorphine, Journal of Alzheimer's Disease, 10.3233/JAD-2011-110140, 27, 1, 225-237, 2011.01, Apomorphine hydrochloride (APO) is known to be a dopamine receptor agonist, and has recently been found to be a novel drug for Alzheimer's disease (AD). We found that APO treatment ameliorated oxidative stress in an AD mouse model and specifically attenuated the hydrogen peroxide-induced p53-related apoptosis in the SH-SY5Y neuroblastoma cell line. To further understand the mechanism behind this action, we investigated the actions of APO on intracellular redox systems, such as the glutathione cycle and catalase. We studied the effects of specific inhibitors for glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (BCNU, MCS, and ATZ, respectively) on the effects of APO. Treatments with MCS or BCNU, but not ATZ, significantly attenuated the protective effects of APO. Interestingly, APO treatment elevated GPx activity, but did not increase the expression of the GPx1 protein. Although BCNU treatment attenuated APO effects, GR activity was not elevated by APO treatment. The same effects were observed in primary neuronal cultures. In addition, treatment with dopamine D1, D2, D3 and D4 receptor antagonists did not counteract the protective action of APO. Thus, APO may enhance GPx activity through dopamine receptor-independent pathways.. |
| 380. |
Hua Piao, Motozumi Minohara, Nobutoshi Kawamura, Wei Li, Takuya Matsushita, Ryo Yamasaki, Yoshimitsu Mizunoe, Jun Ichi Kira, Tissue binding patterns and in vitro effects of campylobacter jejuni DNA-binding protein from starved cells, Neurochemical Research, 10.1007/s11064-010-0263-7, 36, 1, 58-66, 2011.01, Campylobacter jejuni (C. jejuni) is frequently associated with axonal Guillain-Barré syndrome (GBS). We reported that C. jejuni DNA-binding protein from starved cells (C-Dps) binds to and damages myelinated nerves in vivo. We studied the binding patterns of C-Dps to nervous tissues and its in vitro effects on neural cells. Immunohistochemically, C-Dps labeled the nodes of Ranvier, the outermost parts of internodal myelin and the basement membrane in the peripheral nerves, and neurons and myelin in the central nervous tissues. Its binding was blocked by sulfatide. C-Dps bound to the cell surfaces of nerve growth factor (NGF)-treated PC12 cells leading to dose-dependent LDH release, which was inhibited by either heat-denaturation of C-Dps or coincubation with an anti-C-Dps mAb. However, its binding to the surfaces of cultured NSC34 cells, S16 cells, or dorsal root ganglion cells, did not induce cytotoxicity. These findings suggest a possible involvement of C-Dps in C. jejuni-related GBS.. |
| 381. |
Hua Piao, Motozumi Minohara, Nobutoshi Kawamura, Wei Li, Takuya Matsushita, Ryo Yamasaki, Yoshimitsu Mizunoe, Jun-Ichi Kira, Tissue binding patterns and in vitro effects of Campylobacter jejuni DNA-binding protein from starved cells., Neurochemical research, 10.1007/s11064-010-0263-7, 36, 1, 58-66, 2011.01, Campylobacter jejuni (C. jejuni) is frequently associated with axonal Guillain-Barré syndrome (GBS). We reported that C. jejuni DNA-binding protein from starved cells (C-Dps) binds to and damages myelinated nerves in vivo. We studied the binding patterns of C-Dps to nervous tissues and its in vitro effects on neural cells. Immunohistochemically, C-Dps labeled the nodes of Ranvier, the outermost parts of internodal myelin and the basement membrane in the peripheral nerves, and neurons and myelin in the central nervous tissues. Its binding was blocked by sulfatide. C-Dps bound to the cell surfaces of nerve growth factor (NGF)-treated PC12 cells leading to dose-dependent LDH release, which was inhibited by either heat-denaturation of C-Dps or coincubation with an anti-C-Dps mAb. However, its binding to the surfaces of cultured NSC34 cells, S16 cells, or dorsal root ganglion cells, did not induce cytotoxicity. These findings suggest a possible involvement of C-Dps in C. jejuni-related GBS.. |
| 382. |
Ryo Yamasaki, Tanaka M, Fukunaga M, Tateishi T, Kikuchi H, Motomura K, Matsushita T, Ohyagi Y, Kira J, Restoration of microglial function by granulocyte-colony stimulating factor in ALS model mice., J Neuroimmunol. , 2010.12. |
| 383. |
Ryo Yamasaki, Masahito Tanaka, Mami Fukunaga, Takahisa Tateishi, Hitoshi Kikuchi, Kyoko Motomura, Takuya Matsushita, Yasumasa Ohyagi, Jun ichi Kira, Restoration of microglial function by granulocyte-colony stimulating factor in ALS model mice, Journal of Neuroimmunology, 10.1016/j.jneuroim.2010.07.002, 229, 1-2, 51-62, 2010.12, We studied the effects of G-CSF on microglial reactions in mutant SOD1 (mSOD1)-Tg (G93A) ALS model mice. Following hypoglossal axotomy, the numbers of neurons and microglia expressing GDNF were significantly lower in mSOD1-Tg mice than in non-transgenic (NTG) littermates. This decrease in the number of neurons after axotomy and a decrease in the number of large myelinated axons in mSOD1-Tg mice over the disease course were improved by G-CSF, which also increased microglial recruitment. Impaired migration of cultured mSOD1-Tg microglia to MCP-1 was recovered following G-CSF treatment. Restoration of microglial responses by G-CSF may contribute to its neuroprotective effects.. |
| 384. |
