2021/10/20 更新

写真a

カキタ アキヨシ
柿田 明美
KAKITA Akiyoshi
所属
脳研究所 教授
医歯学総合研究科 生体機能調節医学専攻 教授
職名
教授
外部リンク

学位

  • 医学博士 ( 1993年9月   新潟大学 )

研究分野

  • ライフサイエンス / 神経形態学

経歴

  • 新潟大学   脳研究所 生命科学リソース研究センター 脳疾患標本資源解析学   教授

    2011年10月 - 現在

  • 新潟大学   医歯学総合研究科 医科学専攻   教授

    2011年10月 - 現在

  • 新潟大学   医歯学総合研究科 生体機能調節医学専攻   教授

    2011年10月 - 現在

  • 新潟大学   脳研究所 生命科学リソース研究センター 脳疾患標本資源解析学   准教授

    2002年4月 - 2011年9月

  • 新潟大学   脳研究所   准教授

    2000年10月 - 2002年3月

  • 新潟大学   脳研究所   助手

    1995年11月 - 2000年10月

▶ 全件表示

 

論文

  • Novel CHP1 mutation in autosomal-recessive cerebellar ataxia: autopsy features of two siblings. 査読 国際誌

    Rie Saito, Norikazu Hara, Mari Tada, Yoshiaki Honma, Akinori Miyashita, Osamu Onodera, Takeshi Ikeuchi, Akiyoshi Kakita

    Acta neuropathologica communications   8 ( 1 )   134 - 134   2020年8月

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  • Praja1 RING-finger E3 ubiquitin ligase suppresses neuronal cytoplasmic TDP-43 aggregate formation. 査読 国際誌

    Kazuhiko Watabe, Yoichiro Kato, Miho Sakuma, Makiko Murata, Motoko Niida-Kawaguchi, Taro Takemura, Nobutaka Hanagata, Mari Tada, Akiyoshi Kakita, Noriyuki Shibata

    Neuropathology : official journal of the Japanese Society of Neuropathology   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Transactivation response DNA-binding protein of 43 kDa (TDP-43) is a major constituent of cytoplasmic aggregates in neuronal and glial cells in cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We have previously shown neuronal cytoplasmic aggregate formation induced by recombinant adenoviruses expressing human wild-type and C-terminal fragment (CTF) TDP-43 under the condition of proteasome inhibition in vitro and in vivo. In the present study, we demonstrated that the formation of the adenoviral TDP-43 aggregates was markedly suppressed in rat neural stem cell-derived neuronal cells by co-infection of an adenovirus expressing heat shock transcription factor 1 (HSF1), a master regulator of heat shock response. We performed DNA microarray analysis and searched several candidate molecules, located downstream of HSF1, which counteract TDP-43 aggregate formation. Among these, we identified Praja 1 RING-finger E3 ubiquitin ligase (PJA1) as a suppressor of phosphorylation and aggregate formation of TDP-43. Co-immunoprecipitation assay revealed that PJA1 binds to CTF TDP-43 and the E2-conjugating enzyme UBE2E3. PJA1 also suppressed formation of cytoplasmic phosphorylated TDP-43 aggregates in mouse facial motor neurons in vivo. Furthermore, phosphorylated TDP-43 aggregates were detected in PJA1-immunoreactive human ALS motor neurons. These results indicate that PJA1 is one of the principal E3 ubiquitin ligases for TDP-43 to counteract its aggregation propensity and could be a potential therapeutic target for ALS and FTLD.

    DOI: 10.1111/neup.12694

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  • MicroRNA-5572 Is a Novel MicroRNA-Regulating SLC30A3 in Sporadic Amyotrophic Lateral Sclerosis. 査読 国際誌

    Hisaka Kurita, Saori Yabe, Tomoyuki Ueda, Masatoshi Inden, Akiyoshi Kakita, Isao Hozumi

    International journal of molecular sciences   21 ( 12 )   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease caused by the loss of motor neurons. Although the pathogenesis of sporadic ALS (sALS) remains unclear, it has recently been suggested that disorders of microRNA (miRNA) may be involved in neurodegenerative conditions. The purpose of this study was to investigate miRNA levels in sALS and the target genes of miRNA. Microarray and real-time RT-PCR analyses revealed significantly-decreased levels of miR-139-5p and significantly increased levels of miR-5572 in the spinal cords of sALS patients compared with those in controls. We then focused on miR-5572, which has not been reported in ALS, and determined its target gene. By using TargetScan, we predicted SLC30A3 as the candidate target gene of miR-5572. In a previous study, we found decreased SLC30A3 levels in the spinal cords of sALS patients. We revealed that SLC30A3 was regulated by miR-5572. Taken together, these results demonstrate that the level of novel miRNA miR-5572 is increased in sALS and that SLC30A3 is one of the target genes regulated by miR-5572.

    DOI: 10.3390/ijms21124482

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  • Oculopharyngodistal myopathy with coexisting histology of systemic neuronal intranuclear inclusion disease: Clinicopathologic features of an autopsied patient harboring CGG repeat expansions in LRP12. 査読 国際誌

    Rie Saito, Hiroshi Shimizu, Takeshi Miura, Norikazu Hara, Naomi Mezaki, Yo Higuchi, Akinori Miyashita, Izumi Kawachi, Kazuhiro Sanpei, Yoshiaki Honma, Osamu Onodera, Takeshi Ikeuchi, Akiyoshi Kakita

    Acta neuropathologica communications   8 ( 1 )   75 - 75   2020年6月

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  • Expression of the ghrelin/growth hormone secretagogue receptor axis and its functional role in promoting tumor growth in primary central nervous system lymphomas 査読

    Hiroko Muta, Yasuo Sugita, Takuya Furuta, Yuki Shiimura, Koichi Ohshima, Kazutaka Nakashima, Kensaku Sato, Motohiro Morioka, Hideyuki Abe, Takanori Nozawa, Yukihiko Fujii, Akiyoshi Kakita

    Neuropathology   40 ( 3 )   232 - 239   2020年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/neup.12634

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/neup.12634

  • Versatile whole-organ/body staining and imaging based on electrolyte-gel properties of biological tissues. 査読 国際誌

    Etsuo A Susaki, Chika Shimizu, Akihiro Kuno, Kazuki Tainaka, Xiang Li, Kengo Nishi, Ken Morishima, Hiroaki Ono, Koji L Ode, Yuki Saeki, Kazunari Miyamichi, Kaoru Isa, Chihiro Yokoyama, Hiroki Kitaura, Masako Ikemura, Tetsuo Ushiku, Yoshihiro Shimizu, Takashi Saito, Takaomi C Saido, Masashi Fukayama, Hirotaka Onoe, Kazushige Touhara, Tadashi Isa, Akiyoshi Kakita, Mitsuhiro Shibayama, Hiroki R Ueda

    Nature communications   11 ( 1 )   1982 - 1982   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Whole-organ/body three-dimensional (3D) staining and imaging have been enduring challenges in histology. By dissecting the complex physicochemical environment of the staining system, we developed a highly optimized 3D staining imaging pipeline based on CUBIC. Based on our precise characterization of biological tissues as an electrolyte gel, we experimentally evaluated broad 3D staining conditions by using an artificial tissue-mimicking material. The combination of optimized conditions allows a bottom-up design of a superior 3D staining protocol that can uniformly label whole adult mouse brains, an adult marmoset brain hemisphere, an ~1 cm3 tissue block of a postmortem adult human cerebellum, and an entire infant marmoset body with dozens of antibodies and cell-impermeant nuclear stains. The whole-organ 3D images collected by light-sheet microscopy are used for computational analyses and whole-organ comparison analysis between species. This pipeline, named CUBIC-HistoVIsion, thus offers advanced opportunities for organ- and organism-scale histological analysis of multicellular systems.

    DOI: 10.1038/s41467-020-15906-5

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  • 【まれな感染症-ウイルス,細菌,寄生虫,輸入感染症-】脳神経領域のまれな感染症 画像診断のポイント 査読

    岡本 浩一郎, 高橋 陽彦, 鈴木 倫明, 小野寺 理, 柿田 明美, 阿部 博史

    臨床放射線   65 ( 4 )   317 - 324   2020年4月

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    記述言語:日本語   出版者・発行元:金原出版(株)  

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  • Soluble iron accumulation induces microglial glutamate release in the spinal cord of sporadic amyotrophic lateral sclerosis. 査読 国際誌

    Motoko Niida-Kawaguchi, Akiyoshi Kakita, Noriko Noguchi, Miku Kazama, Kenta Masui, Yoichiro Kato, Tomoko Yamamoto, Tatsuo Sawada, Kazuo Kitagawa, Kazuhiko Watabe, Noriyuki Shibata

    Neuropathology : official journal of the Japanese Society of Neuropathology   40 ( 2 )   152 - 166   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Previous studies on sporadic amyotrophic lateral sclerosis (SALS) demonstrated iron accumulation in the spinal cord and increased glutamate concentration in the cerebrospinal fluid. To clarify the relationship between the two phenomena, we first performed quantitative and morphological analyses of substances related to iron and glutamate metabolism using spinal cords obtained at autopsy from 12 SALS patients and 12 age-matched control subjects. Soluble iron content determined by the Ferrozine method as well as ferritin (Ft) and glutaminase C (GLS-C) expression levels on Western blots were significantly higher in the SALS group than in the control group, while ferroportin (FPN) levels on Western blots were significantly reduced in the SALS group as compared to the control group. There was no significant difference in aconitase 1 (ACO1) and tumor necrosis factor-alpha (TNFα)-converting enzyme (TACE) levels on Western blots between the two groups. Immunohistochemically, Ft, ACO1, TACE, TNFα, and GLS-C were proven to be selectively expressed in microglia. Immunoreactivities for FPN and hepcidin were localized in neuronal and glial cells. Based on these observations, it is predicted that soluble iron may stimulate microglial glutamate release. To address this issue, cell culture experiments were carried out on a microglial cell line (BV-2). Treatment of BV-2 cells with ferric ammonium citrate (FAC) brought about significant increases in intracellular soluble iron and Ft expression levels and conditioned medium glutamate and TNFα concentrations. Glutamate concentration was also significantly increased in conditioned media of TNFα-treated BV-2 cells. While the FAC-driven increases in glutamate and TNFα release were completely canceled by pretreatment with ACO1 and TACE inhibitors, respectively, the TNFα-driven increase in glutamate release was completely canceled by GLS-C inhibitor pretreatment. Moreover, treatment of BV-2 cells with hepcidin resulted in a significant reduction in FPN expression levels on Western blots of the intracellular total protein extracts. The present results provide in vivo and in vitro evidence that microglial glutamate release in SALS spinal cords is enhanced by intracellular soluble iron accumulation-induced activation of ACO1 and TACE and by increased extracellular TNFα-stimulated GLS-C upregulation, and suggest a positive feedback mechanism to maintain increased intracellular soluble iron levels, involving TNFα, hepcidin, and FPN.

    DOI: 10.1111/neup.12632

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  • [Amyloid β-related angiitis presenting extensive brain involvement without detection of hemorrhagic lesions: A case report]. 査読

    Yuya Hatano, Akihiro Sugai, Takuma Yamagishi, Akihiro Nakajima, Akiyoshi Kakita, Osamu Onodera

    Rinsho shinkeigaku = Clinical neurology   60 ( 3 )   187 - 192   2020年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    In amyloid β-related angiitis, cortical or subcortical microbleeding or cortical superficial siderosis supports clinical diagnosis. However, here we present a 75-year-old female case of amyloid β-related angiitis that did not initially show these lesions. The patient developed right homonymous hemianopia and aphasia, and subsequently became comatose. Her brain lesions progressed extensively from the left occipital lobe to the bilateral cerebral hemispheres, with diffused leptomeningeal lesions and scattered DWI high-intensity lesions. After pathological diagnosis, steroid treatment improved her symptoms as well as imaging findings. No hemorrhagic lesions were detected in the T2*-weighted imaging performed before treatment. However, susceptibility-weighted imaging performed after treatment showed a number of lesions with microbleeding. The clinical features of amyloid β-related angiitis that do not show hemorrhagic lesions at onset should be investigated for rapid therapeutic intervention in the future.

    DOI: 10.5692/clinicalneurol.cn-001340

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  • Amyotrophic Lateral Sclerosis with Pallidonigroluysian Degeneration: A Clinicopathological Study. 査読 国際誌

    Junko Ito, Hiroshi Shimizu, Kentaro Ohta, Jiro Idezuka, Hajime Tanaka, Hiroshi Kondo, Takashi Nakajima, Hitoshi Takahashi, Kohei Akazawa, Osamu Onodera, Akiyoshi Kakita

    Annals of neurology   87 ( 2 )   302 - 312   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: The pallidonigroluysian (PNL) system, the primary component of corticosubcortical circuits, is generally spared in amyotrophic lateral sclerosis (ALS). We evaluated the clinicopathological features of an unusual form of ALS with PNL degeneration (PNLD) and assessed whether ALS with PNLD represents a distinct ALS subtype. METHODS: From a cohort of 97 autopsied cases of sporadic ALS with phosphorylated 43kDa TAR DNA-binding protein (TDP-43) inclusions, we selected those with PNLD and analyzed their clinicopathological features. RESULTS: Eleven cases (11%) that showed PNLD were divided into 2 subtypes depending on the lesion distribution: (1) extensive type (n = 6), showing widespread TDP-43 pathology and multisystem degeneration, both involving the PNL system; and (2) limited type (n = 5), showing selective PNL and motor system involvement, thus being unclassifiable in terms of Brettschneider's staging or Nishihira's typing of ALS. The limited type showed a younger age at onset and predominant PNLD that accounted for the early development of extrapyramidal signs. The limited type exhibited the heaviest pathology in the subthalamus and external globus pallidus, suggesting that TDP-43 inclusions propagated via indirect or hyperdirect pathways, unlike ALS without PNLD, where the direct pathway is considered to convey TDP-43 aggregates from the cerebral cortex to the substantia nigra. INTERPRETATION: The PNL system can be involved in the disease process of ALS, either nonselectively as part of multisystem degeneration, or selectively. ALS with selective involvement of the PNL and motor systems exhibits unique clinicopathological features and TDP-43 propagation routes, thus representing a distinct subtype of ALS. ANN NEUROL 2020;87:302-312.

    DOI: 10.1002/ana.25652

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  • MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas 査読 国際誌

    Hideaki Abe, Manabu Natsumeda, Masayasu Okada, Jun Watanabe, Yoshihiro Tsukamoto, Yu Kanemaru, Junichi Yoshimura, Makoto Oishi, Rintaro Hashizume, Akiyoshi Kakita, Yukihiko Fujii

    Frontiers in Oncology   9   1568 - 1568   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    © Copyright © 2020 Abe, Natsumeda, Okada, Watanabe, Tsukamoto, Kanemaru, Yoshimura, Oishi, Hashizume, Kakita and Fujii. Diffuse midline gliomas (DMGs) show resistance to many chemotherapeutic agents including temozolomide (TMZ). Histone gene mutations in DMGs trigger epigenetic changes including DNA hypomethylation, one of which is a frequent lack of O6-methyl-guanine-DNA methyltransferase (MGMT) promoter methylation, resulting in increased MGMT expression. We established the NGT16 cell line with HIST1H3B K27M and ACVR1 G328E gene mutations from a DMG patient and used this cell line and other DMG cell lines with H3F3A gene mutation (SF7761, SF8628, JHH-DIPG1) to analyze MGMT promoter methylation, MGMT protein expression, and response to TMZ. Three out of 4 DMG cell lines (NGT16, SF8628, and JHH-DIPG1) had unmethylated MGMT promoter, increased MGMT expression, and showed resistance to TMZ treatment. SF7761 cells with H3F3A gene mutation showed MGMT promoter methylation, lacked MGMT expression, and sensitivity to TMZ treatment. NGT16 line showed response to ALK2 inhibitor K02288 treatment in vitro. We confirmed in vitro that MGMT expression contributes to TMZ resistance in DMG cell lines. There is an urgent need to develop new strategies to treat TMZ-resistant DMGs.

    DOI: 10.3389/fonc.2019.01568

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  • Skull diploë is rich in aquaporin-4 査読

    Yuji Suzuki, Hiroki Kitaura, Yukimi Nakamura, Akiyoshi Kakita, Vincent J. Huber, Nicholas Capozzoli, Ingrid L. Kwee, Tsutomu Nakada

    Heliyon   6 ( 1 )   e03259 - e03259   2020年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.heliyon.2020.e03259

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  • Rare Brain Metastasis From a Pancreatobiliary Subtype of Intraductal Papillary Mucinous Neoplasm. 査読 国際誌

    Yoshihisa Arao, Kenya Kamimura, Masatoshi Ikemi, Kazunao Hayashi, Masayuki Takaki, Shunsaku Takahashi, Satoshi Seino, Hiroyuki Abe, Shintaro Tsuboguchi, Yutaka Otsu, Kazuhiro Sanpei, Junji Kohisa, Shuhei Kondo, Yusuke Tani, Junko Ito, Yasuko Toyoshima, Akiyoshi Kakita, Yoichi Ajioka, Shuji Terai

    Pancreas   49 ( 1 )   e8-e11 - e11   2020年1月

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  • Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. 査読 国際誌

    Yingyue Zhou, Wilbur M Song, Prabhakar S Andhey, Amanda Swain, Tyler Levy, Kelly R Miller, Pietro L Poliani, Manuela Cominelli, Shikha Grover, Susan Gilfillan, Marina Cella, Tyler K Ulland, Konstantin Zaitsev, Akinori Miyashita, Takeshi Ikeuchi, Makoto Sainouchi, Akiyoshi Kakita, David A Bennett, Julie A Schneider, Michael R Nichols, Sean A Beausoleil, Jason D Ulrich, David M Holtzman, Maxim N Artyomov, Marco Colonna

    Nature medicine   26 ( 1 )   131 - 142   2020年1月

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    記述言語:英語  

    Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

    DOI: 10.1038/s41591-019-0695-9

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  • Identification of VGF nerve growth factor inducible-producing cells in human spinal cords and expression change in patients with amyotrophic lateral sclerosis. 査読 国際誌

    Yasuhiro Noda, Miruto Tanaka, Shinsuke Nakamura, Junko Ito, Akiyoshi Kakita, Hideaki Hara, Masamitsu Shimazawa

    International journal of medical sciences   17 ( 4 )   480 - 489   2020年

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    記述言語:英語  

    Amyotrophic lateral sclerosis (ALS) is a serious disease characterized by the degeneration of motor neurons resulting in muscle weakness and paralysis. The neuroendocrine polypeptide VGF is localized in the central nervous system and peripheral endocrine neurons and is cleaved into several polypeptides with multiple functions. Previous studies revealed that VGF was decreased in the cerebrospinal fluid of ALS model mice and sporadic ALS patients. However, it is unknown which cells supply VGF in the spinal cord and a detailed localization is lacking. In this study, we evaluated the VGF-producing cells and protein localization using in situ hybridization and immunostaining in the spinal cords of ALS and control patients. VGF mRNA was localized both in the dorsal and anterior horns of the spinal cords. Moreover, in the anterior horn, VGF mRNA co-localized with a neurofilament heavy chain, which is a motor neuron marker, and VGF mRNA-positive motor neurons were decreased in the spinal cords of ALS patients. We revealed that VGF protein level was decreased in the anterior horn of ALS patients; however, the expression level of VGF protein was not changed in the posterior horn or white matter. Furthermore, the expression level of VGF protein was conserved in ALS patients with long-term survival. These results reveal that VGF is mainly supplied by human motor neurons, and suggest that VGF expression changes may be involved in ALS pathology.

    DOI: 10.7150/ijms.39101

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  • Reciprocal connectivity between secondary auditory cortical field and amygdala in mice. 査読 国際誌

    Hiroaki Tsukano, Xubin Hou, Masao Horie, Hiroki Kitaura, Nana Nishio, Ryuichi Hishida, Kuniyuki Takahashi, Akiyoshi Kakita, Hirohide Takebayashi, Sayaka Sugiyama, Katsuei Shibuki

    Scientific reports   9 ( 1 )   19610 - 19610   2019年12月

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    記述言語:英語  

    Recent studies have examined the feedback pathway from the amygdala to the auditory cortex in conjunction with the feedforward pathway from the auditory cortex to the amygdala. However, these connections have not been fully characterized. Here, to visualize the comprehensive connectivity between the auditory cortex and amygdala, we injected cholera toxin subunit b (CTB), a bidirectional tracer, into multiple subfields in the mouse auditory cortex after identifying the location of these subfields using flavoprotein fluorescence imaging. After injecting CTB into the secondary auditory field (A2), we found densely innervated CTB-positive axon terminals that were mainly located in the lateral amygdala (La), and slight innervations in other divisions such as the basal amygdala. Moreover, we found a large number of retrogradely-stained CTB-positive neurons in La after injecting CTB into A2. When injecting CTB into the primary auditory cortex (A1), a small number of CTB-positive neurons and axons were visualized in the amygdala. Finally, we found a near complete absence of connections between the other auditory cortical fields and the amygdala. These data suggest that reciprocal connections between A2 and La are main conduits for communication between the auditory cortex and amygdala in mice.

    DOI: 10.1038/s41598-019-56092-9

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  • Neuromyelitis optica spectrum disorder with massive basal ganglia involvement: a case report. 査読

    Ohara S, Miyahira TA, Oguchi K, Takei YI, Yanagimura F, Kawachi I, Oyanagi K, Kakita A

    BMC neurology   19 ( 1 )   351   2019年12月

  • Phosphorylated TDP-43 aggregates in skeletal and cardiac muscle are a marker of myogenic degeneration in amyotrophic lateral sclerosis and various conditions. 査読 国際誌

    Fumiaki Mori, Mari Tada, Tomoya Kon, Yasuo Miki, Kunikazu Tanji, Hidekachi Kurotaki, Masahiko Tomiyama, Tomohiko Ishihara, Osamu Onodera, Akiyoshi Kakita, Koichi Wakabayashi

    Acta neuropathologica communications   7 ( 1 )   165 - 165   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized pathologically by the occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system. Recent studies have shown that pTDP-43 aggregates also occur in the skeletal muscles in a certain proportion of ALS patients. AIM: The aim of this study was to clarify the distribution and incidence of pTDP-43 aggregates in the skeletal and cardiac muscles of patients with ALS, and also those of patients with neuromuscular diseases (NMDs) and non-NMDs. MATERIAL AND METHODS: Five regions of muscle (tongue, cervical muscle, diaphragm, iliopsoas muscle and heart) were examined histologically and immunohistochemically in patients with ALS (n = 30), NMDs (n = 13) and non-NMDs (n = 7). RESULTS: Two types of pTDP-43 aggregates were distinguishable morphologically: dense filamentous and short linear inclusions. These inclusions were found in at least one of the five muscle regions in all 30 cases of ALS; skeletal muscles in 28 cases and myocardium in 12. pTDP-43 aggregates were also found in 9 of 13 patients with NMDs, including myositis, muscular dystrophy and mitochondrial myopathy, as well as in 3 of 7 patients with non-NMDs. In ALS, pTDP-43 aggregates were most frequent in the diaphragm (19 cases). The mean density of pTDP-43 aggregates in ALS was significantly higher than that in NMDs and non-NMDs. In contiguous sections stained with hematoxylin and eosin and anti-pTDP-43, muscle fibers with dense filamentous inclusions demonstrated single-fiber atrophy with vacuolar degeneration. CONCLUSION: The present findings indicate that pTDP-43 aggregates in skeletal and cardiac muscle are a myogenic pathological marker in multiple diseases including ALS.