Ryo Yamasaki, Masahito Tanaka, Mami Fukunaga, Takahisa Tateishi, Hitoshi Kikuchi, Kyoko Motomura, Takuya Matsushita, Yasumasa Ohyagi, Jun-ichi Kira, Restoration of microglial function by granulocyte-colony stimulating factor in ALS model mice., Journal of neuroimmunology, 10.1016/j.jneuroim.2010.07.002, 229, 1-2, 51-62, 2010.12, We studied the effects of G-CSF on microglial reactions in mutant SOD1 (mSOD1)-Tg (G93A) ALS model mice. Following hypoglossal axotomy, the numbers of neurons and microglia expressing GDNF were significantly lower in mSOD1-Tg mice than in non-transgenic (NTG) littermates. This decrease in the number of neurons after axotomy and a decrease in the number of large myelinated axons in mSOD1-Tg mice over the disease course were improved by G-CSF, which also increased microglial recruitment. Impaired migration of cultured mSOD1-Tg microglia to MCP-1 was recovered following G-CSF treatment. Restoration of microglial responses by G-CSF may contribute to its neuroprotective effects.. |
| 385. |
Maki Ueda, Takahisa Tateishi, Hiroshi Shigeto, Ryo Yamasaki, Yasumasa Ohyagi, Jun Ichi Kira, A case of acute disseminated encephalomyelitis associated with Epstein-Barr virus reactivation during infliximab therapy, Clinical Neurology, 10.5692/clinicalneurol.50.461, 50, 7, 461-466, 2010.07, A 31-year-old woman with Crohn's disease that had been refractory to drug therapies for 7 years had been treated with infliximab for a year. She was admitted to our hospital because of truncal ataxia and bulbar palsy, which presented following aseptic meningitis. Neurological examination revealed abducens paresis on the left, gaze-evoked nystagmus on upward and rightward gaze, right facial muscle weakness, bulbar palsy, weakness in the right upper extremity, limb ataxia predominantly on the left side, diminished sense in the lower extremities predominantly on the right, diffuse hyperreflexia in all extremities. Antibodies to Epstein-Barr virus (EBV) in serum demonstrated a previous infection pattern, and EBV-DNA was detected in peripheral blood and cerebrospinal fluid (CSF) by PCR. CSF analysis indicated pleocytosis, an elevation of IgG index and a marked increase in the level of myelin basic protein. FLAIR MRI images revealed multiple hyperintense lesions in the brainstem, subcortical white matter, and cervical spinal cord. Accordingly, we diagnosed her as having acute disseminated encephalomyelitis (ADEM), associated with reactivated EBV infection. Although gancyclovir, plasma exchange and intravenous high dose immunoglobulins were not effective, repetitive use of methylprednisolone pulse therapy alleviated her symptoms and the abnormal MRI lesions. It is suggested that the reactivated EBV infection caused by infliximab may have contributed to the development of ADEM in this case. Besides the demyelinating event directly induced by anti-TNF-α therapy, we should pay attention to the occurrence of reactivated EBV-triggered ADEM during anti-TNF-α therapy.. |
| 386. |
Tateishi T, Ryo Yamasaki, Tanaka M, Matsushita T, Kikuchi H, Isobe N, Ohyagi Y, Kira J, CSF chemokine alterations related to the clinical course of amyotrophic lateral sclerosis., J Neuroimmunol., 2010.05. |
| 387. |
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.. |
| 388. |
Hikaru Doi, Takahisa Tateishi, Noriko Isobe, Ryo Yamasaki, Yasumasa Ohyagi, Jun Ichi Kira, Sporadic hemiplegic migraine-like headache in a patient with systemic lupus erythematosus, Clinical Neurology, 10.5692/clinicalneurol.50.332, 50, 5, 332-334, 2010.05, A 39-year old women suddenly developed numbness of the left arm following mild weakness of the left upper and lower extremities, blindness in the left visual field, and difficulty finding words. Her symptoms lasted for two hours with no deficit remaining. Six months after the first episode, the first of several more occurred. Two of the episodes were followed by nausea and a non-pulsative headache around the left temporo-parietal regions and the orbit. She had also been suffering recurrent skin eruptions for the previous two years. There was no family history of migraine. Her neurological symptoms fulfilled the criteria of sporadic hemiplegic migraine (SHM). Biopsy of skin eruption revealed lymphocytic infiltration and liquefied degeneration of basal lamina. These findings were compatible with systemic lupus erythematosus (SLE). There were no lesions evident on brain MR. We diagnosed SLE and after administration of aspirin (100 mg/day) and lomerizine hydrochloride (10 mg/day), her neurological symptom completely disappeared. SHM-like headache in patients with SLE is extremely rare. Although an autoimmune or thrombotic mechanism has been suggested for neurological symptoms in SLE, further studies are needed to elucidate the mechanism. We propose that SLE should be considered as one of the differential diagnoses of SHM.. |
| 389. |
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.. |
| 390. |
Matsushita T, Isobe N, Piao H, Matsuoka T, Ishizu T, Doi H, Masaki K, Yoshiura T, Ryo Yamasaki, Ohyagi Y, Kira J, Reappraisal of brain MRI features in patients with multiple sclerosis and neuromyelitis optica according to anti-aquaporin-4 antibody status., J Neurol Sci., 2010.04. |
| 391. |
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 (Pcorr = 0.017) and higher frequency of anti-AQP4 antibody (Pcorr |
| 392. |
Ken Ichi Shibata, Takahisa Tateishi, Ryo Yamasaki, Yasumasa Ohyagi, Jun Ichi Kira, Successful treatment of a case of steroid-dependent neuro-Sweet disease with dapsone, Clinical Neurology, 10.5692/clinicalneurol.50.257, 50, 4, 257-261, 2010.04, A 35-year-old Japanese man was admitted to our hospital with recurrent meningoencephalitis of unknown etiology. He presented with fever, convulsions and loss of consciousness, which started at age 33. We diagnosed him with neuro-Sweet disease (NSD) based on human leukocyte antigen (HLA) B-54/Cwl positivity and neutrophilic infiltration into the dermis in a biopsied skin plaque. Intravenous methylprednisolone and oral prednisolone markedly improved his fever and CSF pleocytosis. Five years later he was again admitted to our hospital with high fever, oral aphthae and dull-red edematous plaques on the face and body. He was conscious, but he had neck stiffness, mild hyperreflexia in all limbs and an extensor plantar response. Laboratory tests revealed increased white blood cell, erythrocyte sedimentation rate (ESR) and C-reactive protein level. CSF analysis indicated mild pleocytosis. A skin biopsy from an edematous plaque revealed neurotrophils infiltlating the upper dermis. We treated him with intravenous methylprednisolone (1 g/day) for 3 days, followed by oral prednisolone (50 mg/day). His symptoms improved remarkably; however, he had recurrence of symptoms, such as fever, meningial irritation and oral aphtae, with attempted taper of prednisolone. We started treatment with dapsone (75 mg/day) in addition to prednisolone, and could taper oral prednisolone, without a relapse. However, because some mildly recurred with the tapering of dapson, we maintained dapsone treatment at 75 mg daily, added colchicine (1 mg/day) and tapered only prednisolone. His symptoms were improved and no relapse has been observed. NSD is characterized by neurotrophic hyperactivation and infiltration of tissues. It is highly responsive to systemic corticosteroid therapy; however, some cases show frequent recurrences on tapering of corticosteroids. Dapsone is considered to prevent neurotrophic overactivity. In this case, dapsone was supposed to be effective to prevent reccurence of NSD upon tappering corticosteroids. Dapsone should be a therapeutic options for steroiddependent NSD showing frequent recurrence.. |
| 393. |
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) |
| 394. |
Tateishi T, Hokonohara T, Ryo Yamasaki, Miura S, Kikuchi H, Iwaki A, Tashiro H, Furuya H, Nagara Y, Ohyagi Y, Nukina N, Iwaki T, Fukumaki Y, Kira J, Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation., Acta Neuropathol., 2010.03. |
| 395. |
Takahisa Tateishi, Toshihiro Hokonohara, Ryo Yamasaki, Shiro Miura, Hitoshi Kikuchi, Akiko Iwaki, Hiroshi Tashiro, Hirokazu Furuya, Yuko Nagara, Yasumasa Ohyagi, Nobuyuki Nukina, Toru Iwaki, Yasuyuki Fukumaki, Jun Ichi Kira, Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation, Acta neuropathologica, 10.1007/s00401-009-0621-1, 119, 3, 355-364, 2010.03, Mutations in the fused in sarcoma gene (FUS) were recently found in patients with familial amyotrophic lateral sclerosis (ALS). The present study aimed to clarify unique features of familial ALS caused by FUS mutation in the Japanese population. We carried out clinical, neuropathological, and genetic studies on a large Japanese pedigree with familial ALS. In six successive generations of this family, 16 individuals of both sexes were affected by progressive muscle atrophy and weakness, indicating an autosomal dominant trait. Neurological examination of six patients revealed an age at onset of 48.2 ± 8.1 years in fourth generation patients, while it was 31 and 20 years in fifth and sixth generation patients, respectively. Motor paralysis progressed rapidly in these patients, culminating in respiratory failure within 1 year. The missense mutation c.1561 C>T (p.R521C) was found in exon 15 of FUS in the four patients examined. Neuropathological study of one autopsied case with the FUS mutation revealed multiple system degeneration in addition to upper and lower motor neuron involvement: the globus pallidus, thalamus, substantia nigra, cerebellum, inferior olivary nucleus, solitary nucleus, intermediolateral horn, Clarke's column, Onuf's nucleus, central tegmental tract, medial lemniscus, medial longitudinal fasciculus, superior cerebellar peduncle, posterior column, and spinocerebellar tract were all degenerated. Argyrophilic and basophilic neuronal or glial cytoplasmic inclusions immunoreactive for FUS, GRP78/BiP, p62, and ubiquitin were detected in affected lesions. The FUS R521C mutation in this Japanese family caused familial ALS with pathological features of multiple system degeneration and neuronal basophilic inclusions.. |
| 396. |