    DOI: 10.1186/s40478-019-0824-1

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  • Differential protein expression of DARPP-32 versus Calcineurin in the prefrontal cortex and nucleus accumbens in schizophrenia and bipolar disorder. 査読 国際誌

    Yasuto Kunii, Mizuki Hino, Junya Matsumoto, Atsuko Nagaoka, Hiroyuki Nawa, Akiyoshi Kakita, Hiroyasu Akatsu, Yoshio Hashizume, Hirooki Yabe

    Scientific reports   9 ( 1 )   14877 - 14877   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) integrates dopaminergic signaling into that of several other neurotransmitters. Calcineurin (CaN), located downstream of dopaminergic pathways, inactivates DARPP-32 by dephosphorylation. Despite several studies have examined their expression levels of gene and protein in postmortem patients' brains, they rendered inconsistent results. In this study, protein expression levels of DARPP-32 and CaN were measured by enzyme-linked immunosorbent assay (ELISA) in the prefrontal cortex (PFC), and nucleus accumbens (NAc) of 49 postmortem samples from subjects with schizophrenia, bipolar disorder, and normal controls. We also examined the association between this expression and genetic variants of 8 dopaminergic system-associated molecules for 55 SNPs in the same postmortem samples. In the PFC of patients with schizophrenia, levels of DARPP-32 were significantly decreased, while those of CaN tended to increase. In the NAc, both of DARPP-32 and CaN showed no significant alternations in patients with schizophrenia or bipolar disorder. Further analysis of the correlation of DARPP-32 and CaN expressions, we found that positive correlations in controls and schizophrenia in PFC, and schizophrenia in NAc. In PFC, the expression ratio of DARPP-32/CaN were significantly lower in schizophrenia than controls. We also found that several of the aforementioned SNPs may predict protein expression, one of which was confirmed in a second independent sample set. This differential expression of DARPP-32 and CaN may reflect potential molecular mechanisms underlying the pathogenesis of schizophrenia and bipolar disorder, or differences between these two major psychiatric diseases.

    DOI: 10.1038/s41598-019-51456-7

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  • Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model. 査読 国際誌

    Mika Terumitsu-Tsujita, Hiroki Kitaura, Ikuo Miura, Yuji Kiyama, Fumiko Goto, Yoshiko Muraki, Shiho Ominato, Norikazu Hara, Anna Simankova, Norihisa Bizen, Kazuhiro Kashiwagi, Takuhiro Ito, Yasuko Toyoshima, Akiyoshi Kakita, Toshiya Manabe, Shigeharu Wakana, Hirohide Takebayashi, Hironaka Igarashi

    Journal of neurochemistry   2019年10月

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    Vanishing white matter disease (VWM) is an autosomal recessive neurological disorder caused by mutation(s) in any subunit of eukaryotic translation initiation factor 2B (eIF2B), an activator of translation initiation factor eIF2. VWM occurs with mutation of the genes encoding eIF2B subunits (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5). However, little is known regarding the underlying pathogenetic mechanisms or how to treat patients with VWM. Here we describe the identification and detailed analysis of a new spontaneous mutant mouse harboring a point mutation in the Eif2b5 gene (p.Ile98Met). Homozygous Eif2b5I98M mutant mice exhibited a small body, abnormal gait, male and female infertility, epileptic seizures, and a shortened lifespan. Biochemical analyses indicated that the mutant eIF2B protein with the Eif2b5I98M mutation decreased guanine nucleotide exchange activity on eIF2, and the level of the endoplasmic reticulum stress marker activating transcription factor 4 was elevated in the 1-month-old Eif2b5I98M brain. Histological analyses indicated up-regulated glial fibrillary acidic protein immunoreactivity in the astrocytes of the Eif2b5I98M forebrain and translocation of Bergmann glia in the Eif2b5I98M cerebellum, as well as increased mRNA expression of an endoplasmic reticulum stress marker, C/EBP homologous protein. Disruption of myelin and clustering of oligodendrocyte progenitor cells were also indicated in the white matter of the Eif2b5I98M spinal cord at 8 months old. Our data show that Eif2b5I98M mutants are a good model for understanding VWM pathogenesis and therapy development.

    DOI: 10.1111/jnc.14887

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  • ヒト死後脳におけるAPP・APOEの遺伝子発現解析 査読

    Lixin Liu, 宮下 哲典, 村上 涼太, Bin Zhu, 原 範和, 菊地 正隆, 月江 珠緒, 樋口 陽, 春日 健作, 中谷 明弘, 赤津 裕康, 柿田 明美, 村山 繁雄, 池内 健

    Dementia Japan   33 ( 4 )   519 - 519   2019年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • TΔΠ-43 プロテイノパチー (1) 前頭側頭葉変性症 (FTLD) 査読

    他田 真理, 柿田 明美

    病理と臨床   37 ( 9 )   2019年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    連載 –変性疾患のみかた–

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  • G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10. 査読

    Anisimov S, Takahashi M, Kakihana T, Katsuragi Y, Kitaura H, Zhang L, Kakita A, Fujii M

    Scientific reports   9 ( 1 )   12896   2019年9月

  • Rapid chemical clearing of white matter in post-mortem human brain by 1,2-hexanediol delipidation. 査読

    Bioorganic Medicinal Chem Lett   29 ( 15 )   1886 - 1890   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bmcl.2019.05.049.

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  • USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells. 査読 国際誌

    Svetlana Piatnitskaia, Masahiko Takahashi, Hiroki Kitaura, Yoshinori Katsuragi, Taichi Kakihana, Lu Zhang, Akiyoshi Kakita, Yuriko Iwakura, Hiroyuki Nawa, Takeshi Miura, Takeshi Ikeuchi, Toshifumi Hara, Masahiro Fujii

    Scientific reports   9 ( 1 )   10591 - 10591   2019年7月

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    記述言語:英語  

    Tau aggregates in neurons of brain lesions is a hallmark pathology of tauopathies, including Alzheimer's disease (AD). Recent studies suggest that the RNA-binding protein TIA1 initiates Tau aggregation by inducing the formation of stress granules (SGs) containing Tau. SGs are stress-inducible cytoplasmic protein aggregates containing many RNA-binding proteins that has been implicated as an initial site of multiple pathogenic protein aggregates in several neurodegenerative diseases. In this study, we found that ubiquitin-specific protease 10 (USP10) is a critical factor for the formation of Tau/TIA1/USP10-positive SGs. Proteasome inhibition or TIA1-overexpression in HT22 neuronal cells induced the formation of TIA1/Tau-positive SGs, and the formations were severely attenuated by depletion of USP10. In addition, the overexpression of USP10 without stress stimuli in HT22 cells induced TIA1/Tau/USP10-positive SGs in a deubiquitinase-independent manner. In AD brain lesions, USP10 was colocalized with Tau aggregates in the cell body of neurons. The present findings suggest that USP10 plays a key role in the initiation of pathogenic Tau aggregation in AD through SG formation.

    DOI: 10.1038/s41598-019-47033-7

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  • A mouse model of adult-onset multiple system atrophy. 査読 国際誌

    Kunikazu Tanji, Yasuo Miki, Fumiaki Mori, Yoshikazu Nikaido, Hidemi Narita, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    Neurobiology of disease   127   339 - 349   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder clinically characterized by autonomic failure in addition to various combinations of symptoms of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Despite extensive research, the mechanisms underlying the progression of MSA remain unknown. Animal models of human diseases that recapitulate their clinical, biochemical and pathological features are indispensable for increasing our understanding of their underlying molecular mechanisms, which allows preclinical studies to be advanced. Because the onset of MSA occurs in middle age, an animal model that first manifests abnormal protein aggregates in adulthood would be most appropriate. We therefore used the Cre-loxP system to express inducible α-synuclein (Syn), a major component of the pathological hallmark of MSA, to generate a mouse model of MSA. Beginning in adulthood, these MSA model mice express excessive levels of Syn in oligodendrocytes, resulting in abnormal Syn accumulation and modifications similar to those observed in human MSA pathology. Additionally, MSA model mice exhibit some clinical features of MSA, including decreased motor activity. These findings suggest that this new mouse model of MSA represents a useful tool for analyzing the pathophysiological alterations that underlie the progression of this disease.

    DOI: 10.1016/j.nbd.2019.03.020

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  • Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy. 査読

    Kanemaru Y, Natsumeda M, Okada M, Saito R, Kobayashi D, Eda T, Watanabe J, Saito S, Tsukamoto Y, Oishi M, Saito H, Nagahashi M, Sasaki T, Hashizume R, Aoyama H, Wakai T, Kakita A, Fujii Y

    Acta neuropathologica communications   7 ( 1 )   119   2019年7月

  • パーキンソン病、筋萎縮性側索硬化症、進行性核上性麻痺の合併を認めた高齢女性剖検例 査読

    田中 英智, 清水 宏, 豊島 靖子, 若林 允甫, 柿田 明美

    The Kitakanto Medical Journal   69 ( 2 )   170 - 170   2019年5月

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    記述言語:日本語   出版者・発行元:北関東医学会  

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  • An autopsy case of peliosis hepatis with X-linked myotubular myopathy. 査読 国際誌

    Kazuhisa Funayama, Hiroshi Shimizu, Hidetomo Tanaka, Izumi Kawachi, Ichizo Nishino, Kou Matsui, Naoya Takahashi, Akihide Koyama, Rieka Katsuragi-Go, Ryoko Higuchi, Takashi Aoyama, Hiraku Watanabe, Akiyoshi Kakita, Hisakazu Takatsuka

    Legal medicine (Tokyo, Japan)   38   77 - 82   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    This report describes the autopsy case of a 4-year-old boy who died from hepatic hemorrhage and rupture caused by peliosis hepatis with X-linked myotubular myopathy. Peliosis hepatis is characterized by multiple blood-filled cavities of various sizes in the liver, which occurs in chronic wasting disease or with the use of specific drugs. X-linked myotubular myopathy is one of the most serious types of congenital myopathies, in which an affected male infant typically presents with severe hypotonia and respiratory distress immediately after birth. Although each disorder is rare, 12 cases of pediatric peliosis hepatis associated with X-linked myotubular myopathy have been reported, including our case. Peliosis hepatis should be considered as a cause of hepatic hemorrhage despite its low incidence, and it requires adequate gross and histological investigation for correct diagnosis.

    DOI: 10.1016/j.legalmed.2019.04.005

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  • 統合失調症として長期入院していた特発性基底核石灰化症 (Fahr病) の臨床病理学的特徴 査読

    伊藤 陽, 吉田浩樹, 清水敬三, 長谷川まこと, 今野公和, 中原亜紗, 原 範和, 宮下哲典, 池内 健, 豊島靖子, 柿田明美

    精神医学   61 ( 5 )   595 - 603   2019年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • High detection rate of MYD88 mutations in cerebrospinal fluid from patients with central nervous system lymphomas. 査読

    Watanabe J, Matsumeda M, Olada M, Kobayashi D, Kanemaru Y, Tsukamoto Y, Oishi M, Kakita A, Fujii Y

    JCO Precis Oncol,   e1 - e10   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1200/PO.18.00308.

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  • Globular glial tauopathy Type II: Clinicopathological study of two autopsy cases. 査読 国際誌

    Hidetomo Tanaka, Shinobu Kawakatsu, Yasuko Toyoshima, Takeshi Miura, Naomi Mezaki, Atsushi Mano, Kazuhiro Sanpei, Ryota Kobayashi, Hiroshi Hayashi, Koichi Otani, Takeshi Ikeuchi, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

    Neuropathology : official journal of the Japanese Society of Neuropathology   39 ( 2 )   111 - 119   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Globular glial tauopathies (GGTs) are four-repeat tauopathies characterized by the presence of two types of tau-positive globular glial inclusions (GGIs): globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). GGTs are classified into three different neuropathological subtypes: Types I, II and III. We report two patients with GGTs - a 76-year-old woman and a 70-year-old man - in whom the disease duration was 5 and 6 years, respectively. Both patients exhibited upper and lower motor neuron signs and involuntary movements, and the latter also had dementia with frontotemporal cerebral atrophy evident on magnetic resonance imaging. Neuropathologically, in both cases, the precentral gyrus was most severely affected, and at the gray-white matter junction there was almost complete loss of Betz cells and occurrence of GOIs and coiled bodies with numerous neuropil threads. Both patients also showed neuronal loss and GGIs (mostly GOIs) in many other central nervous system regions, including the basal ganglia. Apart from the degree of regional severity, the distribution pattern was essentially the same in both cases. However, GAIs were not conspicuous in any of the affected regions. Based on the morphology and distribution pattern of the GGIs, we diagnosed the present two patients as having GGT Type II. Electron microscopic and biochemical findings in the former were consistent with the diagnosis. Type II cases are reported to be characterized by pyramidal features reflecting predominant motor cortex and corticospinal tract degeneration. The present observations suggest that a variety of neurological features, including dementia, can occur in GGT Type II reflecting widespread degeneration beyond the motor neuron system.

    DOI: 10.1111/neup.12532

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  • 経過中にBálint症候群を発症し、塩酸メフロキンとミルタザピンの併用療法により改善した進行性多巣性白質脳症の1例. 査読

    竹腰顕, 吉倉延亮, 小澤憲司, 生駒良和, 竹島明, 大槻美佳, 中道一生, 西條政幸, 望月清文, 柿田明美, 下畑享良

    Brain Nerve   71 ( 3 )   281 - 286   2019年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.11477/mf.1416201256.

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  • EGFRvIII is expressed in cellular areas of tumor in a subset of glioblastoma. 査読

    Neurol Med Chir   59 ( 3 )   89 - 97   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.2176/nmc.oa.2018-0078.

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  • Multiplex ligation-dependent probe amplification analysis is useful for detecting a copy number gain of the FGFR1 tyrosine kinase domain in dysembryoplastic neuroepithelial tumors. 査読

    Matsumura N, Nobusawa S, Ito J, Kakita A, Suzuki H, Fujii Y, Fukuda M, Iwasaki M, Nakasato N, Yominaga T, Natsume A, Mikami Y, Shinojima N, Yamazaki T, Nakazato Y, Hirato J, Yokoo H

    J Neurooncol   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s11060-019-03138-7.

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  • [A Patient with Progressive Multifocal Leukoencephalopathy Who Developed Bálint Syndrome Improved by Combination Therapy Using Mefloquine and Mirtazapine]. 査読

    Takekoshi A, Yoshikura N, Ozawa K, Ikoma Y, Kitagawa J, Takeshima A, Otsuki M, Nakamichi K, Saijo M, Ohe N, Mochizuki K, Kakita A, Shimohata T

    Brain and nerve = Shinkei kenkyu no shinpo   71 ( 3 )   281 - 286   2019年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.11477/mf.1416201256

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  • Retinal Vasculopathy With Cerebral Leukodystrophy: Clinicopathologic Features of an Autopsied Patient With a Heterozygous TREX 1 Mutation. 査読 国際誌

    Rie Saito, Hiroaki Nozaki, Taisuke Kato, Yasuko Toyoshima, Hajime Tanaka, Yutaka Tsubata, Tetsuo Morioka, Yoh Horikawa, Kiyomitsu Oyanagi, Takashi Morita, Osamu Onodera, Akiyoshi Kakita

    Journal of neuropathology and experimental neurology   78 ( 2 )   181 - 186   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an autosomal-dominant disorder involving the cerebral, retinal, renal, and other systemic microvessels due to frameshift mutations in the TREX1 gene. Under physiological conditions, the TREX1 protein is localized in the cellular cytoplasm and perinuclear area, but translocates into the nucleus in response to oxidative DNA damage. It has been speculated that aberrant localization of the protein may be associated with systemic microangiopathy in patients with RVCL. However, cellular expression of TREX1 in the brain and visceral organs of patients with RVCL has been unclear. Here, we report the clinicopathologic features of an autopsied patient with a heterozygous T249fs mutation in TREX1. The patient showed the clinical phenotype of vasculopathy with retinopathy, nephropathy, and stroke. CT with contrast enhancement demonstrated a tumorous lesion in the subcortical white matter. Histologically, the lesion consisted of confluent foci of necrosis with calcification and fibrous thickening of small vessel walls. TREX1 immunohistochemistry demonstrated positivity in the nuclei of cells in the CNS and visceral organs, indicating aberrant localization of the truncated protein, and the expression was remarkable in oligodendrocytes within the lesion, suggesting possible involvement of the protein in the pathomechanism of vasculopathy leading to white matter degeneration.

    DOI: 10.1093/jnen/nly115

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  • Autopsy findings and clinical feature of a mild-type xeroderma pigmentosum complementation group A siblings: 40 years of follow-up 査読

    Masaki T, Tsujimoto M, Kitazawa R, Nakano E, Funasaka Y, Ichihashi M, Kitazawa S, Kakita A, Kanda F, Nishigori C

    J Am Acad Dermatol Case Reports   5 ( 3 )   205 - 208   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jdcr.2018.04.017.

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  • Sushi repeat-containing protein 1 co-accumulates with cerebrovascular Abeta deposits in cerebral amyloid angiopathy 査読

    Inoue Yasuteru, Ueda Mitsuharu, Tasaki Masayoshi, Takeshima Akari, Misumi Yohei, Kosaka Takayuki, Yamashita Taro, Takahashi Hitoshi, Kakita Akiyoshi, Ando Yukio

    BRAIN PATHOLOGY   29   179 - 180   2019年2月

  • 病理所見を理解する基礎 - 海馬硬化 - 査読

    張 璐, 田中英智, 柿田明美

    てんかん研究   39 ( 3 )   664 - 666   2019年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    てんかんをわかり易く理解するための神経科学

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  • An attempt of non-human primate modeling of schizophrenia with neonatal challenges of epidermal growth factor 査読

    Sakai M, Kashiwahara M, Kakita A, Nawa H

    J Addict Res Ther   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Surgical strategy for focal cortical dysplasia based on the analysis of the spike onset and peak zones on magnetoencephalography. 査読

    Sergei A, Takahashi M, Katsuragi Y, Kakihana T, Kitaura H, Zhang L, Kakita A, Fujii M

    J Neurosurg   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Phosphorylated NUB1 distinguishes α-synuclein in Lewy bodies from that in glial cytoplasmic inclusions of multiple system atrophy. 査読

    Tanji K, Miki Y, Mori F, Kon T, Kakita A, Takahashi H, Wakabayashi K

    Brain Pathology   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/bpa.12728.

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  • αシヌクレイノパチー (2) 多系統萎縮症 査読

    齋藤 理恵, 柿田明美

    病理と臨床   2019年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    連載-変性疾患のみかた-

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  • A minimal amount of tissue-based pH measurement to improve quality control in neuropsychiatryic postmortem brain studies. 査読

    Ono C, Yu Z, Kikuchi Y, Kunii Y, Hino M, Matsumoto J, Nagaoka A, Ito J, Iwasaki Y, Hagihara H, Miyakawa T, Yoshida M, Saito Y, Niwa S, Yabe H, Kakita A, Tomita H

    Psychiatry Clin Neurosci   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/pcn.12863.

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  • Comparison of circulating tumor DNA between body fluids in patients with primary central nervous system lymphoma. 査読

    Watanabe J, natsumeda M, kanemaru Y, Okada M, Oishi M, kakita A, Fujii Y

    Leukemia Lymphoma   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Immunoreactivity of myelin-associated oligodendrocytic basic protein in Lewy bodies. 査読

    Kon T, Tanji K, Mori F, Kimura A, Kakita A, Wakabayashi K

    Neuropathology   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/neup.12564.

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  • Podoplanin expression and IDH-wildtype status predicts venous thrombolism in patients with high-grade gliomas in early postoperative period. 査読

    Watanabe J, Natsumeda M, Okada M, Kanemaru Y, Tsukamoto Y, Oishi M, Kakita A, Fujii Y

    World Neurosurg   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.wneu.2019.05.049.

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  • A case of cerebral amyloid angiopathy-type hereditary ATTR amyloidosis with Y69H (p.Y89H) variant displaying transient focal neurological episodes as the main symptom. 査読

    Yamada Y, Fukushima T, Kodama S, Shimizu H, Kakita A, Makino K, Sekijima Y

    Amyloid   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/13506129.2019.1632829.

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  • G3BP1 inhibits ubiquitinated protein aggregations by interacting with p62 and USP10. 査読

    Sergei A, Takahashi M, Katsuragi Y, Kakihana T, Kitaura H, Zhang L, Kakita A, Fujii M

    Sci Rep   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Epigenome-wide association study of narcolepsy-affected lateral hypothalamic brain and overlapping DNA methylation profiles between narcolepsy and multiple sclerosis. 査読

    Sleep   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Investigation of betaine as a novel psychotherapyeutic for schizophrenia. 査読

    Ohnishi T, Balan S, Toyoshima M, Maekawa M, Ohba H, Watanabe A, Iwayama Y, Shimamoto C, Nozaki Y, Hisano Y, Esaki K, Mataga N, Hayashi-Takagi A, Kunii Y, Kakita A, Yabe H, Yoshikawa T

    EBioMedicine   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ebiom.2019.05.062.

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  • The epileptogenic zone in pharmacy-resistant temporal lobe epilepsy with amygdala enlargement. 査読

    Suzuki H, Sugano H, Nakajima M, Higo T, Iimura Y, Mitsuhashi T, Fusegi K, Kakita A, Otsubo H, Arai H

    Epileptic Disord   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1684/epd.2019.1075.

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  • Morphological characterizeation of glial and neuronal tau pathology in globular glial tauopathy (types II and III). 査読

    Neuropathol Appl Neurobiol   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Pathologic alterations of chondroitin sulfate moiety in the postmortem hippocampus of patients with schizophrenia. 査読

    Yukawa T, Iwakura Y, Takei N, Saito M, Watanabe Y, Toyooka K, Igarashi M, Niizato K, Ohima K, Kunii Y, Yabe H, Matsumoto J, Wada A, Hino M, Iritani S, Niwa S, Takeuchi R, Takahashi H, Kakita A, Someya T, Nawa H

    Psychiatry Res   270   940 - 946   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.psychres.2018.10.062.

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  • Clinicopathologic Features of Two Patients With Sporadic Amyotrophic Lateral Sclerosis Who Maintained Communication Ability for Over 30 Years. 査読 国際誌

    Junko Ito, Tetsuro Shimada, Mari Tada, Hiroshi Shimizu, Masatoshi Wakabayashi, Akio Yokoseki, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

    Journal of neuropathology and experimental neurology   77 ( 11 )   981 - 986   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report the clinicopathologic features of 2 unrelated patients with sporadic amyotrophic lateral sclerosis (SALS) supported by tracheostomy and invasive ventilation (TIV) who were able to maintain communication ability for more than 30 years after disease onset. In both cases, the age at onset was younger than the mean, initially the progression of muscle weakness was consistent with that in the majority of SALS patients, and TIV became necessary several years after disease onset. Thereafter, however, their neurologic deterioration slowed and the patients were able to operate computers by facial movements for several decades. At autopsy, neuronal loss appeared to be confined to the motor neuron system. Furthermore, while Betz cells and lower motor neurons in the spinal anterior horns and hypoglossal nucleus were severely depleted, other pyramidal neurons in the motor cortex, and lower motor neurons in the other brainstem motor nuclei were retained. Neuronal and glial cytoplasmic inclusions immunoreactive for phosphorylated 43-kDa TAR DNA-binding protein (TDP-43) were evident in the CNS, but in extremely small numbers. The present patients may represent a distinct subgroup of patients with SALS who are able to maintain communication ability for an extremely long period, accompanied by very mild TDP-43 pathology.