Tomo Iwashima, Takahisa Tateishi, Ryo Yamasaki, Kyoko Motomura, Yasumasa Ohyagi, Jun Ichi Kira, Two cases of familial amyotrophic lateral sclerosis with a SODI L126S mutation showing high age at onset and slow progression, Clinical Neurology, 10.5692/clinicalneurol.50.163, 50, 3, 163-167, 2010.03, An 80-year-old man (patient 1) was admitted to our hospital with numbness of the right leg and weakness of the lower extremities, predominantly in the right leg, for 1 year previously. Neurological examination revealed moderate weakness without atrophy, and fasciculation in the bilateral lower extremities. No hyperreflexia was noted, and the plantar response was flexor. Neither bulbar palsy nor sensory disturbance was observed. Electromyography (EMG) showed a chronic neurogenic pattern, including giant motor unit potentials and reduced interference in all four limb muscles. MRI images of the cervical and lumbar spines showed severe age-related spondylosis. The clinical and laboratory findings led to a diagnosis of spinal progressive muscular atrophy. Motor paralysis progressed slowly for the following four years, culminating in respiratory failure. A 79-year-man, the younger brother of patient 1 (patient 2), suffered from gait disturbance for 3 years before the admission to our hospital. During the following 3 years, bilateral leg weakness developed, causing difficulty walking. Neurological examination revealed a diffuse mild weakness with atrophy and fasciculation in the bilateral lower extremities; the right deltoid muscle was also mildly weak. Mild hyperreflexia was also noted on the left side, and the plantar response was extensor on the left. EMG showed acute and chronic neurogenic patterns in the four limb muscles. Because the missense mutation c.377 T >C; p.L126S was found on exon 5 of the superoxide dismutase (SOD) 1 gene in this patient, a diagnosis of familial ALS was made. Eight patients reported as familial ALS with the SOD1L126S mutation, including the present cases, all developed an onset of weakness in the lower extremities, but showed few upper motor neuron signs. It is important to consider the possibility of this type of familial ALS in a case of spinal progressive muscular atrophy with late-onset and mild progression, if family history is positive.. |
| 397. |
Takahisa Tateishi, Toshihiro Hokonohara, Ryo Yamasaki, Shiro Miura, Hitoshi Kikuchi, Akiko Iwaki, Hiroshi Tashiro, Hirokazu Furuya, Yuko Nagara, Yasumasa Ohyagi, Nobuyuki Nukina, Toru Iwaki, Yasuyuki Fukumaki, Jun-ichi Kira, Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation., Acta neuropathologica, 10.1007/s00401-009-0621-1, 119, 3, 355-64, 2010.03, Mutations in the fused in sarcoma gene (FUS) were recently found in patients with familial amyotrophic lateral sclerosis (ALS). The present study aimed to clarify unique features of familial ALS caused by FUS mutation in the Japanese population. We carried out clinical, neuropathological, and genetic studies on a large Japanese pedigree with familial ALS. In six successive generations of this family, 16 individuals of both sexes were affected by progressive muscle atrophy and weakness, indicating an autosomal dominant trait. Neurological examination of six patients revealed an age at onset of 48.2+/-8.1 years in fourth generation patients, while it was 31 and 20 years in fifth and sixth generation patients, respectively. Motor paralysis progressed rapidly in these patients, culminating in respiratory failure within 1 year. The missense mutation c.1561 C>T (p.R521C) was found in exon 15 of FUS in the four patients examined. Neuropathological study of one autopsied case with the FUS mutation revealed multiple system degeneration in addition to upper and lower motor neuron involvement: the globus pallidus, thalamus, substantia nigra, cerebellum, inferior olivary nucleus, solitary nucleus, intermediolateral horn, Clarke's column, Onuf's nucleus, central tegmental tract, medial lemniscus, medial longitudinal fasciculus, superior cerebellar peduncle, posterior column, and spinocerebellar tract were all degenerated. Argyrophilic and basophilic neuronal or glial cytoplasmic inclusions immunoreactive for FUS, GRP78/BiP, p62, and ubiquitin were detected in affected lesions. The FUS R521C mutation in this Japanese family caused familial ALS with pathological features of multiple system degeneration and neuronal basophilic inclusions.. |
| 398. |
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-DRB1*09 (adjusted odds ratio (OR) = 0.243, 95% confidence interval (CI) 0.099-0.533) and HLA-DRB1*01 (adjusted OR = 0.327, 95% CI 0.103-0.873) decreased the incidence of anti-AQP4 antibody-negative MS. By contrast, HLA-DRB1*12 increased the risk of anti-AQP4 antibody-positive MS (adjusted OR = 3.691, 95% CI 1.233-10.565). Individuals with HLA-DRB1*09/15 decreased the risk of anti-AQP4 antibody-negative MS (adjusted OR = 0.164, 95% CI 0.026-0.593), while those with HLA-DRB1*12/15 increased the risk of anti-AQP4 antibody-positive MS (adjusted OR = 10.870, 95% CI 2.004-81.752). Conclusions: The ability of HLA-DRB1*09 to reduce the risk of anti-AQP4 antibody-negative MS may arise from an interaction with HLA-DRB1*15. By contrast, HLA-DRB1*12 increases susceptibility to anti-AQP4 antibody-positive MS, possibly via an interaction with HLA-DRB1*15.. |
| 399. |
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-DRB1*09 (adjusted odds ratio (OR) = 0.243, 95% confidence interval (CI) 0.099-0.533) and HLA-DRB1*01 (adjusted OR = 0.327, 95% CI 0.103-0.873) decreased the incidence of anti-AQP4 antibody-negative MS. By contrast, HLA-DRB1*12 increased the risk of anti-AQP4 antibody-positive MS (adjusted OR = 3.691, 95% CI 1.233-10.565). Individuals with HLA-DRB1*09/15 decreased the risk of anti-AQP4 antibody-negative MS (adjusted OR = 0.164, 95% CI 0.026-0.593), while those with HLA-DRB1*12/15 increased the risk of anti-AQP4 antibody-positive MS (adjusted OR = 10.870, 95% CI 2.004-81.752).
Conclusions: The ability of HLA-DRB1*09 to reduce the risk of anti-AQP4 antibody-negative MS may arise from an interaction with HLA-DRB1*15. By contrast, HLA-DRB1*12 increases susceptibility to anti-AQP4 antibody-positive MS, possibly via an interaction with HLA-DRB1*15.. |
| 400. |
N. Isobe, T. Matsushita, R. Yamasaki, S. V. Ramagopalan, Y. Kawano, Y. Nishimura, G. C. Ebers, J. Kira, The influence of HLA-DRB1 alleles on the susceptibility and resistance to multiple sclerosis with respect to the criteria of neuromyelitis optica, MULTIPLE SCLEROSIS, 16, 2, 270-270, 2010.02. |
| 401. |
Piao H, Minohara M, Kawamura N, Li W, Mizunoe Y, Umehara F, Goto Y, Kusunoki S, Matsushita T, Ikenaka K, Maejima T, Nabekura J, Ryo Yamasaki, Kira J, Induction of paranodal myelin detachment and sodium channel loss in vivo by Campylobacter jejuni DNA-binding protein from starved cells (C-Dps) in myelinated nerve fibers., J Neurol Sci., 2010.01. |
| 402. |
Hua Piao, Motozumi Minohara, Nobutoshi Kawamura, Wei Li, Yoshimitsu Mizunoe, Fujio Umehara, Yoshinobu Goto, Susumu Kusunoki, Takuya Matsushita, Kazuhiro Ikenaka, Takashi Maejima, Jun ichi Nabekura, Ryo Yamasaki, Jun ichi Kira, Induction of paranodal myelin detachment and sodium channel loss in vivo by Campylobacter jejuni DNA-binding protein from starved cells (C-Dps) in myelinated nerve fibers, Journal of the Neurological Sciences, 10.1016/j.jns.2009.10.007, 288, 1-2, 54-62, 2010.01, In an axonal variant of Guillain-Barré syndrome (GBS) associated with Campylobacter jejuni (C. jejuni) enteritis, the mechanism underlying axonal damage is obscure. We purified and characterized a DNA-binding protein from starved cells derived from C. jejuni (C-Dps). This C-Dps protein has significant homology with Helicobacter pylori neutrophil-activating protein (HP-NAP), which is chemotactic for human neutrophils through binding to sulfatide. Because sulfatide is essential for paranodal junction formation and for the maintenance of ion channels on myelinated axons, we examined the in vivo effects of C-Dps. First, we found that C-Dps specifically binds to sulfatide by ELISA and immunostaining of thin-layer chromatograms loaded with various glycolipids. Double immunostaining of peripheral nerves exposed to C-Dps with anti-sulfatide antibody and anti-C-Dps antibody revealed co-localization of them. When C-Dps was injected into rat sciatic nerves, it densely bound to the outermost parts of the myelin sheath and nodes of Ranvier. Injection of C-Dps rapidly induced paranodal myelin detachment and axonal degeneration; this was not seen following injection of PBS or heat-denatured C-Dps. Electron microscopically, C-Dps-injected nerves showed vesiculation of the myelin sheath at the nodes of Ranvier. Nerve conduction studies disclosed a significant reduction in compound muscle action potential amplitudes in C-Dps-injected nerves compared with pre-injection values, but not in PBS-, heat-denatured C-Dps-, or BSA-injected nerves. However, C-Dps did not directly affect Na+ currents in dissociated hippocampal neurons. Finally, when C-Dps was intrathecally infused into rats, it was deposited in a scattered pattern in the cauda equina, especially in the outer part of the myelin sheath and the nodal region. In C-Dps-infused rats, but not in BSA-infused ones, a decrease in the number of sodium channels, vesiculation of the myelin sheath, axonal degeneration and infiltration of Iba-1-positive macrophages were observed. Thus, we consider that C-Dps damages myelinated nerve fibers, possibly through interference with paranodal sulfatide function, and may contribute to the axonal pathology seen in C. jejuni-related GBS.. |
| 403. |
Hua Piao, Motozumi Minohara, Nobutoshi Kawamura, Wei Li, Yoshimitsu Mizunoe, Fujio Umehara, Yoshinobu Goto, Susumu Kusunoki, Takuya Matsushita, Kazuhiro Ikenaka, Takashi Maejima, Jun-ichi Nabekura, Ryo Yamasaki, Jun-ichi Kira, Induction of paranodal myelin detachment and sodium channel loss in vivo by Campylobacter jejuni DNA-binding protein from starved cells (C-Dps) in myelinated nerve fibers., Journal of the neurological sciences, 10.1016/j.jns.2009.10.007, 288, 1-2, 54-62, 2010.01, In an axonal variant of Guillain-Barré syndrome (GBS) associated with Campylobacter jejuni (C. jejuni) enteritis, the mechanism underlying axonal damage is obscure. We purified and characterized a DNA-binding protein from starved cells derived from C. jejuni (C-Dps). This C-Dps protein has significant homology with Helicobacter pylori neutrophil-activating protein (HP-NAP), which is chemotactic for human neutrophils through binding to sulfatide. Because sulfatide is essential for paranodal junction formation and for the maintenance of ion channels on myelinated axons, we examined the in vivo effects of C-Dps. First, we found that C-Dps specifically binds to sulfatide by ELISA and immunostaining of thin-layer chromatograms loaded with various glycolipids. Double immunostaining of peripheral nerves exposed to C-Dps with anti-sulfatide antibody and anti-C-Dps antibody revealed co-localization of them. When C-Dps was injected into rat sciatic nerves, it densely bound to the outermost parts of the myelin sheath and nodes of Ranvier. Injection of C-Dps rapidly induced paranodal myelin detachment and axonal degeneration; this was not seen following injection of PBS or heat-denatured C-Dps. Electron microscopically, C-Dps-injected nerves showed vesiculation of the myelin sheath at the nodes of Ranvier. Nerve conduction studies disclosed a significant reduction in compound muscle action potential amplitudes in C-Dps-injected nerves compared with pre-injection values, but not in PBS-, heat-denatured C-Dps-, or BSA-injected nerves. However, C-Dps did not directly affect Na(+) currents in dissociated hippocampal neurons. Finally, when C-Dps was intrathecally infused into rats, it was deposited in a scattered pattern in the cauda equina, especially in the outer part of the myelin sheath and the nodal region. In C-Dps-infused rats, but not in BSA-infused ones, a decrease in the number of sodium channels, vesiculation of the myelin sheath, axonal degeneration and infiltration of Iba-1-positive macrophages were observed. Thus, we consider that C-Dps damages myelinated nerve fibers, possibly through interference with paranodal sulfatide function, and may contribute to the axonal pathology seen in C. jejuni-related GBS.. |