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  • Neuronal intranuclear inclusion disease showing intranuclear inclusions in renal biopsy 12 years earlier. 査読

    Motoki M, Nakajima H, Sato T, Tada M, Kakita A, Arawaka S

    Neurology   91 ( 19 )   884 - 886   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1212/WNL.0000000000006480

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  • USP10 is a driver of ubiquitinated protein aggregation and aggresome formation to inhibit apoptosis. 査読

    Takahashi M, Kitaura H, Kakita A, Kakihana T, Katsuragi Y, Nameta M, Zhang L, Iwakura Y, Nawa H, Higuchi M, Komatsu M, Fujii M

    iScience   9   433 - 450   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.isci.2018.11.006

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  • 診断が困難であった進行性核上性麻痺の剖検例 査読

    田中 弘, 田中 英智, 清水 宏, 柿田 明美, 高橋 均

    新潟医学会雑誌   132 ( 10 )   368 - 368   2018年10月

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    記述言語:日本語   出版者・発行元:新潟医学会  

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  • Altered expression of glutamate transporter-1 and water channel protein aquaporin-4 in human temporal cortex with Alzheimer's disease. 査読

    Hoshi A, Tsunoda A, Yamamoto T, Tada M, Kakita A, Ugawa Y

    Neuropathology and applied neurobiology   44 ( 6 )   628 - 638   2018年10月

  • Autophagy mediators (FOXO1, SESN3 and TSC2) in Lewy body disease and aging. 査読 国際誌

    Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, Jun Utsumi, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    Neuroscience letters   684   35 - 41   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neurodegenerative disorders such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by impairment of autophagy. Cellular survival is dependent on efficient clearance of phosphorylated α-synuclein, which accumulates as fibrils in the neuronal cytoplasm as Lewy bodies (LBs). The forkhead box O 1 (FOXO1) is a member of the FOXO family that functions in various intracellular processes including regulation of autophagy. Transcriptional activation of FOXO1 has been reported to initiate autophagy by inhibiting the expression of Mechanistic Target of Rapamycin (mTOR), mediated by sestrin 3 (SESN3) and tuberous sclerosis complex 2 (TSC2). Although many autophagy-related proteins are known to be incorporated into LBs, no report has documented the involvement of these autophagy modulators (FOXO1, SESN3 and TSC2) in the pathogenesis of PD and DLB. In the present study, we performed immunostaining and Western blot analysis using the brains of normal controls and patients with PD and DLB in order to clarify the involvement of FOXO1, SESN3 and TSC2 in LBs. Our study demonstrated for the first time the presence of FOXO1, SESN3 and TSC2 in brainstem-type LBs. The expression levels of these proteins in the brain did not differ between the normal controls and patients with PD or DLB. We further utilized mice model to investigate the effect of α-synuclein overexpression on these proteins, and found that TSC2 was significantly increased in α-synuclein transgenic mice relative to wild type mice at 9 weeks of age, but not at 30 weeks of age. Together with expression data showing gradual increase of these molecules with age in wild type mice, these findings suggest that autophagy modulators are incorporated into LBs and that the expression of these proteins can be increased by various factors including aging.

    DOI: 10.1016/j.neulet.2018.06.052

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  • Astroblastoma: a distinct tumor entity characterized by alterations of the X chromosome and MN1 rearrangement 査読

    Takanori Hirose, Sumihito Nobusawa, Kazuhiko Sugiyama, Vishwa J. Amatya, Naomi Fujimoto, Atsushi Sasaki, Yoshiki Mikami, Akiyoshi Kakita, Shinya Tanaka, Hideaki Yokoo

    Brain Pathology   28 ( 5 )   684 - 694   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    © 2017 International Society of Neuropathology Astroblastoma is a rare, enigmatic tumor of the central nervous system (CNS) which shares some clinicopathologic aspects with other CNS tumors, especially ependymoma. To further clarify the nature of astroblastoma, we performed clinicopathologic and molecular genetic studies on eight cases of astroblastoma. The median age of the patients was 14.5 years, ranging from 5 to 60 years, and seven of the patients were female. All tumors arose in the cerebral hemisphere and radiologically appeared to be well-bordered, nodular tumors often associated with cystic areas and contrast-enhancement. Six of the seven patients with prognosis data survived without recurrences during the follow-up periods ranging from six to 76 months. One patient had multiple recurrences and died six years later. All tumors exhibited salient microscopic features, such as being well demarcated from the surrounding brain tissue, perivascular arrangement of epithelioid tumor cells (represented by “astroblastic” pseudorosettes, trabecular alignment, and pseudopapillary patterns), and hyalinized blood vessels. Immunoreactivity for GFAP, S-100 protein, Olig2, and EMA was variably demonstrated in all tumors, and IDH1 R132H and L1CAM were negative. Array comparative genomic hybridization revealed numerous heterozygous deletions on chromosome X in the four tumors studied, and break-apart fluorescence in situ hybridization demonstrated rearrangement of MN1 in five tumors with successful testing. The characteristic clinicopathologic and genetic findings support the idea that astroblastoma is distinct from other CNS tumors, in particular, ependymoma. In addition, MN1 rearrangement and aberrations of chromosome X may partly be involved in the pathogenesis of astroblastoma.

    DOI: 10.1111/bpa.12565

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  • Chemical Landscape for Tissue Clearing Based on Hydrophilic Reagents. 査読 国際誌

    Kazuki Tainaka, Tatsuya C Murakami, Etsuo A Susaki, Chika Shimizu, Rie Saito, Kei Takahashi, Akiko Hayashi-Takagi, Hiroshi Sekiya, Yasunobu Arima, Satoshi Nojima, Masako Ikemura, Tetsuo Ushiku, Yoshihiro Shimizu, Masaaki Murakami, Kenji F Tanaka, Masamitsu Iino, Haruo Kasai, Toshikuni Sasaoka, Kazuto Kobayashi, Kohei Miyazono, Eiichi Morii, Tadashi Isa, Masashi Fukayama, Akiyoshi Kakita, Hiroki R Ueda

    Cell reports   24 ( 8 )   2196 - 2210   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We describe a strategy for developing hydrophilic chemical cocktails for tissue delipidation, decoloring, refractive index (RI) matching, and decalcification, based on comprehensive chemical profiling. More than 1,600 chemicals were screened by a high-throughput evaluation system for each chemical process. The chemical profiling revealed important chemical factors: salt-free amine with high octanol/water partition-coefficient (logP) for delipidation, N-alkylimidazole for decoloring, aromatic amide for RI matching, and protonation of phosphate ion for decalcification. The strategic integration of optimal chemical cocktails provided a series of CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) protocols, which efficiently clear mouse organs, mouse body including bone, and even large primate and human tissues. The updated CUBIC protocols are scalable and reproducible, and they enable three-dimensional imaging of the mammalian body and large primate and human tissues. This strategy represents a future paradigm for the rational design of hydrophilic clearing cocktails that can be used for large tissues.

    DOI: 10.1016/j.celrep.2018.07.056

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  • フラビン蛍光イメージングによるてんかん原性の解析 査読

    北浦弘樹, 柿田明美

    Clin Neurosci   36 ( 8 )   970 - 972   2018年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Human-specific features of spatial gene expression and regulation in eight brain regions. 査読

    Xu C, Li Q, Efimova O, He L, Tatsumoto S, Stepanova V, Oishi T, Udono T, Yamaguchi K, Shigenobu S, Kakita A, Nawa H, Khaitovich P, Go Y

    Genome research   28 ( 8 )   1097 - 1110   2018年8月

  • Aquaporin Positron Emission Tomography Differentiates Between Grade III and IV Human Astrocytoma. 査読 国際誌

    Yuji Suzuki, Yukihiro Nakamura, Kenichi Yamada, Satoshi Kurabe, Kouichirou Okamoto, Hiroshi Aoki, Hiroki Kitaura, Akiyoshi Kakita, Yukihiko Fujii, Vincent J Huber, Hironaka Igarashi, Ingrid L Kwee, Tsutomu Nakada

    Neurosurgery   82 ( 6 )   842 - 846   2018年6月

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    記述言語:英語  

    BACKGROUND: Aquaporin (AQP) water channels play a significant role in mesenchymal microvascular proliferation and infiltrative growth. AQPs are highly expressed in malignant astrocytomas, and a positive correlation is observed between their expression levels and histological tumor grade. OBJECTIVE: To examine the utility of aquaporin positron emission tomography (PET) for differentiating between astrocytoma grade III and grade IV using the AQP radioligand [11C]TGN-020. METHODS: Fifteen astrocytoma patients, grade III (n = 7) and grade IV (n = 8), and 10 healthy volunteers underwent [11C]TGN-020 aquaporin PET imaging. Surgical tissues of astrocytoma patients were examined for histopathological grading using the WHO classification standard and expression of AQP1 and AQP4 immunohistochemically. RESULTS: Mean standardized uptake values of astrocytoma grade III and IV (0.51 ± 0.11 vs 1.50 ± 0.44, respectively) were higher than normal white matter (0.17 ± 0.02, P < .001) for both tumor grades. Importantly, mean standardized uptake values of astrocytoma grade IV were significantly higher than grade III (P < .01). CONCLUSION: Our study demonstrated that [11C]TGN-020 aquaporin PET imaging differentiated between astrocytoma grades III and IV. We suggest its clinical application as a noninvasive diagnostic tool would lead to advancements in the management of these malignant brain tumors.

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  • Effects of the −141C insertion/deletion polymorphism in the dopamine D2 receptor gene on the dopamine system in the striatum in patients with schizophrenia 査読

    Junya Matsumoto, Atsuko Nagaoka, Yasuto Kunii, Itaru Miura, Mizuki Hino, Shin-ichi Niwa, Hiroyuki Nawa, Hitoshi Takahashi, Akiyoshi Kakita, Hirooki Yabe

    Psychiatry Research   264   116 - 118   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier Ireland Ltd  

    The relationships between −141C insertion/deletion (Ins/Del) polymorphisms in the dopamine D2 receptor gene and the two dopamine system integrators, i.e., dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN), are still unclear. In this study, we assessed the effect of this polymorphism on DARPP-32 and CaN protein expression in the postmortem striatum of patients with schizophrenia and control individuals. The expression levels of truncated DARPP and CaN were lower in Del allele carriers. These findings provide important insights into the mechanism by which this genotype could result in a poor response to antipsychotic drugs.

    DOI: 10.1016/j.psychres.2018.03.029

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  • Intractable epilepsy due to a rosette-forming glioneuronal tumor with a dysembryoplastic neuroepithelial background. 査読 国際誌

    Noriko Sumitomo, Akihiko Ishiyama, Makoto Shibuya, Eiji Nakagawa, Yu Kaneko, Akio Takahashi, Taisuke Otsuki, Akiyoshi Kakita, Yuko Saito, Noriko Sato, Kenji Sugai, Masayuki Sasaki

    Neuropathology : official journal of the Japanese Society of Neuropathology   38 ( 3 )   300 - 304   2018年6月

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    記述言語:英語  

    A rosette-forming glioneuronal tumor (RGNT) was initially reported as an infratentorial tumor that comprised both small neurocytic rosettes and astrocytic components. However, a few studies have reported supratentorial RGNTs arising in the cerebral hemispheres. Here, we report an unusual case involving a 9-year-old boy with a supratentorial RGNT who presented with intractable epilepsy and behavioral changes. Brain MRI revealed a well-circumscribed space-occupying lesion with septae in the right inferomedial parietal lobe. Electroencephalography showed multifocal spikes over the right frontal, temporal and parietal regions. The seizure frequency decreased dramatically after tumorectomy. Histopathological examination revealed prominent neurocytic rosette formation appearing with the specific glioneuronal element of a dysembryoplastic neuroepithelial tumor (DNT). Although the pathogenesis has not been elucidated, a supratentorial RGNT presenting with epilepsy may exhibit a rosette component, which is the major feature of this tumor, against the background of a specific glioneuronal element mimicking DNT. However, RGNT arising in regions other than the fourth ventricle is rare, and the pathogenesis of epilepsy due to RGNT has not been fully elucidated. Further clinical and histological studies are required to understand the pathology underlying epilepsy caused by RGNT.

    DOI: 10.1111/neup.12450

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  • Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation. 査読 国際誌

    Junko Ito, Hiroaki Nozaki, Yasuko Toyoshima, Takashi Abe, Aki Sato, Hideki Hashidate, Shuichi Igarashi, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

    Neuropathology : official journal of the Japanese Society of Neuropathology   38 ( 4 )   428 - 432   2018年5月

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    記述言語:英語  

    Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary cerebral small vessel disease (CSVD) caused by homozygous or compound heterozygous mutations of the high temperature requirement A serine peptidase 1 gene (HTRA1). Affected patients suffer from cognitive impairment, recurrent strokes, lumbago and alopecia. Recently, clinical studies have indicated that some patients with heterozygous mutations in HTRA1 may also suffer CSVD. Here, we report the histopathologic features of an autopsied 55-year-old male patient who had shown cognitive impairment and multiple cerebral infarcts, and was found to have a heterozygous missense mutation (p.R302Q) in the HTRA1 gene. Histologically, small vessels in the brain and spinal cord showed intimal proliferation, splitting of the internal elastic lamina, and degeneration of smooth muscle cells in the tunica media. Thus, although less severe, the features were quite similar to those of patients with CARASIL, indicating that patients with heterozygous mutations develop CSVD through underlying pathomechanisms similar to those of CARASIL.

    DOI: 10.1111/neup.12473

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  • 前頭側頭葉変性症の組織学的分類 査読

    他田真理, 柿田明美

    Brain Nerve   70 ( 5 )   501 - 516   2018年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    特集:非アルツハイマー型認知症の病理学

    DOI: 10.11477/mf.1416201033.

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  • 遺伝性脳血管障害の神経病理 査読

    齋藤理恵, 伊藤慎治, 野崎洋明, 柿田明美

    神経内科   88 ( 5 )   516 - 523   2018年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    特集:神経病理:update

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  • Globular glial tauopathyの神経病理 査読

    田中英智, 豊島靖子, 柿田明美

    神経内科   88 ( 5 )   477 - 482   2018年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    特集:神経病理:update

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  • 限局性皮質異形成でT1強調高信号を呈した症例の検討 査読

    老谷 嘉樹, 木村 有喜男, 須貝 研司, 齊藤 祐子, 池谷 直樹, 岩崎 真樹, 竹下 絵里, 本橋 裕子, 石山 昭彦, 齋藤 貴志, 小牧 宏文, 中川 栄二, 柿田 明美, 佐藤 典子, 佐々木 征行

    脳と発達   50 ( Suppl. )   S336 - S336   2018年5月

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    記述言語:日本語   出版者・発行元:(一社)日本小児神経学会  

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  • [Neuropathologic Subtypes of Frontotemporal Lobar Degeneration]. 査読

    Tada M, Kakita A

    Brain and nerve = Shinkei kenkyu no shinpo   70 ( 5 )   501 - 516   2018年5月

  • Loss of Motor Neurons Innervating Cervical Muscles in Patients With Multiple System Atrophy and Dropped Head. 査読 国際誌

    Rie Saito, Mari Tada, Yasuko Toyoshima, Masatoyo Nishizawa, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

    Journal of neuropathology and experimental neurology   77 ( 4 )   317 - 324   2018年4月

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    記述言語:英語  

    We investigated whether loss of motor neurons innervating the neck muscles contributes to dropped head (DH) in multiple system atrophy (MSA). From 75 patients with autopsy-proven MSA, we retrieved 3 who had DH (MSA-DH), and examined the 4th cervical cord segments. Neurons of the medial and lateral nuclear groups (MNG and LNG) innervate the neck and shoulder muscles, respectively. We measured the area of individual neurons in the MNG and LNG, and created an area-frequency histogram. Neurons were classified as large or small based on their area, and their total numbers in the MNG and LNG were counted. In the MNG, the numbers of both total neurons and large neurons were significantly lower in MSA patients than in the controls (214.2 ± 91.4 vs 521.3 ± 74.8, p = 0.0030, and 26.2 ± 9.1 vs 88.0 ± 34.6, p = 0.020, respectively), and were significantly lower in MSA-DH than in MSA-nonDH (139.7 ± 7.6 vs 288.7 ± 74.6, p = 0.048, and 18.0 ± 4.1 vs 34.3 ± 4.1, p = 0.016, respectively). There were no differences in the LNG neuron counts between the MSA-DH and MSA-nonDH groups. Loss of cervical motor neurons may be responsible for DH in MSA.

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  • The perivascular microenvironment in Epstein–Barr virus positive primary central nervous system lymphoma: The role of programmed cell death 1 and programmed cell death ligand 1 査読

    Yasuo Sugita, Takuya Furuta, Koichi Ohshima, Satoru Komaki, Junko Miyoshi, Motohiro Morioka, Hideyuki Abe, Takanori Nozawa, Yukihiko Fujii, Hitoshi Takahashi, Akiyoshi Kakita

    Neuropathology   38 ( 2 )   125 - 134   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blackwell Publishing  

    It has been shown that high expression of certain immune checkpoint molecules, including those of the programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) axis, can be utilized to regulate immunosuppression in the microenvironment of malignant neoplasms. For the purpose of clarifying the immune-escape mechanism of primary central nervous system lymphomas (PCNSLs), particularly in Epstein–Barr virus (EBV)-positive cases, markers for PD-1, PD-L1, tumor-associated macrophages (TAMs), and tumor-infiltrating lymphocytes (TILs) in 39 surgical specimens of PCNSLs (17 EBV-positive, 22 EBV-negative) were investigated by immunohistochemistry. Staining for PD-L1 was scored as follows: (−), no staining
    (1+), 0–30% positive cells
    (2+), 30–60% positive cells
    and (3+), &gt
    60% positive cells. In EBV-positive cases, PD-L1 was detected in both lymphoma cells and TAMs in 12/17 cases, and in TAMs only in 4/17 cases. The mean number of PD-1, TIA-1 (a marker for cytotoxic T-cells), and FOXP3 (a marker for regulatory T-cells)-positive TILs in EBV-positive cases was 36.4 ± 45.9, 390 ± 603, and 9.88 ± 15.1, respectively. In EBV-negative cases, PD-L1 was detected in both lymphoma cells and TAMs in 11/22 cases, and in TAMs only in 4/22 cases. The mean of PD-1, TIA-1 and FOXP3-positive lymphocytes in EBV-negative cases was 67.3 ± 82.0, 158 ± 206 and 9.32 ± 17.5, respectively. We found no significant difference in the number of FOXP3-positive, lymphocytes between EBV-positive and negative cases. However, there were significantly higher numbers of PD-1-positive lymphocytes in the former, and significantly higher numbers of TIA-1-positive lymphocytes in the latter (P &lt
    0.05). The combined data indicate that expression of PD-L1 by lymphoma cells and TAMs mediate the trafficking of TILs, which may explain the immune-escape process of PCNSLs. In addition, EBV infection appears to affect the trafficking mechanism of TILs, and may thus play an important role in the microenvironment immunity of these tumors.

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  • Reliable diagnosis of IDH-mutant glioblastoma by 2-hydroxyglutarate detection: a study by 3-T magnetic resonance spectroscopy. 査読 国際誌

    Manabu Natsumeda, Kunio Motohashi, Hironaka Igarashi, Takanori Nozawa, Hideaki Abe, Yoshihiro Tsukamoto, Ryosuke Ogura, Masayasu Okada, Tsutomu Kobayashi, Hiroshi Aoki, Hitoshi Takahashi, Akiyoshi Kakita, Kouichirou Okamoto, Tsutomu Nakada, Yukihiko Fujii

    Neurosurgical review   41 ( 2 )   641 - 647   2018年4月

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    記述言語:英語  

    We have previously reported that reliable detection of 2-hydroxyglutarate (2HG) in isocitrate dehydrogenase (IDH)-mutant WHO grade 2 and 3 gliomas is possible utilizing 3.0-T single-voxel magnetic resonance spectroscopy (SVMRS). We set out to determine whether the same method could be applied to detect 2HG in IDH-mutant glioblastoma. Forty-four patients harboring glioblastoma underwent pre-operative MRS evaluation to detect 2HG and other metabolites. Presence of IDH-mutations was determined by IDH1 R132H immunohistochemical analysis and DNA sequencing of surgically obtained tissues. Six out of 44 (13.6%) glioblastomas were IDH-mutant. IDH-mutant glioblastoma exhibited significantly higher accumulation of 2HG (median 3.191 vs. 0.000 mM, p < 0.0001, Mann-Whitney test). A cutoff of 2HG = 0.897 mM achieved high sensitivity (100.0%) and specificity (92.59%) in determining IDH-mutation in glioblastoma. Glioblastoma with high 2HG accumulation did not have significantly longer overall survival than glioblastoma with low 2HG accumulation (p = 0.107, log-rank test). Non-invasive and reliable detection of 2HG in IDH-mutant glioblastoma was possible by 3.0-T SVMRS.

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  • Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy 査読

    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, Satomi Inomata-Terada, Masashi Hamada, Yuichiro Shirota, Akatsuki Kubota, Yoshikazu Ugawa, Kishin Koh, Yoshihisa Takiyama, Natsumi Ohsawa-Yoshida, Shoichi Ishiura, Ryo Yamasaki, Akira Tamaoka, Hiroshi Akiyama, Taisuke Otsuki, Akira Sano, Akio Ikeda, Jun Goto, Shinichi Morishita, Shoji Tsuji

    Nature Genetics   50 ( 4 )   581 - 590   2018年4月

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    掲載種別:研究論文(学術雑誌)  

    © 2018 The Author(s). 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.

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  • YOD1 attenuates neurogenic proteotoxicity through its deubiquitinating activity. 査読 国際誌

    Kunikazu Tanji, Fumiaki Mori, Yasuo Miki, Jun Utsumi, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    Neurobiology of disease   112   14 - 23   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ubiquitination, a fundamental post-translational modification of intracellular proteins, is enzymatically reversed by deubiquitinase enzymes (deubiquitinases). >90 deubiquitinases have been identified. One of these enzymes, YOD1, possesses deubiquitinase activity and is similar to ovarian tumor domain-containing protein 1, which is associated with regulation of the endoplasmic reticulum (ER)-associated degradation pathway. Indeed, YOD1 is reported to be involved in the ER stress response induced by mislocalization of unfolded proteins in mammalian cells. However, it has remained unclear whether YOD1 is associated with pathophysiological conditions such as mitochondrial damage, impaired proteostasis, and neurodegeneration. We demonstrated that YOD1 possesses deubiquitinating activity and exhibits preference for K48- and K63-linked ubiquitin. Furthermore, YOD1 expression levels increased as a result of various stress conditions. We demonstrated that the neurogenic proteins that cause Huntington disease and Parkinson's disease induced upregulation of YOD1 level. We observed that YOD1 reduced disease cytotoxicity through efficient degradation of mutant proteins, whereas this activity was abolished by catalytically inactive YOD1. Additionally, YOD1 localized to Lewy bodies in Parkinson's disease patients. Collectively, these data suggest that the deubiquitinase YOD1 contributes to pathogenesis of neurodegenerative disease by decreasing ubiquitination of abnormal proteins and their subsequent degradation.

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  • Pathophysiological Characteristics Associated With Epileptogenesis in Human Hippocampal Sclerosis 査読

    Hiroki Kitaura, Hiroshi Shirozu, Hiroshi Masuda, Masafumi Fukuda, Yukihiko Fujii, Akiyoshi Kakita

    EBioMedicine   29   38 - 46   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier B.V.  

    Mesial temporal lobe epilepsy (MTLE) is the most frequent focal epileptic syndrome in adults, and the majority of seizures originate primarily from the hippocampus. The resected hippocampal tissue often shows severe neuronal loss, a condition referred to as hippocampal sclerosis (HS). In order to understand hippocampal epileptogenesis in MTLE, it seems important to clarify any discrepancies between the clinical and pathological features of affected patients. Here we investigated epileptiform activities ex vivo using living hippocampal tissue taken from patients with MTLE. Flavoprotein fluorescence imaging and local field potential recordings revealed that epileptiform activities developed from the subiculum. Moreover, physiological and morphological experiments revealed possible impairment of K+ clearance in the subiculum affected by HS. Stimulation of mossy fibers induced recurrent trans-synaptic activity in the granule cell layer of the dentate gyrus, suggesting that mossy fiber sprouting in HS also contributes to the epileptogenic mechanism. These results indicate that pathophysiological alterations involving the subiculum and dentate gyrus could be responsible for epileptogenesis in patients with MTLE.

    DOI: 10.1016/j.ebiom.2018.02.013

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  • Frontoethmoidal Schwannoma with Exertional Cerebrospinal Fluid Rhinorrhea: Case Report and Review of Literature 査読

    Yuichiro Yoneoka, Katsuhiko Akiyama, Yasuhiro Seki, Go Hasegawa, Akiyoshi Kakita

    World Neurosurgery   111   381 - 385   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier Inc.  

    Background: Frontoethmoidal schwannomas are rare. No case manifesting exertional cerebrospinal fluid (CSF) rhinorrhea has ever been reported to the best of our knowledge. Case Description: In this report, we describe an extremely rare case of frontoethmoidal schwannoma extending through the olfactory groove with exertional CSF rhinorrhea as the initial symptom. A 50-year-old woman was presented to our clinic for frequent nasal discharge on exertion. A postcontrast computed tomographic scan demonstrated heterogeneously enhanced tumor from the anterior cranial fossa to the anterior ethmoid sinus. A gadolinium-enhanced T1-weighted magnetic resonance image revealed a well-defined heterogeneously enhanced tumor situated in the midline anterior cranial fossa and anterior ethmoid sinus. After the resection, the defect of the right anterior skull base was reconstructed with a fascia graft and adipose tissue taken from the abdomen, as well as a pedicle periosteum flap. A histologic examination revealed the tumor as schwannoma. Her rhinorrhea completely resolved. She regained her sense of smell and taste 1 month after the operation. Conclusion: According to previous reports, olfactory groove, and paraolfactory groove/periolfactory groove schwannomas can be divided into 4 types: subfrontal, nasoethmoidal, frontoethmoidal, and ethmofrontal. Among them, a frontoethmoidal schwannoma can manifest exertional CSF rhinorrhea as an initial symptom.

    DOI: 10.1016/j.wneu.2018.01.015

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  • ミクログリアの組織学的特徴 査読

    他田真理, 柿田明美

    Clinical Neuroscience   36 ( 3 )   276 - 277   2018年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    臨床医のための神経病理 再入門

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  • Loss of kallikrein-related peptidase 7 exacerbates amyloid pathology in Alzheimer's disease model mice. 査読 国際誌

    Kiwami Kidana, Takuya Tatebe, Kaori Ito, Norikazu Hara, Akiyoshi Kakita, Takashi Saito, Sho Takatori, Yasuyoshi Ouchi, Takeshi Ikeuchi, Mitsuhiro Makino, Takaomi C Saido, Masahiro Akishita, Takeshi Iwatsubo, Yukiko Hori, Taisuke Tomita

    EMBO molecular medicine   10 ( 3 )   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Deposition of amyloid-β (Aβ) as senile plaques is one of the pathological hallmarks in the brains of Alzheimer's disease (AD) patients. In addition, glial activation has been found in AD brains, although the precise pathological role of astrocytes remains unclear. Here, we identified kallikrein-related peptidase 7 (KLK7) as an astrocyte-derived Aβ degrading enzyme. Expression of KLK7 mRNA was significantly decreased in the brains of AD patients. Ablation of Klk7 exacerbated the thioflavin S-positive Aβ pathology in AD model mice. The expression of Klk7 was upregulated by Aβ treatment in the primary astrocyte, suggesting that Klk7 is homeostatically modulated by Aβ-induced responses. Finally, we found that the Food and Drug Administration-approved anti-dementia drug memantine can increase the expression of Klk7 and Aβ degradation activity specifically in the astrocytes. These data suggest that KLK7 is an important enzyme in the degradation and clearance of deposited Aβ species by astrocytes involved in the pathogenesis of AD.

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  • Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset Epileptic Encephalopathy. 査読 国際誌

    Hiroki Mutoh, Mitsuhiro Kato, Tenpei Akita, Takuma Shibata, Hiroyuki Wakamoto, Hiroko Ikeda, Hiroki Kitaura, Kazushi Aoto, Mitsuko Nakashima, Tianying Wang, Chihiro Ohba, Satoko Miyatake, Noriko Miyake, Akiyoshi Kakita, Kensuke Miyake, Atsuo Fukuda, Naomichi Matsumoto, Hirotomo Saitsu

    American journal of human genetics   102 ( 2 )   321 - 329   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Early-onset epileptic encephalopathies, including West syndrome (WS), are a group of neurological disorders characterized by developmental impairments and intractable seizures from early infancy. We have now identified biallelic CNPY3 variants in three individuals with WS; these include compound-heterozygous missense and frameshift variants in a family with two affected siblings (individuals 1 and 2) and a homozygous splicing variant in a consanguineous family (individual 3). All three individuals showed hippocampal malrotation. In individuals 1 and 2, electroencephalography (EEG) revealed characteristic fast waves and diffuse sharp- and slow-wave complexes. The fast waves were clinically associated with seizures. CNPY3 encodes a co-chaperone in the endoplasmic reticulum and regulates the subcellular distribution and responses of multiple Toll-like receptors. The amount of CNPY3 in lymphoblastoid cells derived from individuals 1 and 2 was severely lower than that in control cells. Cnpy3-knockout mice exhibited spastic or dystonic features under resting conditions and hyperactivity and anxiolytic behavior during the open field test. Also, their resting EEG showed enhanced activity in the fast beta frequency band (20-35 Hz), which could mimic the fast waves in individuals 1 and 2. These data suggest that CNPY3 and Cnpy3 perform essential roles in brain function in addition to known Toll-like receptor-dependent immune responses.

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  • Biallelic variants in CNPY3, which encodes an endoplasmic reticulum chaperone, cause early-onset epileptic encephalaopathy. 査読

    Mutoh H, Kato M, Akita T, Shibata T, Wakamoto H, Ikeda H, Kitaura H, Aoto K, Nakashima M, Wang T, Ohba C, Miyatake S, Miyake N, Kakita A, Miyake K, Fukuda A, Matsumoto N, Saitsu H

    Am J Hum Genet   102 ( 2 )   321 - 329   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ajhg.2018.01.004.

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  • Immunohistochemical localization of exoribonucleases (DIS3L2 and XRN1) in intranuclear inclusion body disease. 査読 国際誌

    Fumiaki Mori, Kunikazu Tanji, Yasuo Miki, Yasuko Toyoshima, Hidenao Sasaki, Mari Yoshida, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    Neuroscience letters   662   389 - 394   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    mRNA turnover controls gene expression under various conditions in aging and neurodegenerative diseases. Polyglutamine (polyQ) diseases and intranuclear inclusion body disease (INIBD) are neurodegenerative diseases characterized by the formation of nuclear inclusions. These inclusions are immunopositive for several proteins associated with amyotrophic lateral sclerosis. In amyotrophic lateral sclerosis, the processing of RNA from gene transcription through degradation (RNA metabolism) has been reported to be altered. We hypothesized that the proteins associated with RNA metabolism are also involved in the formation of nuclear inclusions in polyQ diseases and INIBD. 3'-5' exoribonuclease DIS3L2 and 5'-3' exoribonuclease XRN1 play critical roles in mRNA decay. Using immunohistochemistry with antibodies against DIS3L2 and XRN1, we examined the brains of patients with polyQ diseases and INIBD and normal control subjects. In controls, immunoreactivity for DIS3L2 and XRN1 was found in the neuronal cytoplasm and neuropil, respectively. In INIBD, immunoreactivity for DIS3L2 and XRN1 was present in neuronal and glial nuclear inclusions. Co-localization of ubiquitin and DIS3L2 or XRN1 was demonstrated in these inclusions. In polyQ diseases, however, nuclear inclusions were immunonegative for DIS3L2 and XRN1. These findings suggest that sequestration of exoribonucleases to nuclear inclusions may be related to the pathogenesis of INIBD.

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  • AMBRA1, a novel α-synuclein-binding protein, is implicated in the pathogenesis of multiple system atrophy. 査読 国際誌

    Miki Y, Tanji K, Mori F, Tatara Y, Utsumi J, Sasaki H, Kakita A, Takahashi H, Fimia GM, Wakabayashi K

    Brain pathology (Zurich, Switzerland)   28 ( 1 )   28 - 42   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/bpa.12461

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  • Comprehensive genetic characterization of rosette-forming glioneuronal tumors: independent component analysis by tissue microdissection. 査読 国際誌

    Yohei Kitamura, Takashi Komori, Makoto Shibuya, Kentaro Ohara, Yuko Saito, Saeko Hayashi, Aya Sasaki, Eiji Nakagawa, Ryosuke Tomio, Akiyoshi Kakita, Masashi Nakatsukasa, Kazunari Yoshida, Hikaru Sasaki

    Brain pathology (Zurich, Switzerland)   28 ( 1 )   87 - 93   2018年1月

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    記述言語:英語  

    A rosette-forming glioneuronal tumor (RGNT) is a rare mixed neuronal-glial tumor characterized by biphasic architecture of glial and neurocytic components. The number of reports of genetic analyses of RGNTs is few. Additionally, the genetic background of the unique biphasic pathological characteristics of such mixed neuronal-glial tumors remains unclear. To clarify the genetic background of RGNTs, we performed separate comprehensive genetic analyses of glial and neurocytic components of five RGNTs, by tissue microdissection. Two missense mutations in FGFR1 in both components of two cases, and one mutation in PIK3CA in both components of one case, were detected. In the latter case with PIK3CA mutation, the additional FGFR1 mutation was detected only in the glial component. Moreover, the loss of chromosome 13q in only the neurocytic component was observed in one other case. Their results suggested that RGNTs, which are tumors harboring two divergent differentiations that arose from a single clone, have a diverse genetic background. Although previous studies have suggested that RGNTs and pilocytic astrocytomas (PAs) represent the same tumor entity, their results confirm that the genetic background of RGNTs is not identical to that of PA.

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  • Ectopic pituitary null cell adenoma arising from the infundibulum in the third ventricle: A successful endonasal transsphenoidal resection after long-term follow-up MR imaging – A technical note 査読

    Yuichiro Yoneoka, Masayasu Okada, Naoto Watanabe, Satoru Aoki, Akiyoshi Kakita, Yukihiko Fujii

    Interdisciplinary Neurosurgery: Advanced Techniques and Case Management   10   122 - 125   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier B.V.  

    Background Since the origin and growth pattern of third ventricle ectopic pituitary adenoma (ectPA) remain unclear, its optimal surgical approach is debatable. Clinical presentation We present a rare case of null cell pituitary adenoma arising from the pituitary infundibulum with long-term preoperative follow-up images. The tumor was resected gross-totally via an extended transsphenoidal approach. Conclusion To our best knowledge, this is the first case with long-term preoperative follow-up images, which can bridge the knowledge gap in operations of third ventricle ectPA as following: (1) Truly third ventricle ectPA can exist, (2) the third ventricle ectPA extended into the sella turcica along the pituitary stalk, (3) this ectPA can arise from the suprasellar peri-infundibular ectopic pituitary cells or the pars tuberalis of the adenohypophysis, and therefore adhere to the optic chiasm, (4) thus neurosurgeons should take great care in resection of ectPA arising from the infundibulum, and (5) it can be resected through an endoscopic extended transsphenoidal approach.

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  • Third Ventricle Germ Cell Tumor Originating from the Infundibulum with Rapidly Expansive Enlargement 査読

    Yuichiro Yoneoka, Junichi Yoshimura, Masakazu Sano, Masayasu Okada, Akiyoshi Kakita, Yukihiko Fujii

    Pediatric Neurosurgery   53 ( 1 )   49 - 54   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:S. Karger AG  

    We present a pediatric case of a rapidly expanding third ventricle germ cell tumor (GCT). A 14-year-old boy suffered from gradual-onset central diabetes insipidus (DI) and received desmopressin treatment. Magnetic resonance imaging (MRI) showed nonspecific findings of the pituitary-hypothalamic axis. Nine months after the initial DI diagnosis, he developed progressively worsening headache. MRI demonstrated a third ventricle tumor causing noncommunicating hydrocephalus, although an MRI 16 weeks before admission did not show the lesion. We performed gross total resection (GTR) of the tumor in 2 stages: a translamina terminalis approach and an extended transsphenoidal approach. The lesion was histologically diagnosed as immature teratoma with some germinoma. His noncommunicating hydrocephalus resolved after surgery. Through postoperative radiochemotherapy (whole ventricle: 23.4 Gy/13 fractions, tumor bed: 27.0 Gy/15 fractions, and 3 courses of carboplatin-etoposide), he has was in complete remission at the 3-year follow-up and has continued his high school program. This case suggests the following: (1) a mixed GCT originating from the neurohypophysis/infundibulum can show rapidly expansive growth in a child with central DI
    (2) GTR and adjuvant radiochemotherapy can result in a good therapeutic outcome in rapidly expanding GCT
    and (3) the extended transsphenoidal approach is a complementary approach to transcranial resection of anterior third ventricle GCTs.

    DOI: 10.1159/000480021

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  • PKA activation and endothelial claudin-5 breakdown in the schizophrenic prefrontal cortex 査読

    Keisuke Nishiura, Naoki Ichikawa-Tomikawa, Kotaro Sugimoto, Yasuto Kunii, Korehito Kashiwagi, Mizuko Tanaka, Yuichi Yokoyama, Mizuki Hino, Takashi Sugino, Hirooki Yabe, Hitoshi Takahashi, Akiyoshi Kakita, Tetsuya Imura, Hideki Chiba

    ONCOTARGET   8 ( 55 )   93382 - 93391   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IMPACT JOURNALS LLC  

    Schizophrenia is thought to be caused by a combination of genetic and environmental factors; however, its pathogenesis remains largely unknown. Here, we focus on the endothelial tight-junction protein claudin-5 (CLDN5), because the CLDN5 gene is mapped to the schizophrenia-associated 22q11.2 deletion region, and a single nucleotide polymorphism in the CLDN5 locus is also linked to schizophrenia. We show, by RT-qPCR and immunohistochemistry, that the expressions of CLDN5 mRNA and protein are significantly increased and decreased, respectively, in the schizophrenic prefrontal cortex (PFC) compared with control PFC. These changes were not observed in the schizophrenic visual cortex (VC), and neither the density nor diameter of the CD34-positive microvessels was altered in the schizophrenic PFC or VC. Interestingly, protein kinase A (PKA) was activated in the microvascular and perivascular regions of the schizophrenic PFC, and the pPKA-positive microvascular endothelial cells occasionally exhibited focal loss of CLND5. Since we previously demonstrated that cAMP induced CLDN5 mRNA expression and size-selective loosening of the endothelial barrier in PKA-independent and -dependent manners, respectively, a similar mechanism could contribute to the discrepancy between mRNA and protein expression of CLDN5 in the schizophrenic PFC. Taken collectively, these findings provide novel insights into the pathophysiology of schizophrenia.

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  • The SMN gene copy number states in Japanese ALS patients

    Ishihara T, Toyoda S, Koyama A, Tada M, Atsuta N, Nakamura R, Tohnai G, Sone J, Izumi Y, Kaji R, Morita M, Taniguchi A, Kakita A, Sobue G, Nishizawa M, Onodera O

    JOURNAL OF THE NEUROLOGICAL SCIENCES   381   211-211   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • 脳アミロイドアンギオパチーの新規病態関連因子SRPX1の解析 査読

    井上 泰輝, 植田 光晴, 田崎 雅義, 竹島 明, 永利 聡仁, 増田 曜章, 三隅 洋平, 小阪 崇幸, 野村 隼也, 水上 真由美, 松本 紗也加, 山下 太郎, 高橋 均, 柿田 明美, 安東 由喜雄

    Dementia Japan   31 ( 4 )   565 - 565   2017年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • Sushi repeat-containing protein 1: a novel disease-associated molecule in cerebral amyloid angiopathy 査読

    Yasuteru Inoue, Mitsuharu Ueda, Masayoshi Tasaki, Akari Takeshima, Akihito Nagatoshi, Teruaki Masuda, Yohei Misumi, Takayuki Kosaka, Toshiya Nomura, Mayumi Mizukami, Sayaka Matsumoto, Taro Yamashita, Hitoshi Takahashi, Akiyoshi Kakita, Yukio Ando

    ACTA NEUROPATHOLOGICA   134 ( 4 )   605 - 617   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (A beta) deposits and causes cerebral hemorrhage and dementia. The exact molecules that co-accumulate with cerebrovascular A beta deposits are still not fully known. In our study here, we performed proteomic analyses with microdissected leptomeningeal arteries and cerebral neocortical arterioles from 8 cases with severe CAA, 12 cases with mild CAA, and 10 control cases without CAA, and we determined the levels of highly expressed proteins in cerebral blood vessels in CAA. We focused on sushi repeat-containing protein 1 (SRPX1), which is specifically expressed in CAA-affected cerebral blood vessels. Because SRPX1, which is known as a tumor suppressor gene, reportedly induced apoptosis in tumor cells, we hypothesized that SRPX1 may play an important role in A beta-induced apoptosis in CAA. Immunohistochemical studies revealed that SRPX1 co-accumulated with A beta deposits in cerebral blood vessels of all autopsied cases with severe CAA. In contrast, no SRPX1 co-accumulated with A beta deposits in senile plaques. Furthermore, we demonstrated that both A beta 40 and A beta 42 bound to SRPX1 in vitro and enhanced SRPX1 expression in primary cultures of cerebrovascular smooth muscle cells. SRPX1 enhanced caspase activity induced by A beta 40. Knockdown of SRPX1, in contrast, reduced the formation of A beta 40 accumulations and the activity of caspase in cultured cerebrovascular smooth muscle cells. SRPX1 may thus be a novel molecule that is up-regulated in cerebrovascular A beta deposits and that may increase A beta-induced cerebrovascular degeneration in CAA.

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  • Features of amygdala in patients with mesial temporal lobe epilepsy and hippocampal sclerosis: An MRI volumetric and histopathological study 査読

    Yoko Nakayama, Hiroshi Masuda, Hiroshi Shirozu, Yosuke Ito, Takefumi Higashijima, Hiroki Kitaura, Yukihiko Fujii, Akiyoshi Kakita, Masafumi Fukuda

    EPILEPSY RESEARCH   135   50 - 55   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Objective: It is well-known that there is a correlation between the neuropathological grade of hippocampal sclerosis (HS) and neuroradiological atrophy of the hippocampus in mesial temporal lobe epilepsy (mTLE) patients. However, there is no strict definition or criterion regarding neuron loss and atrophy of the amygdala neighboring the hippocampus. We examined the relationship between HS and neuronal loss in the amygdala.
    Materials and methods: Nineteen mTLE patients with neuropathological proof of HS were assigned to Group A, while seven mTLE patients without HS were assigned to Group B. We used FreeSurfer software to measure amygdala volume automatically based on pre-operation magnetic resonance images. Neurons observed using Kltiver-Barrera (KB) staining in resected amygdala tissue were counted. and the extent of immunostaining with stress marker antibodies was semiquantitatively evaluated.
    Results: There was no significant difference in amygdala volume between the two groups (Group A: 1.41 +/- 0.24; Group B: 1.41 +/- 0.29 cm(3); p = 0.98), nor in the neuron cellularity of resected amygdala specimens (Group A: 3.98 +/- 0.97; Group B: 3.67 +/- 0.67 10 x (-4) number of neurons/mu m(2); p = 0.40). However, the HSP70 level, representing acute stress against epilepsy, in Group A patients was significantly larger than that in Group B. There was no significant difference in the level of Bcl-2, which is known as a protein that inhibits cell death, between the two groups.
    Conclusions: Neuronal loss and volume loss in the amygdala may not necessarily follow hippocampal sclerosis. From the analysis of stress proteins, epileptic attacks are as likely to damage the amygdala as the hippocampus but do not lead to neuronal death in the amygdala.

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  • GPNMB ameliorates mutant TDP-43-induced motor neuron cell death 査読

    Yuki Nagahara, Masamitsu Shimazawa, Kazuki Ohuchi, Junko Ito, Hitoshi Takahashi, Kazuhiro Tsuruma, Akiyoshi Kakita, Hideaki Hara

    JOURNAL OF NEUROSCIENCE RESEARCH   95 ( 8 )   1647 - 1665   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP-43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. (c) 2016 Wiley Periodicals, Inc.

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  • Alteration of mitochondrial protein PDHA1 in Lewy body disease and PARK14 査読

    Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   489 ( 4 )   439 - 444   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The histopathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is the occurrence of insoluble fibrillary aggregates known as Lewy bodies. Mitochondria play a vital role in energy production, and the pathogenesis of PD is associated with altered cellular metabolism due to mitochondrial dysfunction. The pyruvate dehydrogenase (PDH) complex provides a primary step in aerobic glucose metabolism by catalyzing the oxidative decarboxylation of pyruvate to acetyl CoA. Pyruvate dehydrogenase alpha 1 (PDHA1) forms the core structure of the PDH complex. Dysfunction of the PDH complex leads to energy production failure, resulting in various neurological disorders. However, no study has investigated the involvement of PDHA1 in the pathogenesis of PD. In the present study, we performed immunohistochemistry and immunoblotting to clarify the involvement of PDHA1 in idiopathic PD, DLB, PARK14-linked parkinsonism (PARK14; a familial form of PD), and multiple system atrophy, in comparison with normal controls. Here we report PDHA1 as a new component of brainstemtype Lewy bodies in idiopathic PD, DLB and PARK14, the level of PDHA1 protein being significantly decreased in the putamen and substantia nigra of patients with idiopathic PD. Our findings suggest that alteration of glucose metabolism through dysfunction of the PDH complex might occur in the pathogenesis of Lewy body disease and PARK14. (C) 2017 Elsevier Inc. All rights reserved.

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  • Striatal hypodopamine phenotypes found in transgenic mice that overexpress glial cell line-derived neurotrophic factor 査読

    Hidekazu Sotoyama, Yuriko Iwakura, Kanako Oda, Toshikuni Sasaoka, Nobuyuki Takei, Akiyoshi Kakita, Hideki Enomoto, Hiroyuki Nawa

    NEUROSCIENCE LETTERS   654   99 - 106   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Glial cell line-derived neurotrophic factor (GDNF) positively regulates the development and maintenance of in vitro dopaminergic neurons. However, the in vivo influences of GDNF signals on the brain dopamine system are controversial and not fully defined. To address this question, we analyzed dopaminergic phenotypes of the transgenic mice that overexpress GDNF under the control of the glial Gfap promoter. Compared with wild-type, the GDNF transgenic mice contained higher levels of GDNF protein and phosphorylated RET receptors in the brain. However, there were reductions in the levels of tyrosine hydroxylase (TH), dopamine, and its metabolite homovanillic acid in the striatum of transgenic mice. The TH reduction appeared to occur during postnatal development. Immunohistochemistry revealed that striatal TH density was reduced in transgenic mice with no apparent signs of neurodegeneration. In agreement with these neurochemical traits, basal levels of extracellular dopamine and high K+-induced dopamine efflux were decreased in the striatum of transgenic mice. We also explored the influences of GDNF overexpression on lomomotor behavior. GDNF transgenic mice exhibited lower stereotypy and rearing in a novel environment compared with wild-type mice. These results suggest that chronic overexpression of GDNF in brain astrocytes exerts an opposing influence on nigrostriatal dopamine metabolism and neurotransmission. (C) 2017 Elsevier B.V. All rights reserved.