| 404. |
T. Tateishi, R. Yamasaki, M. Tanaka, M. Fukunaga, H. Kikuchi, T. Matsushita, K. Motomura, Y. Ohyagi, J. Kira, Cerebrospinal fluid biomarkers and their dysregulation in amyotrophic lateral sclerosis, JOURNAL OF THE NEUROLOGICAL SCIENCES, 285, S134-S135, 2009.10. |
| 405. |
N. Isobe, T. Matsushita, R. Yamasaki, S. Ramagopalan, Y. Kawano, Y. Nishimura, G. Ebers, J. I. Kira, Epistatic interactions at HLA-DRB1 in Japanese patients with multiple sclerosis, MULTIPLE SCLEROSIS, 15, 9, S184-S184, 2009.09. |
| 406. |
R. Yamasaki, M. Tanaka, T. Tateishi, M. Fukunaga, H. Kikuchi, Y. Oyagi, J. Kira, G-CSF PROTECTS NEURONS THROUGH THE ACTIVATION OF MICROGLIA IN THE MUTANT SOD1 TRANSGENIC ALS MODEL MICE, JOURNAL OF NEUROCHEMISTRY, 110, 111-111, 2009.09. |
| 407. |
Yasushi Miyagi, Takato Morioka, Kimiaki Hashiguchi, Nobuya Murakami, Kazuhiro Samura, Fumiaki Yoshida, Tadahisa Shono, Tomio Sasaki, Ryo Yamasaki, Minako Kawaguchi, Intracerebral hemorrhage during multi-track microrecording of deep brain stimulation surgery
A report of three cases, Neurological Surgery, 37, 6, 559-564, 2009.06, We described three cases with hemorrhagic complication during simultaneous multi-track microelectrode recording (MER) for stereotactic implantation of a subthalamic nucleus electrode. Although preoperative planning with gadolinium-enhanced T1-weighted MR images is recommended to prevent the occurrence of intracerebral hemorrhage, it should be noted that the danger from cerebral vasculatures is still underestimated. Multiple nonspecific white matter hyperintensities and asymptomatic lacunar infarcts may be suspected as potential risk factors, so, it is suggested that the number of MER penetrations should be restricted in such cases.. |
| 408. |
Fumiaki Yoshida, Yasushi Miyagi, Junji Kishimoto, Takato Morioka, Nobuya Murakami, Kimiaki Hashiguchi, Kazuhiro Samura, Nobutaka Sakae, Ryo Yamasaki, Minako Kawaguchi, Tomio Sasaki, Subthalamic nucleus stimulation does not cause deterioration of preexisting hallucinations in Parkinson's disease patients, Stereotactic and Functional Neurosurgery, 10.1159/000195719, 87, 1, 45-49, 2009.02, Background: Among the neuropsychiatric symptoms in Parkinson's disease (PD) patients, hallucination can result from the disease itself or medical treatment. Hallucination associated with subthalamic nucleus stimulation (STN-DBS) has been reported; however, it is still unclear whether PD patients with a history of hallucination are appropriate candidates for STN-DBS or not. Aims: We investigated the effect of STN-DBS on preexisting hallucination associated with advanced PD. Methods: Eighteen STN-DBS patients were investigated retrospectively. The severity of hallucination was assessed by the thought disorder score on the Unified Parkinson's Disease Rating Scale (UPDRS, part 1-item 2) in the patients' interviews; the score 6 months after the initiation of STN-DBS was compared with the highest score throughout the preoperative history and the score 2 weeks before surgery. Results: Hoehn-Yahr stage and motor score (UPDRS part 3) were significantly improved following STN-DBS. Six months after the initiation of STN-DBS, the severity of hallucination, assessed by thought disorder score, did not increase, but rather decreased compared with the preoperative level (p |
| 409. |
Yoshida F, Miyagi Y, Kishimoto J, Morioka T, Murakami N, Hashiguchi K, Samura K, Sakae N, Ryo Yamasaki, Kawaguchi M, Sasaki T, Subthalamic nucleus stimulation does not cause deterioration of preexisting hallucinations in Parkinson's disease patients., Stereotact Funct Neurosurg., 2009.01. |
| 410. |
K. Samura, Y. Miyagi, T. Morioka, N. Murakami, Fumiaki Yoshida, Kimiaki Hashiguchi, N. Sakae, Ryo Yamasaki, M. Kawaguchi, S. Nagata, T. Sasaki, Intractable facial pain in advanced Parkinson's disease alleviated by subthalamic nucleus stimulation, Journal of Neurology, Neurosurgery and Psychiatry, 10.1136/jnnp.2008.149831, 79, 12, 1410-1411, 2008.12. |
| 411. |
K. Samura, Y. Miyagi, T. Morioka, N. Murakami, F. Yoshida, K. Hashiguchi, N. Sakae, R. Yamasaki, M. Kawaguchi, S. Nagata, T. Sasaki, Intractable facial pain in advanced Parkinson's disease alleviated by subthalamic nucleus stimulation, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 10.1136/jnnp.2008.149831, 79, 12, 1410-1411, 2008.12. |
| 412. |
Effect of subthalamic nucleus stimulation on preexisting hallucination of advanced Parkinson's disease. |
| 413. |
Intractable facial pain in advanced Parkinson's disease alleviated by subthalamic stimulation : Case report. |
| 414. |
Ryo Yamasaki, Jian Zhang, Ichiro Koshiishi, Dewi F. Sastradipura Suniarti,
Zhou Wu, Christoph Peters, Michael Schwake, Yasuo Uchiyama, Jun-ichi Kira,
Paul Saftig, Hideo Utsumi, Hiroshi Nakanishi , Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in the cathepsin D-deficient mice. , Molecular and Cellular Neuroscience , 2007.08. |
| 415. |