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  • Ca2+-permeable AMPA receptors associated with epileptogenesis of hypothalamic hamartoma 査読

    Hiroki Kitaura, Masaki Sonoda, Sayaka Teramoto, Hiroshi Shirozu, Hiroshi Shimizu, Tadashi Kimura, Hiroshi Masuda, Yosuke Ito, Hitoshi Takahashi, Shin Kwak, Shigeki Kameyama, Akiyoshi Kakita

    EPILEPSIA   58 ( 4 )   E59 - E63   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Hypothalamic hamartoma (HH), composed of neurons and glia without apparent cytologic abnormalities, is a rare developmental malformation in humans. Patients with HH often have characteristic medically refractory gelastic seizures, and intrinsic epileptogenesis within the lesions has been speculated. Herein we provide evidence to suggest that in HH neurons, Ca2+ permeability through -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is aberrantly elevated. In needle biopsy specimens of HH tissue, field potential recordings demonstrated spontaneous epileptiform activities similar to those observed in other etiologically distinct epileptogenic tissues. In HH, however, these activities were clearly abolished by application of Joro Spider Toxin (JSTX), a specific inhibitor of the Ca2+-permeable AMPA receptor. Consistent with these physiologic findings, the neuronal nuclei showed disappearance of adenosine deaminase acting on RNA 2 (ADAR2) immunoreactivity. Furthermore, examination of glutamate receptor 2 (GluA2) messenger RNA (mRNA) revealed that editing efficiency at the glutamine/arginine site was significantly low. These results suggest that neurons in HH may bear Ca2+-permeable AMPA receptors due to dislocation of ADAR2.

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  • PLA2G6 accumulates in Lewy bodies in PARK14 and idiopathic Parkinson's disease 査読

    Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    NEUROSCIENCE LETTERS   645   40 - 45   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    The histopathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is the occurrence of insoluble fibrillary aggregates known as Lewy bodies, in which phosphorylated alpha-synuclein (alpha-syn) is a major component. To date, familial PD-linked gene products, including a-syn, parkin, PINK-1, DJ-1 and LRRK2, are known to be involved in Lewy body formation. Phospholipase A(2), group VI (PLA2G6) is the causative gene for PARKI4-linked parkinsonism (PARK14), a familial form of juvenile-onset dystonia parkinsonism. Several lines of evidence have suggested that PLA2G6 might play a role in the pathogenesis of not only PARK14, but also idiopathic PD. However, no published studies have investigated the association of PLA2G6 with the formation of Lewy bodies. In the present study, we used immunohistochemistiy and Western blotting to investigate the involvement of PLA2G6 in Lewy body disease (PD and DLB), multiple system atrophy and Alzheimer's disease, in comparison with normal controls. Although cortical Lewy bodies, which lack a definable central core, were unstained with anti-PLA2G6 antibodies, the cores of brainstem-type Lewy bodies from PARK14 and idiopathic PD patients were moderately or intensely immunopositive for PLA2G6. Our results further reinforce the association of PLA2G6 with the pathogenesis of idiopathic PD, in addition to PARK14. (C) 2017 Elsevier B.V. All rights reserved.

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  • Expression of Aquaporin 1 and Aquaporin 4 in the Temporal Neocortex of Patients with Parkinson's Disease 査読

    Akihiko Hoshi, Ayako Tsunoda, Mari Tada, Masatoyo Nishizawa, Yoshikazu Ugawa, Akiyoshi Kakita

    BRAIN PATHOLOGY   27 ( 2 )   160 - 168   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    The astrocytic water channel proteins aquaporin 1 (AQP1) and aquaporin 4 (AQP4) are known to be altered in brains affected by several neurodegenerative disorders, including Alzheimer's disease. However, AQP expression in brains affected by Parkinson's disease (PD) has not been described in detail. Recently, it has been reported that alpha-synuclein (alpha-syn)-immunolabeled astrocytes show preferential distribution in several cerebral regions, including the neocortex, in patients with PD. Here, we investigated whether AQP expression is associated with alpha-syn deposition in the temporal neocortex of PD patients. In accordance with the consensus criteria for dementia with Lewy bodies, the patients were classified into neocortical (PDneo), limbic (PDlim), and brain stem (PDbs) groups. Expressions of alpha-syn, AQP1, and AQP4 in the temporal lobes of the individual PD patients were examined immunohistochemically. Immunohistochemical analysis demonstrated more numerous AQP4-positive and AQP1-positive astrocytes in the PDneo group than in the PDbs, PDlim, and control groups. However, in the PDneo cases, these astrocytes were not often observed in alpha-syn-rich areas, and semiquantitative analysis revealed that there was a significant negative correlation between the levels of AQP4 and alpha-syn in layers V-VI, and between those of AQP1 and alpha-syn in layers II-III. These findings suggest that a defined population of AQP4- and AQP1-expressing reactive astrocytes may modify alpha-syn deposition in the neocortex of patients with PD.

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  • Familial amyotrophic lateral sclerosis with an I104F mutation in the SOD1 gene: Multisystem degeneration with neurofilamentous aggregates and SOD1 inclusions 査読

    Haishan Jiang, Hiroshi Shimizu, Atsushi Shiga, Masami Tanaka, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

    NEUROPATHOLOGY   37 ( 1 )   69 - 77   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    We previously reported familial amyotrophic lateral sclerosis (FALS) of 11years duration in a 57-year-old woman, who received artificial ventilation for 5years prior to death and exhibited widespread multisystem degeneration and neurofilamentous aggregates, so-called conglomerate inclusions (CIs). In the present study, we re-evaluated this autopsied patient (proband) with further immunohistochemical observation as well as mutational analysis of the superoxide dismutase 1 (SOD1) gene. A review of the clinical features of the proband's family revealed five affected members (including the proband) over two successive generations who showed marked variability in clinical presentation, such as the age at onset. The proband was found to harbor a heterozygous missense mutation in exon 4 (I104F) of the SOD1 gene. In the brain and spinal cord, SOD1-positive neuronal cytoplasmic inclusions (NCIs) were found to be more widely distributed than CIs, the latter being weakly positive for SOD1. No Lewy body-like hyaline inclusions were found. This is considered to be the first description of an autopsy case of FALS with an I104F SOD1 gene mutation, suggesting that combination of marked intra-familial clinical variability and multisystem degeneration with occurrence of CIs and SOD1-positive NCIs is a characteristic feature of FALS with this SOD1 gene mutation.

    DOI: 10.1111/neup.12324

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  • Ca2+-permeable AMPA receptors associated with epileptogenesis of hypothalamic hamartoma. 査読

    Kitaura H, Sonoda M, Teramoto S, Shirozu H, Shimizu H, Kimura T, Masuda H, Ito Y, Takahashi H, Kwak S, Kameyama S, Kakita A

    Epilepsia   58 ( 4 )   e59 - e63   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Stable and episodic/bolus patterns of methylmercury exposure on mercury accumulation and histopathologic alterations in the nervous system 査読

    Mineshi Sakamoto, Akiyoshi Kakita, Jose L. Domingo, Hiroshi Yamazaki, Ricardo B. Oliveira, Sandra L. F. Sarrazin, Komyo Eto, Katsuyuki Murata

    ENVIRONMENTAL RESEARCH   152   446 - 453   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The main purpose of the present study was to compare the blood and brain mercury (Hg) accumulation and neurological alterations in adult male and pregnant female/fetal rats following stable and episodic/bolus patterns of methylmercury (MeHg) exposure. In addition, MeHg accumulation in the human body was estimated by a one-compartment model using three different patterns of MeHg exposure. In the adult male rat experiment, doses of 0.3 and 1.5 mg MeHg/kg/day were orally administered to the stable groups for 5 weeks, while 7-fold higher doses of 2.1 and 10.5 mg MeHg/kg/once a week were administered to the bolus groups. The blood Hg levels increased constantly in the stable groups, but increased with repeated waves in the bolus groups. At completion of the experiment, there were no significant differences in the brain Hg concentrations or neurological alterations between the stable and bolus groups, when the total doses of MeHg were the same. In the pregnant female rat experiment, a dose of 1 mg MeHg/kg/day was administered orally to the stable group for 20 days (until 1 day before expected parturition), while a 5-fold higher dose of 5 mg MeHg/kg/once every 5 days was administered to the bolus group. In the brains of the maternal/fetal rats, there were no significant differences in the Hg concentrations and neurological alterations between the stable and bolus groups. The mean Hg concentrations in the fetal brains were approximately 2-fold higher than those in the maternal brains for both stable and bolus groups. Using the one-compartment model, the Hg accumulation curves in humans at doses of 7 mu g MeHg/day, 48 mu g MeHg/once a week, and 96 mu g MeHg/once every 2 weeks were estimated to be similar, while the bolus groups showed dose-dependent amplitudes of repeated waves. These results suggest that stable and episodic/bolus patterns of MeHg exposure do not cause differences in Hg accumulation in the blood and brain, or in neurological alterations, when the total doses are the same. (C) 2016 Elsevier Inc. All rights reserved.

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  • Cerebral venous sinus thrombosis due to oral contraceptive use: Postmortem 3 T-MRI and autopsy findings 査読

    Masahiro Uemura, Yoshihiro Tsukamoto, Yasuhisa Akaiwa, Masaki Watanabe, Ayako Tazawa, Sou Kasahara, Minoru Endou, Ryosuke Ogura, Kouichirou Okamoto, Yukihiko Fujii, Tsutomu Nakada, Akiyoshi Kakita, Masatoyo Nishizawa

    Human Pathology: Case Reports   6   32 - 36   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier Inc  

    Cerebral venous sinus thrombosis (CVST) is an uncommon form of stroke, and mortality of the acute phase is high. We report the clinical, postmortem 3 T-MRI, and autopsy features of a patient, 20-year-old Japanese woman, with CVST who died shortly after starting to use low-dose estrogen combined hormonal contraceptives (CHCs). A postmortem 3 T-MRI study with our originally developed system revealed abnormal intensities suggestive of thrombi extending throughout the straight sinus and left sigmoid sinus. At autopsy, in accordance with the images, we performed careful preparations of the sinuses. Histological examination revealed an organizing white thrombus occupying the lumen of the left sigmoid sinus, and an acute, red thrombus in the lumen of the left transverse, straight, and tentorial sinuses, and vein of Galen, indicating that the thrombus had developed first in the left sigmoid sinus, then extended retrogradely to the more proximal portion of the sinus system, reaching the vein of Galen. The features of the present CVST patient appear to be informative, when encountering CHC users with neurological symptoms, even in those who begun to use low-dose estrogen CHCs only recently.

    DOI: 10.1016/j.ehpc.2016.01.002

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  • Globular Glial Tauopathyの臨床的特徴、自験2例と既報例との比較 査読

    三浦 健, 青木 賢樹, 高嶋 修太郎, 眞野 篤, 堅田 慎一, 目崎 直実, 石黒 敬信, 石黒 舞乃, 畠野 雄也, 相川 あかね, 石澤 伸, 竹内 亮子, 田中 英智, 豊島 靖子, 春日 健作, 三瓶 一弘, 柿田 明美, 高橋 均, 池内 健, 西澤 正豊

    臨床神経学   56 ( Suppl. )   S526 - S526   2016年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • MicroRNA expression profiles of multiple system atrophy from formalin-fixed paraffin-embedded samples 査読

    Koichi Wakabayashi, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Shinya Tanaka, Jun Utsumi, Hidenao Sasaki

    NEUROSCIENCE LETTERS   635   117 - 122   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression. Recently, we have shown that informative miRNA data can be derived from archived formalin-fixed paraffin-embedded (FFPE) samples from postmortem cases of amyotrophic lateral sclerosis and normal controls. miRNA analysis has now been performed on FFPE samples from affected brain regions in patients with multiple system atrophy (MSA) and the same areas in neurologically normal controls. We evaluated 50 samples from patients with MSA (n =13) and controls (n=13). Twenty-six samples were selected for miRNA analysis on the basis of the criteria reported previously: (i) a formalin fixation time of less than 4 weeks, (ii) a total RNA yield per sample of more than 500 ng, and (iii) sufficient quality of the RNA electrophoresis pattern. These included 11 cases of MSA and 5 controls. Thus, the success rate for analysis of RNA from FFPE samples was 52% (26 of 50). For MSA, a total of 395 and 383 miRNAs were identified in the pons and cerebellum, respectively; 5 were up-regulated and 33 were down-regulated in the pons and 5 were up-regulated and 18 were down-regulated in the cerebellum. Several miRNAs down-regulated in the pons (miR-129-2-3p and miR-129-5p) and cerebellum (miR-129-2-3p, miR-129-5p and miR-132-3p) had already been identified in frozen cerebellum from MSA patients. These findings suggest that archived FFPE postmortem samples can be a valuable source for miRNA profiling in MSA. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

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  • mTORとてんかん 査読

    北浦弘樹, 武井延之, 中島光子, 松本直通, 柿田明美

    Epilepsy   10 ( 2 )   97 - 102   2016年11月

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  • Decreased VEGFR2 expression and increased phosphorylated Akt1 in the prefrontal cortex of individuals with schizophrenia 査読

    Mizuki Hino, Yasuto Kunii, Junya Matsumoto, Akira Wada, Atsuko Nagaoka, Shin-ichi Niwa, Hitoshi Takahashi, Akiyoshi Kakita, Hiroyasu Akatsu, Yoshio Hashizume, Sakon Yamamoto, Hirooki Yabe

    JOURNAL OF PSYCHIATRIC RESEARCH   82   100 - 108   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    The Akt signaling pathway involves various cellular processes and depends on extracellular stimuli. Since Akt signaling participates in cytoprotection, synapse plasticity, axon extension, and neurotransmission in the nervous system, alteration in Akt signaling might be a potential cause of schizophrenia. In this study, we performed multiplex fluorescent bead based immunoassays for members of the Akt signaling pathway in postmortem brains of controls and patients with schizophrenia. Vascular endothelial growth factor receptor 2 (VEGFR2/KDR) was significantly decreased in the prefrontal cortex (PFC) of patients with schizophrenia, and the expression level of VEGFR2 was inversely correlated with the positive symptom subscale of the Diagnostic Instrument for Brain Studies (DIBS) in patients with schizophrenia. There was also an increase in phosphorylated Akt1 in the PFC in the patients, though the ratio of phospho/total Akt1 is not significantly different. In the nucleus accumbens (NAcc) there was no significant difference in expression and phosphorylation levels of Akt signaling proteins. Genetic analysis revealed a significant correlation of a SNP of KDR (rs7692791) with ERK1/2 and Akt1 phospho/total rates. Since VEGFR2 participates in angiogenesis and neurotrophic activation, either or both functions might be responsible for onset of schizophrenia. (C) 2016 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jpsychires.2016.07.018

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  • Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy. 査読 国際誌

    Noriko Miyake, Ryoko Fukai, Chihiro Ohba, Takahiro Chihara, Masayuki Miura, Hiroshi Shimizu, Akiyoshi Kakita, Eri Imagawa, Masaaki Shiina, Kazuhiro Ogata, Jiu Okuno-Yuguchi, Noboru Fueki, Yoshifumi Ogiso, Hiroshi Suzumura, Yoshiyuki Watabe, George Imataka, Huey Yin Leong, Aviva Fattal-Valevski, Uri Kramer, Satoko Miyatake, Mitsuhiro Kato, Nobuhiko Okamoto, Yoshinori Sato, Satomi Mitsuhashi, Ichizo Nishino, Naofumi Kaneko, Akira Nishiyama, Tomohiko Tamura, Takeshi Mizuguchi, Mitsuko Nakashima, Fumiaki Tanaka, Hirotomo Saitsu, Naomichi Matsumoto

    American journal of human genetics   99 ( 4 )   950 - 961   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and β-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

    DOI: 10.1016/j.ajhg.2016.08.005

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  • Characteristic Microglial Features in Patients with Hereditary Diffuse Leukoencephalopathy with Spheroids 査読

    Mari Tada, Takuya Konno, Masayoshi Tada, Toshiyuki Tezuka, Takeshi Miura, Naomi Mezaki, Ken-ichi Okazaki, Musashi Arakawa, Kyoko Itoh, Toru Yamamoto, Hideaki Yokoo, Nobuaki Yoshikura, Kenji Ishihara, Masao Horie, Hirohide Takebayashi, Yasuko Toyoshima, Makoto Naito, Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi, Takeshi Ikeuchi, Akiyoshi Kakita

    ANNALS OF NEUROLOGY   80 ( 4 )   554 - 565   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Objective: To clarify the histopathological alterations of microglia in the brains of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) caused by mutations of the gene encoding the colony stimulating factor-1 receptor (CSF-1R).
    Methods: We examined 5 autopsied brains and 1 biopsy specimen from a total of 6 patients with CSF-1R mutations. Detailed immunohistochemical, biochemical, and ultrastructural features of microglia were examined, and quantitative analyses were performed.
    Results: In layers 3 to 4 of the frontal cortex in HDLS brains, microglia showed relatively uniform and delicate morphology, with thin and winding processes accompanying knotlike structures, and significantly smaller areas of Iba1 immunoreactivity and lower numbers of Iba1-positive cells were evident in comparison with control brains. On the other hand, in layers 5 to 6 and the underlying white matter, microglia were distributed unevenly; that is, in some areas they had accumulated densely, whereas in others they were scattered. Immunoblot analyses of microglia-associated proteins, including CD11b and DAP12, revealed that HDLS brains had significantly lower amounts of these proteins than diseased controls, although Ki-67-positive proliferative microglia were not reduced. Ultrastructurally, the microglial cytoplasm and processes in HDLS showed vesiculation of the rough endoplasmic reticulum and disaggregated polyribosomes, indicating depression of protein synthesis. On the other hand, macrophages were immunonegative for GLUT-5 or P2ry12, indicating that they were derived from bone marrow.
    Interpretation: The pathogenesis of HDLS seems to be associated with microglial vulnerability and morphological alterations.

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  • 脳表ヘモジデリン沈着症 査読

    豊島靖子, 柿田明美

    Clinical Neuroscience   34 ( 9 )   956 - 957   2016年9月

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  • Clinicopathological characteristics of patients with amyotrophic lateral sclerosis resulting in a totally locked-in state (communication Stage V). 査読

    Hayashi K, Mochizuki Y, Takeuchi R, Shimizu T, Nagao M, Watabe K, Arai N, Oyanagi K, Onodera O, Hayashi M, Takahashi H, Kakita A, Isozaki E

    Acta Neuropathol Commun   4   107   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/s40478-016-0379-3.

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  • 髄芽腫の予後因子Gli3. 査読

    吉村淳一, 宮原弘明, 棗田 学, 柿田明美, 藤井幸彦

    日本臨床   74 ( 7 )   292 - 297   2016年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    脳腫瘍学 –基礎研究と臨床研究の進歩− Ⅵ.脳腫瘍の予後因子

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  • [Gli3: a favorable prognostic factor for patients with medulloblastoma]. 査読

    Yoshimura J, Miyahara H, Natsumeda M, Kakita A, Fujii Y

    Nihon rinsho. Japanese journal of clinical medicine   74 Suppl 7   292 - 297   2016年9月

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  • Primary central nervous system lymphomas and related diseases: Pathological characteristics and discussion of the differential diagnosis 査読

    Yasuo Sugita, Hiroko Muta, Koichi Ohshima, Motohiro Morioka, Yoshihiro Tsukamoto, Hitoshi Takahashi, Akiyoshi Kakita

    NEUROPATHOLOGY   36 ( 4 )   313 - 324   2016年8月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    Although primary diffuse large B-cell lymphomas of the CNS are designated as primary CNS lymphomas according to the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue in 2008, a variety of other lymphomas (Burkitt lymphomas, EBV-positive diffuse large B-cell lymphoma of the elderly) and related diseases (lymphomatoid granulomatosis) that are also found in the CNS have been spotlighted in recent years. The histopathology of primary CNS Burkitt lymphomasmimics that of primary diffuse large B-cell lymphomas of the CNS after steroid administration. Therefore, for correct diagnosis of the involved lymphoma, comprehensive fluorescent in situ hybridization analysis for c-MYC and BCL2 is recommended in all primary CNS lymphoma cases with aggressive clinical course, multifocal involvement of the CNS, and a high proliferation index. The pathological characteristics of primary CNS EBV-positive diffuse large B-cell lymphoma of the elderly have similarities with those of the latency phenotype III, EBV lymphoproliferative disorders that arise in the setting of immunodeficiency. These age-related lymphomas usually occur in elderly immunocompetent patients, and the incidence of this disease was estimated to range from 4.0% to 13.6% of all primary CNS lymphomas. Shorter overall survival has been reported for patients with this disease. Lymphomatoid granulomatosis (LYG) is a systemic, EBV-driven, angiocentric and angiodestructive lymphoproliferative disorder. Primary LYG that shows distinct clinicopathological features compared with systemic LYG was recently reported. Finally, this review focuses on the relationship between primary CNS lymphomas and demyelinating diseases, and the concomitant use of intraoperative cytology and frozen sections that are helpful in rapid intraoperative diagnosis.

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  • A case of lymphomatosis cerebri mimicking inflammatory diseases 査読

    Takenobu Murakami, Kenji Yoshida, Mari Segawa, Akioh Yoshihara, Akihiko Hoshi, Koichiro Nakamura, Masahiro Ichikawa, Osamu Suzuki, Yuichi Yokoyama, Yasuko Toyoshima, Yoshihiro Sugiura, Hiroshi Ito, Kiyoshi Saito, Yuko Hashimoto, Akiyoshi Kakita, Hitoshi Takahashi, Yoshikazu Ugawa

    BMC NEUROLOGY   16   128   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Lymphomatosis cerebri (LC) is a rare subtype of primary central nervous system malignant lymphoma. The typical features of this disease exhibited on magnetic resonance imaging (MRI) without contrast enhancement are similar to those observed with diffuse leukoencephalopathy, mimicking white matter disorders such as encephalitis. Clinical features and examination findings that are suggestive of inflammatory diseases may indeed confound the diagnosis of LC.
    Case presentation: A 66-year-old woman with continuous fever over a two-month period developed left hemiparesis despite presenting in an alert state with normal cognitive function. Sampling tests showed autoantibodies in the serum and inflammatory changes in the cerebrospinal fluid. The results from an MRI demonstrated multiple non-enhanced brain lesions in the splenium of the corpus callosum and deep white matter. Single photon emission computed tomography revealed increases in blood flow in the basal ganglia, thalamus and brainstem. No systemic malignancies were found. The patient was suspected of having a diagnosis of nonvasculitic autoimmune inflammatory meningoencephalitis and treated with intravenous methylprednisolone pulse therapy. Her fever transiently dropped to within the normal range. However, she had a sudden seizure and a second MRI exhibited infiltrative lesions gradually extending throughout the whole brain. We performed a brain biopsy, and LC was histologically diagnosed. The patient received whole-brain radiation therapy, which diminished the fever and seizures. The patient died one year after the initial onset of fever.
    Conclusions: The present case yields an important consideration that brain neoplasms, especially LC, cannot be ruled out, even in cases with clinical characteristics and examinations consistent with inflammatory diseases. Careful follow-up and histological study are vital for the correct diagnosis of LC.

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  • Significant association of cadaveric dura mater grafting with subpial Aβ deposition and meningeal amyloid angiopathy. 査読

    Hamaguchi T, Taniguchi Y, Sakai K, Kitamoto T, Takao M, Murayama S, Iwasaki Y, Yoshida M, Shimizu H, Kakita A, Takahashi H, Suzuki H, Naiki H, Sanjo N, Mizusawa H, Yamada M

    Acta neuropathologica   132 ( 2 )   313 - 315   2016年8月

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  • Familial idiopathic basal ganglia calcification: Histopathologic features of an autopsied patient with an SLC20A2 mutation 査読

    Tadashi Kimura, Takeshi Miura, Kenju Aoki, Shoji Saito, Hiroaki Hondo, Takuya Konno, Akio Uchiyama, Takeshi Ikeuchi, Hitoshi Takahashi, Akiyoshi Kakita

    NEUROPATHOLOGY   36 ( 4 )   365 - 371   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Idiopathic basal ganglia calcification (IBGC), or Fahr's disease, is a neurological disorder characterized by widespread calcification in the brain. Recently, several causative genes have been identified, but the histopathologic features of the brain lesions and expression of the gene products remain unclear. Here, we report the clinical and autopsy features of a 62-year-old Japanese man with familial IBGC, in whom an SLC20A2 mutation was identified. The patient developed mild cognitive impairment and parkinsonism. A brain CT scan demonstrated abnormal calcification in the bilateral basal ganglia, thalami and cerebellum. An MRI study at this point revealed glioblastoma, and the patient died 6 months later. At autopsy, symmetric calcification in the basal ganglia, thalami, cerebellar white matter and deeper layers of the cerebral cortex was evident. The calcification was observed in the tunica media of small arteries, arterioles and capillaries, but not in veins. Immunohistochemistry using an antibody against type III sodium-dependent phosphate transporter 2 (PiT-2), the SLC20A2 product, demonstrated that astrocytic processes were labeled in several regions in control brains, whereas in the patient, reactivity in astrocytes was apparently weak. Immunoblotting demonstrated a marked decrease of PiT-2 in the patient. There are few autopsy reports of IBGC patients with confirmation of the genetic background. The autopsy features seem informative for better understanding the histogenesis of IBGC lesions.

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  • Spinocerebellar degeneration: Discrepancies between clinical and pathological diagnoses 査読

    Mitsunori Yamada, Yasuko Toyoshima, Takao Makifuchi, Akiyoshi Kakita, Hitoshi Takahashi

    NEUROPATHOLOGY   36 ( 4 )   405 - 410   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    To improve the diagnostic accuracy of sporadic spinocerebellar degeneration (SCD), we assessed the clinical and pathological data of 1494 consecutive autopsy cases. The number of patients who received a diagnosis of sporadic SCD (including multiple system atrophy) either clinically or pathologically was 19 (1.3%). We identified six cases with clinical misdiagnoses of SCD that were confirmed pathologically as progressive supranuclear palsy (PSP, four cases), basilar artery thrombosis (one case) and unclassified tauopathy (one case). The total number of patients who received a clinical diagnosis of sporadic SCD was 93 and the positive predictive value was 93.5%. We also identified 13 autopsy cases that were pathologically confirmed as SCD, but had been clinically misdiagnosed as having other disorders. Their clinical diagnoses comprised progressive supranuclear palsy (five cases) and Parkinson's disease (PD, four cases), as well as parkinsonism with dementia, amyotrophic lateral sclerosis, paraneoplastic syndrome and multiple cerebral infarction (one case each). The results indicate that it is often difficult to distinguish PSP and PD from SCD, because of the atypical combination of symptoms or atypical timing of the appearance of symptoms, such as severe autonomic failure, cognitive impairment, poor L-dopa responsiveness, early cerebellar signs and obvious vertical gaze palsy.

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  • Increased neuronal and astroglial aquaporin-1 immunoreactivity in rat striatum by chemical preconditioning with 3-nitropropionic acid 査読

    Akihiko Hoshi, Ayako Tsunoda, Teiji Yamamoto, Mari Tada, Akiyoshi Kakita, Yoshikazu Ugawa

    NEUROSCIENCE LETTERS   626   48 - 53   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Aquaporin-1 (AQPI) is a water channel expressed in the choroid plexus and participates in forming cerebrospinal fluid. Interestingly, reactive astrocytes also express AQPI in the central nervous system under some pathological conditions. On the other hand, 3-nitropropionic acid (3NP) is a mitochondrial toxin that causes selective degeneration of striatum; however, its chemical preconditioning is neuroprotective against cerebral ischemia. We previously reported that mild 3NP application is accompanied with numerous reactive astrocytes in rat striatum devoid of typical necrotic lesions. Therefore, we studied whether AQPI in the rat striatum could be upregulated with reactive astrocytosis using the 3NP model. Immunohistochemical or immunofluorescence analysis showed that reactive astrocytosis in the striatum, which upregulates glial fibrillary acidic protein and glutamine synthetase, was induced by mild doses of 3NP administration. Intriguingly, after 3NP treatment, AQPI was intensely expressed not only by the subpopulation of astroglia but also by neurons. The AQPI immunoreactivity became more intensified at the early-subtoxic stage (ES: 24-48 h), but not as much in the delayed-subtoxic stage (DS: 96-120 h). In contrast, AQP4 expression in the striatum was downregulated after 3NP treatment, in particular during the ES stage. AQPI upregulation/AQP4 downregulation induced under subtoxic 3NP treatment may play a pivotal role in water homeostasis and cell viability in the striatum. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

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  • Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43 査読

    Akihide Koyama, Akihiro Sugai, Taisuke Kato, Tomohiko Ishihara, Atsushi Shiga, Yasuko Toyoshima, Misaki Koyama, Takuya Konno, Sachiko Hirokawa, Akio Yokoseki, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera

    NUCLEIC ACIDS RESEARCH   44 ( 12 )   5820 - 5836   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons-especially neurons with mislocalized TDP-43-the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS.

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  • Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: evidence for clinic-pathologic subtypes. 査読

    Takeuchi R, Tada M, Shiga A, Toyoshima Y, Konno T, Sato T, Nozaki H, Kato T, Horie M, Shimizu H, Takebayashi H, Onodera O, Nishizawa M, Kakita A, Takahashi H

    Acta Neuropathol Commun   4 ( 1 )   61   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/s40478-016-0335-2.

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  • α-Synuclein pathology in the cranial and spinal nerves in Lewy body disease. 査読

    Nakamura K, Mori F, Tanji K, Miki Y, Toyoshima Y, Kakita A, Takahashi H, Yamada M, Wakabayashi K

    Neuropathology : official journal of the Japanese Society of Neuropathology   36 ( 3 )   262 - 269   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Choreaを伴った非典型的ALSと臨床診断された、Tauopathyの一剖検例 査読

    田中 英智, 豊島 靖子, 三浦 健, 三瓶 一弘, 志賀 篤, 柿田 明美, 高橋 均

    The Kitakanto Medical Journal   66 ( 2 )   175 - 175   2016年5月

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    記述言語:日本語   出版者・発行元:北関東医学会  

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  • Alteration of Upstream Autophagy-Related Proteins (ULK1, ULK2, Beclin1, VPS34 and AMBRA1) in Lewy Body Disease 査読

    Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, Jun Utsumi, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    BRAIN PATHOLOGY   26 ( 3 )   359 - 370   2016年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Autophagy is associated with the pathogenesis of Lewy body disease, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). It is known that several downstream autophagosomal proteins are incorporated into Lewy bodies (LBs). We performed immunostaining and Western blot analysis using a cellular model of PD and human brain samples to investigate the involvement of upstream autophagosomal proteins (ULK1, ULK2, Beclin1, VPS34 and AMBRA1), which initiate autophagy and form autophagosomes. Time course analysis of cultured cells transfected with flag-alpha-synuclein and synphilin-1 revealed upregulation of these upstream proteins with accumulation of LB-like inclusions. In human specimens, only mature LBs were positive for upstream autophagosomal proteins. Western blotting of fractionated brain lysates showed that upstream autophagosomal proteins were detected in the soluble and insoluble fraction in DLB, corresponding to the bands of phosphorylated alpha-synuclein. However, Western blot analysis of total brain lysates in PD and DLB showed that the increase of upstream autophagosomal proteins was only partial. The quantitative, qualitative and locational alteration of upstream autophagosomal proteins in the present study indicates their involvement in the pathogenesis of LB disease. Our data also suggest that misinduction or impairment of upstream autophagy might occur in the disease process of LB disease.

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  • Clinicopathological features in anterior visual pathway in neuromyelitis optica 査読

    Mariko Hokari, Akiko Yokoseki, Musashi Arakawa, Etsuji Saji, Kaori Yanagawa, Fumihiro Yanagimura, Yasuko Toyoshima, Kouichirou Okamoto, Satoshi Ueki, Tetsuhisa Hatase, Riuko Ohashi, Takeo Fukuchi, Kohei Akazawa, Mitsunori Yamada, Akiyoshi Kakita, Hitoshi Takahashi, Masatoyo Nishizawa, Izumi Kawachi

    ANNALS OF NEUROLOGY   79 ( 4 )   605 - 624   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    ObjectiveNeuromyelitis optica spectrum disorder (NMOsd) is an autoimmune disorder of the central nervous system characterized by aquaporin-4 (AQP4) autoantibodies. The aim of this study was to elucidate the characteristics of involvement of the anterior visual pathway (AVP) and neurodegeneration via glia-neuron interaction in NMOsd.
    MethodsThirty Japanese patients with serologically verified NMOsd were assessed with a neuro-ophthalmological study. Using 27 tissue blocks from 13 other cases of NMOsd, we performed neuropathological analysis of glial and neuroaxonal involvement in the AVP.
    ResultsThe AVP involvement in NMOsd was characterized by the following, compared to multiple sclerosis: (1) longitudinally extensive optic neuritis (ON); (2) more severe visual impairment and worse prognosis for ON; (3) unique AQP4 dynamics, including loss of AQP4 immunoreactivity on astrocytes with complement activation in ON lesions, loss of AQP4 immunoreactivity on Muller cells with no deposition of complement in the retinas, and densely packed AQP4 immunoreactivity on astrocytes in gliosis of secondary anterograde/retrograde degeneration in the optic nerves and retinal nerve fiber layer (RNFL); and (4) more severe neurodegeneration, including axonal accumulation of degenerative mitochondria and transient receptor potential melastatin 4 channel with complement-dependent astrocyte pathology in ON lesions, mild loss of horizontal cells, and RNFL thinning and loss of ganglion cells with abundance of AQP4(+) astrocytes, indicating secondary retrograde degeneration after ON.
    InterpretationSevere and widespread neuroaxonal damage and unique dynamics of astrocytes/Muller cells with alterations of AQP4 were prominent in the AVP and may be associated with poor visual function and prognosis in NMOsd. Ann Neurol 2016;79:605-624

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  • Accumulation of phosphorylated α-synuclein in subpial and periventricular astrocytes in multiple system atrophy of long duration. 査読

    Nakamura K, Mori F, Kon T, Tanji K, Miki Y, Tomiyama M, Kurotaki H, Toyoshima Y, Kakita A, Takahashi H, Yamada M, Wakabayashi K

    Neuropathology : official journal of the Japanese Society of Neuropathology   36 ( 2 )   157 - 167   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Pathological and Clinical Spectrum of Progressive Supranuclear Palsy: With Special Reference to Astrocytic Tau Pathology 査読

    Yuichi Yokoyama, Yasuko Toyoshima, Atsushi Shiga, Mari Tada, Hideaki Kitamura, Kazuko Hasegawa, Osamu Onodera, Takeshi Ikeuchi, Toshiyuki Someya, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    BRAIN PATHOLOGY   26 ( 2 )   155 - 166   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Progressive supranuclear palsy (PSP) is a four-repeat tauopathy with tau-positive, argyrophilic tuft-shaped astrocytes (TAs). We performed a pathological and clinical investigation in 40 consecutive autopsied Japanese patients with pathological diagnoses of PSP or PSP-like disease. Unequivocal TAs were present in 22 cases, all of which were confirmed to be PSP. Such TAs were hardly detected in the other 18 cases, which instead exhibited tau-positive, argyrophilic astrocytes, appearing as comparatively small clusters with central nuclei of irregularly shaped, coarse structures (equivocal TAs). Cluster analysis of the distribution pattern of tau-related pathology for these 18 cases identified two subgroups, pallido-nigro-luysian atrophy (PNLA) Type 1 (n=9) and Type 2 (n=9), the former being distinguished from the latter by the presence of tau-related lesions in the motor cortex, pontine nucleus and cerebellar dentate nucleus in addition to the severely affected PNL system. The duration from symptom onset until becoming wheelchair-bound was significantly longer in PNLAType 1. Immunoblotting of samples from the three disease conditions revealed band patterns of low-molecular-mass tau fragments at approximate to 35kDa. These findings shed further light on the wide pathological and clinical spectrum of four-repeat tauopathy, representing PSP in the broad sense rather than classical PSP.

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  • Nonfunctional intra- and suprasellar tumor in a patient with visual disturbance and panhypopituitarism 査読

    Rie Saito, Shinya Jinguji, Yoshinori Taniguchi, Shigekazu Takeuchi, Kouichirou Okamoto, Masatoyo Nishizawa, Hitoshi Takahashi, Akiyoshi Kakita

    NEUROPATHOLOGY   36 ( 1 )   107 - 112   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

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  • G protein-coupled receptor 26 immunoreactivity in intranuclear inclusions associated with polyglutamine and intranuclear inclusion body diseases 査読

    Fumiaki Mori, Kunikazu Tanji, Yasuo Miki, Yasuko Toyoshima, Mari Yoshida, Akiyoshi Kakita, Hitoshi Takahashi, Jun Utsumi, Hidenao Sasaki, Koichi Wakabayashi

    NEUROPATHOLOGY   36 ( 1 )   50 - 55   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    G protein-coupled receptor 26 (GPR26) is one of the G-protein-coupled receptors (GPCRs), which comprise the largest family of membrane proteins and mediate most of the physiological responses to hormones, neurotransmitters and environmental stimulants. Although GPCRs are considered to play an important role in the pathophysiology of neurodegenerative disorders, it is uncertain whether GPR26 is involved in the pathogenesis of polyglutamine and intranuclear inclusion body diseases. We immunohistochemically examined the brain tissues of patients with four polyglutamine diseases (Huntington's disease, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxia types 1 and 3) and intranuclear inclusion body disease, and normal control subjects. In controls, anti-GPR26 antibody immunolabeled the neuronal cytoplasm in a diffuse granular pattern. Neuronal nuclear inclusions in polyglutamine diseases were immunopositive for GPR26. In intranuclear inclusion body disease, GPR26-positive nuclear inclusions were found in both neurons and glial cells. Marinesco bodies in aged control subjects were also positive for GPR26. Double immunofluorescence analysis revealed co-localization of GPR26 with polyglutamine or ubiquitin in these nuclear inclusions. These findings suggest that GPR26 may have a common role in the formation or degradation of intranuclear inclusions in several neurodegenerative diseases.

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  • 新潟大学脳研究所の取り組み:3T MRIを用いたAiと病理解剖 査読

    柿田 明美

    インナービジョン   31 ( 1 )   45 - 47   2016年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • 病理所見を理解する基礎 査読

    柿田 明美

    てんかん研究   33 ( 3 )   688 - 691   2016年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3805/jjes.33.688

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  • Depression-like episodes in mice harboring mtDNA deletions in paraventricular thalamus 査読

    T. Kasahara, A. Takata, T. M. Kato, M. Kubota-Sakashita, T. Sawada, A. Kakita, H. Mizukami, D. Kaneda, K. Ozawa, T. Kato

    MOLECULAR PSYCHIATRY   21 ( 1 )   39 - 48   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Depression is a common debilitating human disease whose etiology has defied decades of research. A critical bottleneck is the difficulty in modeling depressive episodes in animals. Here, we show that a transgenic mouse with chronic forebrain expression of a dominant negative mutant of Polg1, a mitochondrial DNA (mtDNA) polymerase, exhibits lethargic behavioral changes, which are associated with emotional, vegetative and psychomotor disturbances, and response to antidepression drug treatment. The results suggested a symptomatic similarity between the lethargic behavioral change that was recurrently and spontaneously experienced by the mutant mice and major depressive episode as defined by DSM-5. A comprehensive screen of mutant brain revealed a hotspot for mtDNA deletions and mitochondrial dysfunction in the paraventricular thalamic nucleus (PVT) with similar defects observed in postmortem brains of patients with mitochondrial disease with mood symptoms. Remarkably, the genetic inhibition of PVT synaptic output by Cre-loxP-dependent expression of tetanus toxin triggered de novo depression-like episodes. These findings identify a novel preclinical mouse model and brain area for major depressive episodes with mitochondrial dysfunction as its cellular mechanism.

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  • Globular Glial Mixed Four Repeat Tau and TDP-43 Proteinopathy with Motor Neuron Disease and Frontotemporal Dementia. 査読 国際誌

    Ryoko Takeuchi, Yasuko Toyoshima, Mari Tada, Hidetomo Tanaka, Hiroshi Shimizu, Atsushi Shiga, Takeshi Miura, Kenju Aoki, Akane Aikawa, Shin Ishizawa, Takeshi Ikeuchi, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    Brain pathology (Zurich, Switzerland)   26 ( 1 )   82 - 94   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amyotrophic lateral sclerosis (ALS) may be accompanied by frontotemporal dementia (FTD). We report a case of glial mixed tau and TDP-43 proteinopathies in a Japanese patient diagnosed clinically as having ALS-D. Autopsy revealed loss of lower motor neurons and degeneration of the pyramidal tracts in the spinal cord and brain stem. The brain showed frontotemporal lobar degeneration (FTLD), the most severe neuronal loss and gliosis being evident in the precentral gyrus. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. AT8 immunostaining revealed that predominant occurrence of astrocytic tau lesions termed globular astrocytic inclusions (GAIs) was a feature of the affected regions. These GAIs were Gallyas-Braak negative. Neuronal and oligodendrocytic tau lesions were comparatively scarce. pS409/410 immunostaining also revealed similar neuronal and glial TDP-43 lesions. Interestingly, occasional co-localization of tau and TDP-43 was evident in the GAIs. Immunoblot analyses revealed band patterns characteristic of a 4-repeat (4R) tauopathy, corticobasal degeneration and a TDP-43 proteinopathy, ALS/FTLD-TDP Type B. No mutations were found in the MAPT or TDP-43 genes. We consider that this patient harbored a distinct, sporadic globular glial mixed 4R tau and TDP-43 proteinopathy associated with motor neuron disease and FTD.

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  • Globular Glial Mixed Four Repeat Tau and TDP-43 Proteinopathy with Motor Neuron Disease and Frontotemporal Dementia 査読

    Ryoko Takeuchi, Yasuko Toyoshima, Mari Tada, Hidetomo Tanaka, Hiroshi Shimizu, Atsushi Shiga, Takeshi Miura, Kenju Aoki, Akane Aikawa, Shin Ishizawa, Takeshi Ikeuchi, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    BRAIN PATHOLOGY   26 ( 1 )   82 - 94   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Amyotrophic lateral sclerosis (ALS) may be accompanied by frontotemporal dementia (FTD). We report a case of glial mixed tau and TDP-43 proteinopathies in a Japanese patient diagnosed clinically as having ALS-D. Autopsy revealed loss of lower motor neurons and degeneration of the pyramidal tracts in the spinal cord and brain stem. The brain showed frontotemporal lobar degeneration (FTLD), the most severe neuronal loss and gliosis being evident in the precentral gyrus. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. AT8 immunostaining revealed that predominant occurrence of astrocytic tau lesions termed globular astrocytic inclusions (GAIs) was a feature of the affected regions. These GAIs were Gallyas-Braak negative. Neuronal and oligodendrocytic tau lesions were comparatively scarce. pS409/410 immunostaining also revealed similar neuronal and glial TDP-43 lesions. Interestingly, occasional co-localization of tau and TDP-43 was evident in the GAIs. Immunoblot analyses revealed band patterns characteristic of a 4-repeat (4R) tauopathy, corticobasal degeneration and a TDP-43 proteinopathy, ALS/FTLD-TDPTypeB. No mutations were found in the MAPT or TDP-43 genes. We consider that this patient harbored a distinct, sporadic globular glial mixed 4R tau and TDP-43 proteinopathy associated with motor neuron disease and FTD.

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  • Fibromyalgia in a Patient with Cushing's Disease Accompanied by Central Hypothyroidism 査読

    Nobumasa Ohara, Shinichi Katada, Takaho Yamada, Naomi Mezaki, Hiroshi Suzuki, Akiko Suzuki, Osamu Hanyu, Yuichiro Yoneoka, Izumi Kawachi, Takayoshi Shimohata, Akiyoshi Kakita, Masatoyo Nishizawa, Hirohito Sone

    INTERNAL MEDICINE   55 ( 21 )   3185 - 3190   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    A 39-year-old woman with a 3-year history of a rounded face developed widespread myalgia. Detailed examinations revealed no disorders that could explain the pain other than concomitant Cushing's disease and central hypothyroidism. Both the hypercortisolemia and hypothyroidism completely resolved after the patient underwent surgery to treat Cushing's disease, but she continued to experience unresolved myalgia and met the diagnostic criteria for fibromyalgia. Few studies have so far investigated patients with fibromyalgia associated with Cushing's syndrome. In our case, the hypothyroidism caused by Cushing's disease probably played an important role in triggering and exacerbating fibromyalgia. This highlights the need to examine the endocrine function in patients with muscle pain.

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  • Diagnostic performance of positron emission tomography for the presurgical evaluation of patients with non-lesional intractable partial epilepsy: Comparison among 18F-FDG, 11C-Flumazenil, and 11C-Flumazenil binding potential imaging using statistical imaging analysis 査読

    Daisuke Komoto, Koji Iida, Toru Higaki, Yoko Kaichi, Komei Takauchi, Koji Arihiro, Akiyoshi Kakita, Yutaka Hirokawa, Kazuo Awai

    Hiroshima Journal of Medical Sciences   64 ( 4 )   51 - 57   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Hiroshima University Medical Press  

    To compare the diagnostic performance of 18F-FDG PET, nC-FMZ PET, and 11C-FMZ BP imaging for the evaluation of patients with intractable partial epilepsy whose MRI findings are normal by using statistical imaging analysis. Ten patients underwent comprehensive presurgical evaluation, including PET studies, to assess the epileptic foci. The extent of cortical resection was based on the results of intracranial video-electroencephalography (IVEEG) monitoring and brain mapping under stimulation. The images of 10 patients and 30 controls were spatially normalized to templates generated in-house by non-rigid registration and the standardized images of the patients and controls were statistically compared. Epileptic focus candidates were visualized on a color map of axial images of each template and the focus site was identified in candidates for lobar location. In patients with Engel I postoperative seizure outcomes we assessed the sensitivity and specificity of the imaging methods for lobar focus localization. We also compared the concordance scores of patients with Engel I and Engel II-IV postoperative seizures. The sensitivity and specificity for lobar focus localization on 18F-FDG PET scans was 90.0% and 84.8%, respectively
    it was 30.0% and 81.4% for 11C-FMZ PET, 40.0% and 66.7% for 11C-FMZ BP images, and 100.0% and 51.4% for 18F-FDG PET/11C-FMZ PET/11C-FMZ BP images. In one patient the epileptic focus not detected on 18F-FDG PET scans was shown on 11C-FMZ BP images. In patients with Engel I post-treatment seizures the concordance scores were significantly higher for 18F-FDG PET than 11C-FMZ PET and 11C-FMZ BP images (p &lt
    0.05). With respect to sensitivity and specificity, 18F-FDG PET was superior to 11C-FMZ PET and 11C-FMZ BP imaging. However, in some patients with normal MRI results, 11C-FMZ BP studies may complement 18F-FDG PET findings in efforts to identify the epileptogenic lobar regions.