Ryo Yamasaki, Jian Zhang, Ichiro Koshiishi, Dewi F. Sastradipura Suniarti, Zhou Wu, Christoph Peters, Michael Schwake, Yasuo Uchiyama, Jun ichi Kira, Paul Saftig, Hideo Utsumi, Hiroshi Nakanishi, Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice, Molecular and Cellular Neuroscience, 10.1016/j.mcn.2007.05.002, 35, 4, 573-584, 2007.08, Nitric oxide (NO) and peroxynitrite, which are produced by activated microglia, are responsible for accelerated neurodegeneration in cathepsin D-deficient (CD-/-) mice. To elucidate the mechanisms by which microglia are initially activated in CD-/- mice, we analyzed the possible relationship between lysosomal storage and microglial activation. In CD-/- mice, the microglial NO-generating activity that was closely associated with the induction of inducible NO synthase and the cationic amino acid transporter-2 (CAT-2) coincided well with the lysosomal storage of subunit c of mitochondrial F0F1ATPase and the formation of ceroid/lipofuscin. Furthermore, activated microglia, which are often accumulating subunit c and ceroid/lipofuscin, showed proliferation activity and an activation of p38 mitogen-activated protein (MAP) kinase. In the primary cultured microglia, pepstatin A was found to enhance the generation of NO and superoxide anion radicals. In these pepstatin A-treated microglia, both an increased generation of the intracellular reactive oxygen species (ROS) and an activation of p38 MAP kinase were observed. These results suggest that the ceroid/lipofuscin which form in microglia activate the p38 MAP kinase cascade through the increased intracellular generation of ROS in CD-/- mice. The activated p38 MAP kinase cascade then promotes the expression of iNOS and CAT-2, thereby inducing the overproduction of NO.. |
| 416. |
Ryo Yamasaki, Jian Zhang, Ichiro Koshiishi, Dewi F Sastradipura Suniarti, Zhou Wu, Christoph Peters, Michael Schwake, Yasuo Uchiyama, Jun-Ichi Kira, Paul Saftig, Hideo Utsumi, Hiroshi Nakanishi, Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice., Molecular and cellular neurosciences, 10.1016/j.mcn.2007.05.002, 35, 4, 573-84, 2007.08, Nitric oxide (NO) and peroxynitrite, which are produced by activated microglia, are responsible for accelerated neurodegeneration in cathepsin D-deficient (CD-/-) mice. To elucidate the mechanisms by which microglia are initially activated in CD-/- mice, we analyzed the possible relationship between lysosomal storage and microglial activation. In CD-/- mice, the microglial NO-generating activity that was closely associated with the induction of inducible NO synthase and the cationic amino acid transporter-2 (CAT-2) coincided well with the lysosomal storage of subunit c of mitochondrial F0F1ATPase and the formation of ceroid/lipofuscin. Furthermore, activated microglia, which are often accumulating subunit c and ceroid/lipofuscin, showed proliferation activity and an activation of p38 mitogen-activated protein (MAP) kinase. In the primary cultured microglia, pepstatin A was found to enhance the generation of NO and superoxide anion radicals. In these pepstatin A-treated microglia, both an increased generation of the intracellular reactive oxygen species (ROS) and an activation of p38 MAP kinase were observed. These results suggest that the ceroid/lipofuscin which form in microglia activate the p38 MAP kinase cascade through the increased intracellular generation of ROS in CD-/- mice. The activated p38 MAP kinase cascade then promotes the expression of iNOS and CAT-2, thereby inducing the overproduction of NO.. |
| 417. |
Shimizu T, Hayashi Y, Ryo Yamasaki, Yamada J, Zhang J, Ukai K, Koike M, Mine K, von Figura K, Peters C, Saftig P, Fukuda T, Uchiyama Y, Nakanishi H, Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D-deficient mice., J Neurochem. , 2005.08. |
| 418. |
Tokiko Shimizu, Yoshinori Hayashi, Ryo Yamasaki, Jun Yamada, Jian Zhang, Kiyoharu Ukai, Masato Koike, Kazunori Mine, Kurt Von Figura, Christoph Peters, Paul Saftig, Takaichi Fukuda, Yasuo Uchiyama, Hiroshi Nakanishi, Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D-deficient mice, Journal of Neurochemistry, 10.1111/j.1471-4159.2005.03250.x, 94, 3, 680-690, 2005.08, Although of clinical importance, little is known about the mechanism of seizure in neuronal ceroid lipofuscinosis (NCL). In the present study, we have attempted to elucidate the mechanism underlying the seizure of cathepsin D-deficient (CD-/-) mice that show a novel type of lysosomal storage disease with a phenotype resembling late infantile NCL. In hippocampal slices prepared from CD-/- mice at post-natal day (P)24, spontaneous burst discharges were recorded from CA3 pyramidal cells. At P24, the mean amplitude of IPSPs after stimulation of the mossy fibres was significantly smaller than that of wild-type mice, which was substantiated by the decreased level of γ-aminobutyric acid (GABA) contents in the hippocampus measured by high-performance liquid chromatography (HPLC). At this stage, activated microglia were found to accumulate in the pyramidal cell layer of the hippocampal CA3 subfield of CD-/- mice. However, there was no significant change in the numerical density of GABAergic interneurons in the CA3 subfield of CD-/- mice at P24, estimated by counting the number of glutamate decarboxylase (GAD) 67-immunoreactive somata. In the hippocampus and the cortex of CD-/-mice at P24, some GABAergic interneurons displayed extremely high somatic granular immunoreactivites for GAD67, suggesting the lysosomal accumulation of GAD67. GAD67 levels in axon terminals abutting on to perisomatic regions of hippocampal CA3 pyramidal cells was not significantly changed in CD-/- mice even at P24, whereas the total protein levels of GAD67 in both the hippocampus and the cortex of CD-/- mice after P24 were significantly decreased as a result of degradation. Furthermore, the recombinant human GAD65/67 was rapidly digested by the lysosomal fraction prepared from the whole brain of wild-type and CD-/- mice. These observations strongly suggest that the reduction of GABA contents, presumably because of lysosomal degradation of GAD67 and lysosomal accumulation of its degraded forms, are responsible for the dysfunction of GABAergic interneurons in the hippocampal CA3 subfield of CD-/- mice.. |
| 419. |