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  • Localization of nuclear receptor subfamily 4, group A, member 3 (NR4A3) in Lewy body disease and multiple system atrophy 査読

    Tomoya Kon, Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, Masahiko Tomiyama, Yasuko Toyoshima, Akiyoshi Kakita, Hitoshi Takahashi, Jun Utsumi, Hidenao Sasaki, Koichi Wakabayashi

    NEUROPATHOLOGY   35 ( 6 )   503 - 509   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Nuclear receptor subfamily 4, group A, member 3 (NR4A3), also known as neuron-derived orphan receptor-1, is a nuclear receptor which plays key roles in cell cycle, neuronal differentiation, apoptosis and metabolism. These processes may be involved in the pathogenesis of certain neurodegenerative diseases. Previous studies have shown that there are high levels of NR4A3 mRNA in the CNS. Moreover, NR4A2, a transcription factor with homology to NR4A3, has been reported to contribute to the pathogenesis of Parkinson's disease. However, it is uncertain whether NR4A3 is also involved in diseases such as dementia with Lewy bodies, multiple system atrophy, and other neurodegenerative disorders such as tauopathies, TDP-43 proteinopathies and polyglutamine diseases. In the present study we used immunohistochemistry to examine the brain and spinal cord from patients with various neurodegenerative diseases and normal control subjects using two polyclonal anti-NR4A3 antibodies. In controls, the cytoplasm of neurons and glial cells was faintly immunostained with anti-NR4A3 antibodies. In tissues from patients with neurodegenerative diseases, immunoreactivity for NR4A3 was observed in cortical and brainstem-type Lewy bodies in Parkinson's disease and in dementia with Lewy bodies, as well as in neuronal and glial cytoplasmic inclusions in multiple system atrophy. A double-labeled immunofluorescence study showed co-localization of NR4A3 and phosphorylated -synuclein in these inclusions. Neuronal and glial inclusions in other neurodegenerative disorders were NR4A3 negative. These findings suggest that accumulation of NR4A3 is specific to -synucleinopathy.

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  • Spatiotemporal gene expression trajectory in the human and non-human ape brains 査読

    Yasuhiro Go, Shoji Tatsumoto, Li Qian, Takao Oishi, Toshifumi Udono, Shuji Shigenobu, Akiyoshi Kakita, Hiroyuki Nawa, Philipp Khaitovich

    GENES & GENETIC SYSTEMS   90 ( 6 )   372 - 372   2015年12月

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    記述言語:英語   出版者・発行元:GENETICS SOC JAPAN  

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  • フラビン蛍光イメージングによるてんかん原性の解析 査読

    北浦弘樹, 柿田明美

    Epilepsy   9 ( 2 )   82 - 84   2015年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Sortilin-related receptor CNS expressed 2 (SorCS2) is localized to Bunina bodies in amyotrophic lateral sclerosis 査読

    Fumiaki Mori, Yasuo Miki, Kunikazu Tanji, Akiyoshi Kakita, Hitoshi Takahashi, Jun Utsumi, Hidenao Sasaki, Koichi Wakabayashi

    NEUROSCIENCE LETTERS   608   6 - 11   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Sortilin-related receptor CNS expressed 2 (SorCS2) is one of the vacuolar protein sorting 10 family proteins (VPS10Ps) that have pleiotropic roles in protein trafficking and intracellular and intercellular signaling. Bunina bodies (BBs) are specifically detected in the lower motor neurons in patients with amyotrophic lateral sclerosis (ALS). BBs are immunolabeled with antibodies against cystatin C, transferrin and peripherin and are considered to originate from the endoplasmic reticulum, which is part of the protein sorting pathway. The present study investigated whether VPS10Ps are involved in the formation of BBs in ALS. We immunohistochemically examined the spinal cord from patients with ALS and control subjects using antibodies against VPS10Ps (sortilin, SorLA, SorCS1, SorCS2 and SorCS3). In normal controls, antibodies against VPS10Ps immunolabeled the cytoplasm of anterior horn cells in a fine granular pattern. In ALS, almost all BBs (95.1%) were strongly immunopositive for SorCS2, and immunoreativity for sortilin and SorLA was decreased in anterior horn cells. These findings suggest that VPS10Ps may be involved in the disease process of ALS. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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  • Characteristic expression of p57/Kip2 in balloon cells in focal cortical dysplasia 査読

    Tadashi Kimura, Hiroki Kitaura, Hiroshi Masuda, Shigeki Kameyama, Yuko Saito, Kenji Sugai, Taisuke Otsuki, Atsuko Nakazawa, Nobuhito Morota, Takamichi Yamamoto, Kouji Iida, Masanori Nakagawa, Toshiki Mizuno, Hitoshi Takahashi, Akiyoshi Kakita

    NEUROPATHOLOGY   35 ( 5 )   401 - 409   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Balloon cells are a pathognomonic cellular feature of various cortical malformations, including focal cortical dysplasia type IIb (FCD IIb), cortical tubers of tuberous sclerosis (TSC) and hemimegalencephaly (HME). In the present study, we investigated the immunohistochemical expression of p57/Kip2, a member of the Cip/Kip family of cyclin-dependent kinase inhibitory proteins, in balloon cells in surgical specimens taken from 26, 17 and six patients with FCD IIb, TSC and HME, respectively. Characteristic dot-like reactivity with a faint, intense, reticular and process-like pattern was confined to the proximal portion of the cytoplasmic processes of the cells. Immunoelectron microscopy revealed the p57/Kip2 reactivity on intermediate filaments in the proximal portion of the processes. The immunohistochemical profile appeared similar to that of CD34; however, a double immunofluorescence study demonstrated that no cells showed reactivity for both p57/Kip2 and CD34. The frequencies of the p57/Kip2-positive cells in FCD IIb and HME were significantly higher than those in TSC, suggesting that the balloon cells may be heterogeneous. These findings suggest some functional significance of the protein on the cytoplasmic processes of balloon cells and appear consistent with the notion that the cells are abnormally differentiated progenitor cells.

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  • Variable expression of microglial DAP12 and TREM2 genes in Nasu-Hakola disease 査読

    Atsushi Sasaki, Akiyoshi Kakita, Kunihiro Yoshida, Takuya Konno, Takeshi Ikeuchi, Shintaro Hayashi, Hidenori Matsuo, Kei Shioda

    NEUROGENETICS   16 ( 4 )   265 - 276   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Nasu-Hakola disease (NHD) is a form of presenile dementia associated with sclerosing leukoencephalopathy and polycystic lipomembranous osteodysplasia. This extremely rare inherited disease is caused by mutations in either DAP12 or TREM2. The present study was designed to assess the relationship between DAP12/TREM2 genotype, mRNA and protein expression levels by both Western blotting and immunohistochemistry, and the tissue distribution and pathomorphological phenotype of the microglia. Molecular genetic testing performed in three NHD cases confirmed that two cases had mutations in DAP12 and that one case carried a mutation in TREM2. Protein levels were analyzed in four cases. Interestingly, significant DAP12 expression was found in numerous microglia in one NHD case with a homozygous DAP12 single-base substitution, and both real-time PCR and Western blotting confirmed the finding. In contrast, levels of both DAP12 and TREM2, respectively, were much lower in the other cases. Immunohistochemistry using established microglial markers revealed consistently mild activation of microglia in the cerebral white matter although there was no or only little expression of DAP12 in three of the NHD cases. The highly different expression of DAP12 represents the first description of such variable expressivity in NHD microglia. It raises important questions regarding the mechanisms underlying dementia and white matter damage in NHD.

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  • Isopentenyl diphosphate isomerase, a cholesterol synthesizing enzyme, is localized in Lewy bodies 査読

    Keiko Nakamura, Fumiaki Mori, Kunikazu Tanji, Yasuo Miki, Masahito Yamada, Akiyoshi Kakita, Hitoshi Takahashi, Jun Utsumi, Hidenao Sasaki, Koichi Wakabayashi

    NEUROPATHOLOGY   35 ( 5 )   432 - 440   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Isopentenyl diphosphate isomerase (IDI) is a cytoplasmic enzyme involved in the biosynthesis of isoprenoids including cholesterols. IDI has two isoforms in humans: IDI1 and IDI2. Since lipids are known to be a component of Lewy bodies (LBs), we investigated the immunohistochemical localization of IDI1 and IDI2 in the brain of patients with LB disease and multiple system atrophy (MSA) and normal control subjects. In normal controls, the cytoplasm of neurons was weakly immunostained with anti-IDI1 and anti-IDI2 antibodies throughout the nervous system. In LB disease, brainstem-type LBs were strongly positive for IDI1 and IDI2, and cortical LBs were unstained or barely immunolabeled. Double immunofluorescence staining revealed co-localization of phosphorylated -synuclein with IDI1 or IDI2. Glial cytoplasmic inclusions in MSA were unstained. Previous studies have shown that levels of cholesterol metabolites are increased in the cerebral cortex of patients with LB disease, and that these metabolites accelerate -synuclein aggregation. The present findings suggest that IDI1 and IDI2 may be associated with the production of cholesterol metabolites in neurons, leading to -synuclein aggregation during the process of LB formation.

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  • Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb 査読

    Mitsuko Nakashima, Hirotomo Saitsu, Nobuyuki Takei, Jun Tohyama, Mitsuhiro Kato, Hiroki Kitaura, Masaaki Shiina, Hiroshi Shirozu, Hiroshi Masuda, Keisuke Watanabe, Chihiro Ohba, Yoshinori Tsurusaki, Noriko Miyake, Yingjun Zheng, Tatsuhiro Sato, Hirohide Takebayashi, Kazuhiro Ogata, Shigeki Kameyama, Akiyoshi Kakita, Naomichi Matsumoto

    ANNALS OF NEUROLOGY   78 ( 3 )   375 - 386   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    ObjectiveFocal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb.
    MethodsWe collected a total of 24 blood-brain paired samples with FCD, including 13 individuals with FCD type IIb, 5 with type IIa, and 6 with type I. We performed whole-exome sequencing using paired samples from 9 of the FCD type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital polymerase chain reaction. The effect of MTOR mutations on mammalian target of rapamycin (mTOR) kinase signaling was evaluated by immunohistochemistry and Western blotting analyses of brain samples and by in vitro transfection experiments.
    ResultsWe identified four lesion-specific somatic MTOR mutations in 6 of 13 (46%) individuals with FCD type IIb showing mutant allele rates of 1.11% to 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD type IIb brain tissues with MTOR mutations was clearly elevated, compared to control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase.
    InterpretationWe found low-prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb. Ann Neurol 2015;78:375-386

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  • Quantitative correlation between cardiac MIBG uptake and remaining axons in the cardiac sympathetic nerve in Lewy body disease 査読

    Makoto Takahashi, Masako Ikemura, Teruaki Oka, Toshiki Uchihara, Koichi Wakabayashi, Akiyoshi Kakita, Hitoshi Takahashi, Mari Yoshida, Shuta Toru, Takayoshi Kobayashi, Satoshi Orimo

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY   86 ( 9 )   939 - 944   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ PUBLISHING GROUP  

    Objectives Reduced cardiac meta-iodobenzylguanidine (MIBG) uptake and loss of cardiac sympathetic axons, as its possible anatomical substrate, were both recognised in Lewy body disease (LBD), while their direct correlation has so far remained speculative. Increasing availability of autopsy-confirmed cases of LBD prompted us to quantify residual cardiac sympathetic axons to establish their relationship to cardiac MIBG uptake.
    Methods We collected cardiac tissue samples from 23 patients with autopsy-confirmed LBD and two non-LBD control patients who underwent I-123-MIBG cardiac scintigraphy in life. Samples of the left ventricular anterior wall were stained with anti-tyrosine hydroxylase (TH) and anti-neurofilament (NF) antibodies as markers of cardiac nerve axons. We quantified the immunolabelled areas and assessed their correlation to standardised heart to mediastinum (H/M) ratios of I-123-MIBG cardiac scintigraphy.
    Results Cardiac MIBG uptake in the early and delayed phases was reduced in 90.9% and 95.7% of patients with LBD, respectively. The area of TH-immunoreactive axons correlated significantly with the H/M ratio in the early (p=0.036) as well as in the delayed (p=0.018) phases. The area of NF-immunoreactive axons also correlated with the H/M ratio in the early (p=0.003) as well as in the delayed (p=0.001) phases.
    Conclusions Tight quantitative correlation between cardiac I-123-MIBG uptake and corresponding loss of sympathetic axons in LBD, as established for the first time by this study, provides a scientific basis to confirm the reliability of MIBG cardiac scintigraphy as a powerful clinical tool to detect loss of these axons as a biomarker for the presence of Lewy body disease.

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  • Inhibitory PAS domain protein is a substrate of PINK1 and Parkin and mediates cell death in a Parkinson's disease model 査読

    S. Kasai, S. Torii, A. Kakita, K. Sogawa

    CELL DEATH & DISEASE   6   e1886   2015年9月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

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  • Somatic Mutations in MTOR Cause Focal cortical dysplasia Type IIb 査読

    Nakashima M, Saitsu H, Takei N, Tohyama J, Kato M, Kitaura H, Shiina M, Shirouzu H, Masuda H, Watanabe K, Ohba C, Tsurusaki Y, Miyake N, Zheng YJ, Sato T, Takebayashi H, Ogata K, Kameyama S, Kakita A, Matsumoto N

    Ann. Neurol   78 ( 3 )   375 - 386   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ana.24444

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  • ファール病(家族性特発性基底核石灰化症) 査読

    木村正志, 柿田明美

    Clin Neurosci   33 ( 8 )   862 - 863   2015年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly. 査読

    Ohnishi T, Yanazawa M, Sasahara T, Kitamura Y, Hiroaki H, Fukazawa Y, Kii I, Nishiyama T, Kakita A, Takeda H, Takeuchi A, Arai Y, Ito A, Komura H, Hirao H, Satomura K, Inoue M, Muramatsu S, Matsui K, Tada M, Sato M, Saijo E, Shigemitsu Y, Sakai S, Umetsu Y, Goda N, Takino N, Takahashi H, Hagiwara M, Sawasaki T, Iwasaki G, Nakamura Y, Nabeshima Y, Teplow DB, Hoshi M

    Proceedings of the National Academy of Sciences of the United States of America   112 ( 32 )   E4465 - E4474   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Immunohistochemical profiles of IDH1, MGMT and P53: Practical significance for prognostication of patients with diffuse gliomas 査読

    Ryosuke Ogura, Yoshihiro Tsukamoto, Manabu Natsumeda, Mizuho Isogawa, Hiroshi Aoki, Tsutomu Kobayashi, Seiichi Yoshida, Kouichiro Okamoto, Hitoshi Takahashi, Yukihiko Fujii, Akiyoshi Kakita

    NEUROPATHOLOGY   35 ( 4 )   324 - 335   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Genetic and epigenetic status, including mutations of isocitrate dehydrogenase (IDH) and TP53 and methylation of O-6-methylguanine-DNA methyltransferase (MGMT), are associated with the development of various types of glioma and are useful for prognostication. Here, using routinely available histology sections from 312 patients with diffuse gliomas, we performed immunohistochemistry using antibodies specific for IDH1 mutation, MGMT methylation status, and aberrant p53 expression to evaluate the possible prognostic significance of these features. With regard to overall survival (OS), univariate analysis indicated that an IDH1-positive profile in patients with glioblastoma (GBM), anaplastic astrocytoma (AA), anaplastic oligoastrocytoma and oligodendroglioma, or a MGMT-negative profile in patients with GBM and AA were significantly associated with a favorable outcome. Multivariate analysis revealed that both profiles were independent factors influencing prognosis. The OS of patients with IDH1-positive/MGMT-negative profiles was significantly longer than that of patients with negative/negative and negative/positive profiles. A p53 profile was not an independent prognostic factor. However, for GBM/AA patients with IDH1-negative/MGMT-negative profiles, p53 overexpression was significantly associated with an unfavorable outcome. Thus, the immunohistochemical profiles of IDH1 and MGMT are of considerable significance in gliomas, and a combination of IDH1, MGMT and p53 profiles may be useful for prognostication of GBM/AA.

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  • Involvement of inhibitory PAS domain protein in neuronal cell death in Parkinson's disease. 査読

    Torii S, Kasai S, Suzuki A, Todoroki Y, Yokozawa K, Yasumoto KI, Seike N, Kiyonari H, Mukumoto Y, Kakita A, Sogawa K

    Cell death discovery   1   15015   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/cddiscovery.2015.15

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  • Assessment of copy number variations in the brain genome of schizophrenia patients. 査読

    Sakai M, Watanabe Y, Someya T, Araki K, Shibuya M, Niizato K, Oshima K, Kunii Y, Yabe H, Matsumoto J, Wada A, Hino M, Hashimoto T, Hishimoto A, Kitamura N, Iritani S, Shirakawa O, Maeda K, Miyashita A, Niwa S, Takahashi H, Kakita A, Kuwano R, Nawa H

    Mol Cytogenet   8   46   2015年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/s13039-015-0144-5.

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  • てんかん外科病理に関する最新の国際分類 査読

    柿田 明美

    最新医学   70 ( 6 )   1031 - 1037   2015年6月

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  • Two siblings with cortical dysplasia: Clinico-electroencephalographic features 査読

    Tatsuya Fukasawa, Tetsuo Kubota, Tamiko Negoro, Shinsuke Maruyama, Ryoko Honda, Yuko Saito, Masayuki Itoh, Akiyoshi Kakita, Kenji Sugai, Taisuke Otsuki, Mitsuhiro Kato, Jun Natsume, Kazuyoshi Watanabe

    PEDIATRICS INTERNATIONAL   57 ( 3 )   472 - 475   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    The older of two siblings began to have spasms and partial seizures at 1 month of age. Head magnetic resonance imaging showed an abnormal area in the left temporo-parieto-occipital region. Interictal electroencephalogram (EEG) showed a suppression-burst pattern. Adrenocorticotropic hormone stopped the spasms, but the seizures continued. Clonazepam, carbamazepine, zonisamide, and clobazam were ineffective. She underwent focal resection at age 8 months. Postoperatively, the seizures disappeared. Histopathologically, the lesion appeared to be focal cortical dysplasia type IIa. The younger sibling had spasms from birth. Head magnetic resonance imaging showed left hemi-megalencephaly. Interictal EEG showed a suppression-burst pattern. Phenobarbital, valproic acid, and zonisamide were ineffective. He underwent hemispherotomy at age 2 months and became seizure free. The histopathological features were consistent with those of hemi-megalencephaly. The siblings' EEG and clinical courses had some similarities. These siblings' conditions may have the same genetic background.

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  • Filamentous aggregations of phosphorylated α-synuclein in Schwann cells (Schwann cell cytoplasmic inclusions) in multiple system atrophy. 査読

    Nakamura K, Mori F, Kon T, Tanji K, Miki Y, Tomiyama M, Kurotaki H, Toyoshima Y, Kakita A, Takahashi H, Yamada M, Wakabayashi K

    Acta neuropathologica communications   3 ( 1 )   29   2015年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • 髄鞘病変を鑑別するポイント 査読

    柿田 明美

    病理と臨床   33 ( 4 )   352 - 358   2015年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    神経病理診断の標準化Ⅱ

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  • 胚芽異型成性神経上皮腫瘍 Dysembryoplastic neuroepithelial tumor. 査読

    清水 宏, 柿田明美

    病理と臨床   33   334   2015年4月

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  • 頭蓋咽頭腫 Craniopharyngioma 査読

    清水 宏, 柿田明美

    病理と臨床   33   332   2015年4月

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  • Variants associated with Gaucher disease in multiple system atrophy 査読

    Jun Mitsui, Takashi Matsukawa, Hidenao Sasaki, Ichiro Yabe, Masaaki Matsushima, Alexandra Duerr, Alexis Brice, Hiroshi Takashima, Akio Kikuchi, Masashi Aoki, Hiroyuki Ishiura, Tsutomu Yasuda, Hidetoshi Date, Budrul Ahsan, Atsushi Iwata, Jun Goto, Yaeko Ichikawa, Yasuo Nakahara, Yoshio Momose, Yuji Takahashi, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Takamichi Hattori, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Tomoyoshi Kondo, Shigeo Murayama, Nobutaka Hattori, Mitsutoshi Yamamoto, Miho Murata, Wataru Satake, Tatsushi Toda, Alessandro Filla, Thomas Klockgether, Ullrich Wuellner, Garth Nicholson, Sid Gilman, Caroline M. Tanner, Walter A. Kukull, Mathew B. Stern, Virginia M. -Y. Lee, John Q. Trojanowski, Eliezer Masliah, Phillip A. Low, Paola Sandroni, Laurie J. Ozelius, Tatiana Foroud, Shoji Tsuji

    ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY   2 ( 4 )   417 - 426   2015年4月

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    Objective: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. Methods: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. Results: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 9 10(-3)). Interpretation: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

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  • [Hip Fracture--Epidemiology, Management and Liaison Service. Osteoporosis liaison service in Japan]. 査読

    Suzuki A, Sekiguchi-Ueda S, Kakita A

    Clinical calcium   25 ( 4 )   559 - 563   2015年4月

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  • 認知症を主症状とし、大脳皮質に変性が強調された進行性核上性麻痺の一剖検例 査読

    田中 英智, 清水 宏, 豊島 靖子, 田中 弘, 田中 政春, 池内 健, 柿田 明美, 高橋 均

    信州医学雑誌   63 ( 1 )   71 - 72   2015年2月

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    記述言語:日本語   出版者・発行元:信州医学会  

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  • Zinc Transporters ZnT3 and ZnT6 Are Downregulated in the Spinal Cords of Patients With Sporadic Amyotrophic Lateral Sclerosis 査読

    Masayuki Kaneko, Takao Noguchi, Saori Ikegami, Takeyuki Sakurai, Akiyoshi Kakita, Yasuko Toyoshima, Taiho Kambe, Mitsunori Yamada, Masatoshi Inden, Hideaki Hara, Kiyomitsu Oyanagi, Takashi Inuzuka, Hitoshi Takahashi, Isao Hozumi

    JOURNAL OF NEUROSCIENCE RESEARCH   93 ( 2 )   370 - 379   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    The loss of homeostasis of essential metals is associated with various diseases, including neurodegenerative diseases. Previous studies have shown that the levels of zinc (Zn) are significantly higher in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Zn transporters and metallothioneins tightly control intracellular and extracellular Zn levels. This study investigated the protein levels of ZnT, a Zn transporter family, in ALS patients and model mice. The mRNA expression of ZnT1, -3, -4, -5, -6, -7, and -10 was assessed in the spinal cords of human control subjects. ZnT3 and ZnT6 protein levels were significantly diminished in the spinal cords of sporadic ALS patients compared with controls. Furthermore, immunohistochemical staining demonstrated decreased ZnT3 and ZnT6 immunoreactivity in the ventral horn of the spinal cords in ALS patients. Moreover, immunohistochemical analysis revealed that all ZnTs expressed in the spinal cords were localized in a distinct subset of motor neurons. In addition, ZnT3 and ZnT6 protein levels were not altered in SOD1 (G93A) mutant transgenic mice before or after the onset of ALS symptoms compared with controls. These results suggest that ZnT3 and ZnT6 protein levels are decreased in the spinal cords of sporadic ALS patients; however, this did not occur merely via loss of motor neurons. (c) 2014 Wiley Periodicals, Inc.