Tokiko Shimizu, Yoshinori Hayashi, Ryo Yamasaki, Jun Yamada, Jian Zhang, Kiyoharu Ukai, Masato Koike, Kazunori Mine, Kurt von Figura, Christoph Peters, Paul Saftig, Takaichi Fukuda, Yasuo Uchiyama, Hiroshi Nakanishi, Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D-deficient mice., Journal of neurochemistry, 10.1111/j.1471-4159.2005.03250.x, 94, 3, 680-90, 2005.08, Although of clinical importance, little is known about the mechanism of seizure in neuronal ceroid lipofuscinosis (NCL). In the present study, we have attempted to elucidate the mechanism underlying the seizure of cathepsin D-deficient (CD-/-) mice that show a novel type of lysosomal storage disease with a phenotype resembling late infantile NCL. In hippocampal slices prepared from CD-/- mice at post-natal day (P)24, spontaneous burst discharges were recorded from CA3 pyramidal cells. At P24, the mean amplitude of IPSPs after stimulation of the mossy fibres was significantly smaller than that of wild-type mice, which was substantiated by the decreased level of gamma-aminobutyric acid (GABA) contents in the hippocampus measured by high-performance liquid chromatography (HPLC). At this stage, activated microglia were found to accumulate in the pyramidal cell layer of the hippocampal CA3 subfield of CD-/- mice. However, there was no significant change in the numerical density of GABAergic interneurons in the CA3 subfield of CD-/- mice at P24, estimated by counting the number of glutamate decarboxylase (GAD) 67-immunoreactive somata. In the hippocampus and the cortex of CD-/- mice at P24, some GABAergic interneurons displayed extremely high somatic granular immunoreactivites for GAD67, suggesting the lysosomal accumulation of GAD67. GAD67 levels in axon terminals abutting on to perisomatic regions of hippocampal CA3 pyramidal cells was not significantly changed in CD-/- mice even at P24, whereas the total protein levels of GAD67 in both the hippocampus and the cortex of CD-/- mice after P24 were significantly decreased as a result of degradation. Furthermore, the recombinant human GAD65/67 was rapidly digested by the lysosomal fraction prepared from the whole brain of wild-type and CD-/- mice. These observations strongly suggest that the reduction of GABA contents, presumably because of lysosomal degradation of GAD67 and lysosomal accumulation of its degraded forms, are responsible for the dysfunction of GABAergic interneurons in the hippocampal CA3 subfield of CD-/- mice.. |
| 420. |
Ryo Yamasaki, Yasumasa Ohyagi, Masakazu Kawajiri, Hiroshi Shigeto, Koji Ikezoe, Hirokazu Furuya, Jun Ichi Kira, A patient with mitochondrial encephalomyopathy presenting gynecomastia with elevation of serum estriol level, Clinical Neurology, 44, 4-5, 291-295, 2004.04, We report a 23-year-old man with mitochondrial encephalomyopathy. At 21 years of age, he noted speech distubance. Since his dysarthria did not improve thereafter, he was admitted to our hospital. On admission, he showed mild gynecomastia. Neurological examination revealed mild decrease in performance IQ in WAIS-R, mild scanning speech, mild left hearing disturbance, mild to moderate muscle weakness in proximal four extremities, mild bilateral limb ataxia, and mild to moderate truncal ataxia. While, no brisk deep tendon reflex, pathological reflex, aberrant muscle tonus, sensory disturbance, retinopathy, myoclonus or autonomic disorder was found. Serum levels of lactate (23.2 mg/dl, normal≤18.7) and pyruvate (1.23 mg/dl, normal1H-MRS showed no lactate peak. Moreover, muscle biopsy from left biceps muscle showed lots of ragged-red fibers, and he was thus diagnosed as having mitochondrial encephalomyopathy. However, nt3243 mutation of mitochondria DNA was not present. Next, we confirmed gynecomastia by mammography, and checked serum levels of estrogens. Mildly decreased estradiol (19.9 pg/ml; normal, 20-59), normal estrone (24.0 pg/ml, normal |
| 421. |
Ryo Yamasaki, Tomoko Kido, Yoriaki Yamashita, Right oculomotor nerve palsy due to juvenile neurosyphilis, Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, 93, 1, 137-138, 2004.01. |
| 422. |
左橋下部被蓋外側の小梗塞によるGasperini症候群の1例. |
| 423. |
左視床出血発症直後より心室性頻拍(VT)を呈した1例. |
| 424. |
Kawamura T, Morioka T, Nishio S, Fukui K, Yamasaki R, Matsuo M, Temporal lobe epilepsy associated with hippocampal sclerosis and a contralateral middle fossa arachnoid cyst., Seizure., 2002.01. |
| 425. |
Tadao Kawamura, Takato Morioka, Shunji Nishio, Kimiko Fukui, Ryo Yamasaki, Muneaki Matsuo, Temporal lobe epilepsy associated with hippocampal sclerosis and a contralateral middle fossa arachnoid cyst, Seizure, 10.1053/seiz.2001.0564, 11, 1, 60-62, 2002.01, We report on a 13-year-old boy with temporal lobe epilepsy associated with left hippocampal sclerosis and a contralateral arachnoid cyst in the middle cranial fossa (ACMCF). Chronic intracranial recording from subdural grid electrodes showed the left medial temporal lobe to be the ictal onset zone. After left anterior temporal lobectomy with hippocampectomy, seizure control was improved. ACMCF was not considered the direct cause of epilepsy; instead the seizures were attributed to hippocampal sclerosis.. |
| 426. |
Tadao Kawamura, Takato Morioka, Shunji Nishio, Kimiko Fukui, Ryo Yamasaki, Muneaki Matsuo, Temporal lobe epilepsy associated with hippocampal sclerosis and a contralateral middle fossa arachnoid cyst., Seizure, 10.1053/seiz.2001.0564, 11, 1, 60-2, 2002.01, We report on a 13-year-old boy with temporal lobe epilepsy associated with left hippocampal sclerosis and a contralateral arachnoid cyst in the middle cranial fossa (ACMCF). Chronic intracranial recording from subdural grid electrodes showed the left medial temporal lobe to be the ictal onset zone. After left anterior temporal lobectomy with hippocampectomy, seizure control was improved. ACMCF was not considered the direct cause of epilepsy; instead the seizures were attributed to hippocampal sclerosis.. |