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  • ALSにおけるspliceosome異常 査読

    石原智彦, 柿田明美, 高橋 均, 小野寺 理, 西澤正豊

    臨床神経   54 ( 12 )   1155 - 1157   2014年12月

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  • ヒト脳病理切片におけるin situ hybridization法を利用したニューロンおよびグリア細胞の同定 査読

    佐藤和彦, 堀江正男, 竹林浩秀, 高橋 均, 柿田明美

    新潟医学会雑誌   128 ( 12 )   625 - 634   2014年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • ヒトてんかん病巣におけるグリア細胞の病理組織学的所見 査読

    柿田明美

    臨床神経   54 ( 12 )   1136 - 1138   2014年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.5692/clinicalneurol.54.1136

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  • Histopathologic features of epileptogenic brain lesions in infants and children 査読

    Akiyoshi Kakita

    No To Hattatsu   46 ( 6 )   413 - 417   2014年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Society of Child Neurology  

    I retrospectively reviewed the histopathologic features of surgical specimens taken consecutively from 600 patients with intractable epilepsy, and showed the scope of variation in lesions responsible for epileptogenesis. The patients were divided into three groups on the basis of age at seizure onset: 94 patients with infantile onset (before 1 year of age), 307 patients with juvenile onset (between 1 and 12 years of age), and 199 patients with adolescent/adult onset (at 13 years of age or beyond). In the infant group, seizure duration was significantly shorter than in the other groups, and malformations caused by abnormalities of cortical development, including focal cortical dysplasia (FCD) type II a/b, tuberous sclerosis, hemimegalencephaly, and polymicrogyria were predominant, whereas in the juvenile and adolescent/adult groups, other lesions such as hippocampal sclerosis (HS), tumors, FCD type I, and vascular lesions were frequently observed. FCD type III a was noted in nearly half of patient with HS in both juvenile and adolescent/adult groups. The causative tumors included dysembryoplastic neuroepithelial tumors, gangliogliomas, astrocytomas, and other glioneuronal and glial tumors. Thus, various histopathological entities and types, showing clear predominance depending on the age at seizure onset, were observed in patients with epilepsy. These features appear to provide information on the pathomechanisms of the lesions and their clinical relevance in affected patients.

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  • 結節性硬化症 査読

    北浦弘樹, 柿田明美

    Epilepsy   8 ( 2 )   74 - 76   2014年11月

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  • Disruption of actin-binding domain-containing Dystonin protein causes dystonia musculorum in mice 査読

    Masao Horie, Keisuke Watanabe, Asim K. Bepari, Jun-ichiro Nashimoto, Kimi Araki, Hiromi Sano, Satomi Chiken, Atsushi Nambu, Katsuhiko Ono, Kazuhiro Ikenaka, Akiyoshi Kakita, Ken-ichi Yamamura, Hirohide Takebayashi

    EUROPEAN JOURNAL OF NEUROSCIENCE   40 ( 10 )   3458 - 3471   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    The Dystonin gene (Dst) is responsible for dystonia musculorum (dt), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. Dst-a isoforms, which contain actin-binding domains, are predominantly expressed in the nervous system. Although sensory neuron degeneration in the peripheral nervous system during the early postnatal stage is a well-recognised phenotype in dt, the histological characteristics and neuronal circuits in the central nervous system responsible for motor symptoms remain unclear. To analyse the causative neuronal networks and roles of Dst isoforms, we generated novel multipurpose Dst gene trap mice, in which actin-binding domain-containing isoforms are disrupted. Homozygous mice showed typical dt phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (Dst(Gt)) encodes a mutant Dystonin-LacZ fusion protein, which is detectable by X-gal (5-bromo-4-chloro-3-indolyl--D-galactoside) staining. We observed wide expression of the actin-binding domain-containing Dystonin isoforms in the central nervous system (CNS) and peripheral nervous system. This raised the possibility that not only secondary neuronal defects in the CNS subsequent to peripheral sensory degeneration but also cell-autonomous defects in the CNS contribute to the motor symptoms. Expression analysis of immediate early genes revealed decreased neuronal activity in the cerebellar-thalamo-striatal pathway in the homozygous brain, implying the involvement of this pathway in the dt phenotype. These novel Dst(Gt) mice showed that a loss-of-function mutation in the actin-binding domain-containing Dystonin isoforms led to typical dt phenotypes. Furthermore, this novel multipurpose Dst(Gt) allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype.

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  • Elevated serum anti-phosphatidylcholine IgG antibodies in patients with influenza vaccination-associated optic neuritis 査読

    Seigo Korematsu, Hiroaki Miyahara, Akiyoshi Kakita, Tatsuro Izumi

    VACCINE   32 ( 48 )   6345 - 6348   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI LTD  

    Introduction: Because the optic nerve is mainly comprised from phospholipids such as phosphatidylcholine, the association between optic neuritis, anti-phospholipids antibodies and vaccination was examined.
    Subjects: Two female pediatric patients suddenly presented bilateral optic neuritis after administration of trivalent inactivated influenza vaccine.
    Methods: These two patients and another 11 patients with central nervous system demyelinating diseases were examined these anti-phospholipids antibodies. And immune histopathology was examined using serum derived from a patient with optic neuritis.
    Results: High serum titer of anti-phosphatidylcholine antibody levels were detected during acute phase in patients with optic neuritis. The patient's serum IgG antibodies were found to have stained the capillary endotheliums in the preserved autopsied optic nerve. Patients with optic neuritis had significantly elevated serum levels of anti-phosphatidylcholine antibody in comparison to the other patients without optic neuritis.
    Conclusion: Anti-phosphatidylcholine antibodies may be one of the causes of optic neuritis. (C) 2014 Elsevier Ltd. All rights reserved.

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  • 小児てんかん原性病巣の外科病理 査読

    柿田明美

    脳と発達   46 ( 6 )   413 - 417   2014年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.11251/ojjscn.46.413

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  • C9ORF72 repeat-associated non-ATG-translated polypeptides are distributed independently of TDP-43 in a Japanese patient with c9ALS 査読

    T. Konno, M. Tada, A. Shiga, A. Tsujino, H. Eguchi, M. Masuda-Suzukake, M. Hasegawa, M. Nishizawa, O. Onodera, A. Kakita, H. Takahashi

    NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY   40 ( 6 )   783 - 788   2014年10月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    DOI: 10.1111/nan.12157

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  • Relocation of p25α/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy. 査読

    Ota K, Obayashi M, Ozaki K, Ichinose S, Kakita A, Tada M, Takahashi H, Ando N, Eishi Y, Mizusawa H, Ishikawa K

    Acta neuropathologica communications   2 ( 1 )   136   2014年9月

  • Elevated postmortem striatal t-DARPP expression in schizophrenia and associations with DRD2/ANKK1 polymorphism 査読

    Yasuto Kunii, Itaru Miura, Junya Matsumoto, Mizuki Hino, Akira Wada, Shin-ichi Niwa, Hiroyuki Nawa, Miwako Sakai, Toshiyuki Someya, Hitoshi Takahashi, Akiyoshi Kakita, Hirooki Yabe

    Progress in Neuro-Psychopharmacology and Biological Psychiatry   53   123 - 128   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier Inc.  

    Background: Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32. kDa (DARPP-32) and calcineurin (CaN) have been implicated in the pathogenesis of schizophrenia because they function as molecular integrators of dopamine and glutamate signaling. DARPP-32 and CaN are mainly expressed in the caudate nucleus and putamen
    however, a few postmortem brain studies have focused on DARPP-32 expression in striatum from patients with schizophrenia. Methods: We used immunoblotting techniques and postmortem tissue samples from patients with schizophrenia and from normal control individuals to examine the expression of two major DARPP-32 isoforms, full-length (FL-DARPP) and truncated (t-DARPP), and of CaN in the striatum. We also assessed whether there was any significant correlation between the expression levels of either protein and the A1 allele of Taq1A genotype in the dopamine D2 receptor ( DRD2) gene/ankyrin-repeat containing kinase 1 ( ANKK1) gene. Results: We found that the mean t-DARPP expression level in the caudate was higher in patients with schizophrenia than in control individuals ( P&lt
    . 0.05) and the A1 allele of Taq1A genotype in DRD2/. ANKK1 was significantly associated with elevated expression of t-DARPP in the caudate. Also, the A1 allele was significantly correlated with the total score of antemortem psychiatric symptoms. Conclusion: These results may reflect potential molecular mechanisms important to the pathogenesis of schizophrenia. © 2014 Elsevier Inc.

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  • Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations 査読

    Y. -J. Fu, I. Aida, M. Tada, M. Tada, Y. Toyoshima, S. Takeda, T. Nakajima, H. Naito, M. Nishizawa, O. Onodera, A. Kakita, H. Takahashi

    NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY   40 ( 5 )   551 - 563   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Aims: Mutations in the SCARB2 gene cause a rare autosomal recessive disease, progressive myoclonus epilepsy (PME) with or without renal failure, the former also being designated action myoclonus-renal failure syndrome. Although reported cases have been accumulating, only a few have described its neuropathology. We studied two Japanese patients with PME without renal failure, in whom the ages at onset and disease durations were 45 and 20 years, and 14 and 8.5 years respectively. Methods: Sequencing and restriction analysis of the SCARB2 gene and neuropathological examination with immunohistochemistry were performed. Results: Gene analyses revealed novel homozygous frameshift and nonsense mutations in the SCARB2 gene. Both cases exhibited deposition of brown pigment in the brain, especially the cerebellar and cerebral cortices. Ultrastructurally, the pigment granules were localized in astrocytes. Neuronal loss and gliosis were also evident in the brain, including the pallidoluysian and cerebello-olivary systems. The spinal cord was also affected. Such changes were less severe in one patient with late-onset disease than in the other patient with early-onset disease. In brain and kidney sections, immunostaining with an antibody against the C-terminus of human SCARB2 revealed decreased levels and no expression of the protein respectively. Conclusions: The frameshift mutation detected in the patient with late-onset disease is a hitherto undescribed, unique type of SCARB2 gene mutation. The present two patients are the first reported to have clearly demonstrated both extraneuronal brown pigment deposition and system neurodegeneration as neuropathological features of PME with SCARB2 mutations.

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  • Bunina bodies in motor and non-motor neurons revisited: A pathological study of an ALS patient after long-term survival on a respirator 査読

    Tadashi Kimura, Haishan Jiang, Takuya Konno, Makiko Seto, Keisuke Iwanaga, Mitsuhiro Tsujihata, Akira Satoh, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

    NEUROPATHOLOGY   34 ( 4 )   392 - 397   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Bunina bodies (BBs) are small eosinophilic neuronal cytoplasmic inclusions (NCIs) found in the remaining lower motor neurons (LMNs) of patients with sporadic amyotrophic lateral sclerosis (SALS), being a specific feature of the cellular pathology. We examined a case of SALS, unassociated with TDP-43 or C9ORF72 mutation, of 12 years duration in a 75-year-old man, who had received artificial respiratory support for 9 years, and showed widespread multisystem degeneration with TDP-43 pathology. Interestingly, in this patient, many NCIs reminiscent of BBs were observed in the oculomotor nucleus, medullary reticular formation and cerebellar dentate nucleus. As BBs in the cerebellar dentate nucleus have not been previously described, we performed ultrastructural and immunohistochemical studies of these NCIs to gain further insight into the nature of BBs. In each region, the ultrastructural features of these NCIs were shown to be identical to those of BBs previously described in LMNs. These three regions and the relatively well preserved sacral anterior horns (S1 and S2) and facial motor nucleus were immunostained with antibodies against cystatin C (CC) and TDP-43. Importantly, it was revealed that BBs exhibiting immunoreactivity for CC were a feature of LMNs, but not of non-motor neurons, and that in the cerebellar dentate nucleus, the ratio of neurons with BBs and TDP-43 inclusions/neurons with BBs was significantly lower than in other regions. These findings suggest that the occurrence of BBs with CC immunoreactivity is intrinsically associated with the particular cellular properties of LMNs, and that the mechanism responsible for the formation of BBs is distinct from that for TDP-43 inclusions.

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  • An autopsy case of incipient Pick's disease: Immunohistochemical profile of early-stage Pick body formation 査読

    Yasuo Miki, Fumiaki Mori, Kunikazu Tanji, Hidekachi Kurotaki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    NEUROPATHOLOGY   34 ( 4 )   386 - 391   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    There is little immunohistochemical information about the early stage of Pick body formation, due to the extremely limited opportunities of studying Pick's disease at the incipient or subclinical stage. We report a 62-year-old man without any clinical manifestations of Pick's disease, who died of B-cell lymphoma of the brainstem. Post mortem examination revealed many Pick bodies without obvious neuronal loss mainly in the left frontal and temporal lobes. Three brains of patients with typical Pick's disease (disease duration: 7, 11 and 16 years) were also examined. Pick bodies were immunopositive for phosphorylated tau and 3-repeat tau, and less consistently for p62 in both incipient and typical cases. In the incipient case, borderline positivity for ubiquitin was evident in only a few Pick bodies, whereas in the typical cases many Pick bodies showed obvious positivity for ubiquitin. These findings suggest that Pick bodies are rarely ubiquitinated in the early stage of Pick body formation.

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  • Elevated postmortem striatal t-DARPP expression in schizophrenia and associations with DRD2/ANKK1 polymorphism 査読

    Yasuto Kunii, Itaru Miura, Junya Matsumoto, Mizuki Hino, Akira Wada, Shin-ichi Niwa, Hiroyuki Nawa, Miwako Sakai, Toshiyuki Someya, Hitoshi Takahashi, Akiyoshi Kakita, Hirooki Yabe

    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY   53   123 - 128   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Background: Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN) have been implicated in the pathogenesis of schizophrenia because they function as molecular integrators of dopamine and glutamate signaling. DARPP-32 and CaN are mainly expressed in the caudate nucleus and putamen; however, a few postmortem brain studies have focused on DARPP-32 expression in striatum from patients with schizophrenia.
    Methods: We used immunoblotting techniques and postmortem tissue samples from patients with schizophrenia and from normal control individuals to examine the expression of two major DARPP-32 isoforms, full-length (FL-DARPP) and truncated (t-DARPP), and of CaN in the striatum. We also assessed whether there was any significant correlation between the expression levels of either protein and the A1 allele of Taq1A genotype in the dopamine D2 receptor (DRD2) gene/ankyrin-repeat containing kinase 1 (ANICK1) gene.
    Results: We found that the mean t-DARPP expression level in the caudate was higher in patients with schizophrenia than in control individuals (P &lt; 0.05) and the A1 allele of Taq1A genotype in DRD2/ANKK1 was significantly associated with elevated expression of t-DARPP in the caudate. Also, the A1 allele was significantly correlated with the total score of antemortem psychiatric symptoms.
    Conclusion: These results may reflect potential molecular mechanisms important to the pathogenesis of schizophrenia. (C) 2014 Elsevier Inc. All rights reserved.

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  • Cerebral amyloid angiopathy-related leukoencephalopathy: successful steroid treatment for neurological deficits and subcortical white matter lesions partly involving the cortical gray matter 査読

    Neurology and Clinical Neuroscience   2 ( 4 )   119 - 121   2014年7月

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  • びまん性メラニン細胞増殖症,髄膜黒色腫症 査読

    柿田 明美

    別冊日本臨牀 新領域別症候群シリーズ   28   307 - 310   2014年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    神経症候群Ⅲ-その他の神経疾患を含めて-

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  • "Gliomatosis encephali" as a novel category of brain tumors by the first autopsy case report of gliomatosis cerebelli 査読

    Asa Nakahara, Toshikazu Yoshida, Masanobu Yazawa, Takashi Ehara, Jun Nakayama, Akiyoshi Kakita, Ryosuke Ogura, Mika Asakawa, Emi Suzuki-Kouyama, Kiyomitsu Oyanagi

    NEUROPATHOLOGY   34 ( 3 )   295 - 303   2014年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Gliomatosis cerebri is a rare diffuse glioma that is neither mass-forming nor necrotic, and does not disrupt existing structures. Gliomatosis occurring in the cerebellum is known as gliomatosis cerebelli, and only three such cases examined by biopsy have been reported. Here we describe the first autopsy findings of a patient who was diagnosed as having gliomatosis in the cerebellum. Neuropathological examination identified the tumor cells as being positive for glial fibrillary acidic protein, vimentin and nestin, with atypical nuclei that were cashew-nut- or dishcloth-gourd-shaped. These tumor cells were dense in the right cerebellum, but also spread broadly throughout the brain including the left cerebrum and optic nerve. Mitotic figures were frequently seen in the cerebellum, brain stem and cerebrum. Scherer's secondary structures were evident not only in the cerebellum but also the cerebrum. No necrosis, microvascular proliferation or destruction of anatomical structures was detected in the whole brain. Differences in the origin of the tumors of the gliomatoses cerbri and cerebelli suggests these tumors are different types of brain tumors. Thus the findings support that the gliomatosis cerebelli is a novel type of brain tumor classification. Furthermore, by the similarities of the histological features among the tumors, it appears appropriate to establish a novel category of gliomatosis encephali which includes both gliomatosis cerebri and gliomatosis cerebelli.

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  • Genes associated with the progression of neurofibrillary tangles in Alzheimer's disease 査読

    A. Miyashita, H. Hatsuta, M. Kikuchi, A. Nakaya, Y. Saito, T. Tsukie, N. Hara, S. Ogishima, N. Kitamura, K. Akazawa, A. Kakita, H. Takahashi, S. Murayama, Y. Ihara, T. Ikeuchi, R. Kuwano

    TRANSLATIONAL PSYCHIATRY   4   e396   2014年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    The spreading of neurofibrillary tangles (NFTs), intraneuronal aggregates of highly phosphorylated microtubule-associated protein tau, across the human brain is correlated with the cognitive severity of Alzheimer's disease (AD). To identify genes relevant to NFT expansion defined by the Braak stage, we conducted whole-genome exon array analysis with an exploratory sample set consisting of 213 human post-mortem brain tissue specimens from the entorinal, temporal and frontal cortices of 71 brain-donor subjects: Braak NFT stages 0 (N = 13), I-II (N = 20), III-IV (N = 19) and V-VI (N = 19). We identified eight genes, RELN, PTGS2, MYO5C, TRIL, DCHS2, GRB14, NPAS4 and PHYHD1, associated with the Braak stage. The expression levels of three genes, PHYHD1, MYO5C and GRB14, exhibited reproducible association on real-time quantitative PCR analysis. In another sample set, including control subjects (N = 30), and in patients with late-onset AD (N = 37), dementia with Lewy bodies (N = 17) and Parkinson disease (N = 36), the expression levels of two genes, PHYHD1 and MYO5C, were obviously associated with late-onset AD. Protein-protein interaction network analysis with a public database revealed that PHYHD1 interacts with MYO5C via POT1, and PHYHD1 directly interacts with amyloid beta-peptide 42. It is thus likely that functional failure of PHYHD1 and MYO5C could lead to AD development.

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  • Entrapment of the inferior horns of the lateral ventricle with enlargement of the bilateral choroid plexus 査読

    Ryosuke Ogura, Junichi Yoshimura, Masakazu Sano, Shouichi Kawasaki, Kenichi Nishiyama, Kouichirou Okamoto, Hitoshi Takahashi, Yukihiko Fujii, Akiyoshi Kakita

    NEUROPATHOLOGY   34 ( 2 )   210 - 213   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

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  • Coexistence of amyotrophic lateral sclerosis with neuro-Behçet's disease presenting as a longitudinally extensive spinal cord lesion: clinicopathologic features of an autopsied patient. 査読

    Sato T, Ouchi H, Shimbo J, Sato A, Yamazaki M, Hashidate H, Igarashi S, Kakita A

    Neuropathology : official journal of the Japanese Society of Neuropathology   34 ( 2 )   185 - 189   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/neup.12074

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  • Superficial siderosis associated with aceruloplasminemia. Case report 査読

    Akira Matsushima, Toshikazu Yoshida, Kunihiro Yoshida, Shinji Ohara, Yasuko Toyoshima, Akiyoshi Kakita, Shu-ichi Ikeda

    JOURNAL OF THE NEUROLOGICAL SCIENCES   339 ( 1-2 )   231 - 234   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    A 63-year-old woman with a past history of right subdural hematoma (SDH) at the age of 61 years was referred to our hospital under a suspicion of aceruloplasminemia (ACP). A neurological examination revealed very mild cognitive impairment and cerebellar ataxia. Blood chemistry data showed deficient ceruloplasmin (Cp), decreased copper, and increased ferritin. A nonsense mutation (c.2630G &gt; A, p.Trp858Ter) was detected in the Cp gene. Brain magnetic resonance imaging (MRI) showed marked hypointensity at the surface of the cerebrum, cerebellum, and brainstem bilaterally, in addition to the bilateral basal ganglia, thalamus, and dentate nucleus, suggesting the coexistence of ACP and superficial siderosis (SS). The characteristics of SS in ACP have not been examined neuroradiologically or neuropathologically in great detail, while SDH and its curative surgery are known to cause SS. The distribution of the hypointensity areas on MRI was expanded bilaterally to the subtentorial areas of this patient, which was much more widespread than observed in typical SS after SDH. We speculate that the underlying ACP may expand the SS induced by SDH. Cp would accelerate iron export from the brain via the blood-cerebrospinal fluid (CSF) barrier, or CSF-brain barrier when excessive iron is loaded into the subarachnoid space. (C) 2014 Elsevier B.V. All rights reserved.

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  • Accumulation of the sigma-1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases 査読

    Yasuo Miki, Fumiaki Mori, Tomoya Kon, Kunikazu Tanji, Yasuko Toyoshima, Mari Yoshida, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    NEUROPATHOLOGY   34 ( 2 )   148 - 158   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    The sigma-1 receptor (SIGMAR1) is now known to be one of the endoplasmic reticulum (ER) chaperones, which participate in the degradation of misfolded proteins in cells via the ER-related degradation machinery linked to the ubiquitin-proteasome pathway. Mutations of the SIGMAR1 gene are implicated in the pathogenesis of familial frontotemporal lobar degeneration and motor neuron disease. Involvement of ER dysfunction in the formation of inclusion bodies in various neurodegenerative diseases has also become evident. We performed immunohistochemical staining to clarify the localization of SIGMAR1 in the brains of patients with neurodegenerative disorders, including trans-activation response DNA protein 43 (TDP-43) proteinopathy, tauopathy, -synucleinopathy, polyglutamine disease and intranuclear inclusion body disease (INIBD). Double-immunocytofluorescence and Western blot analyses of cultured cells were also performed to investigate the role of SIGMAR1 using a specific exportin 1 inhibitor, leptomycin B and an ER stress inducer, thapsigargin. SIGMAR1 was consistently shown to be co-localized with neuronal nuclear inclusions in TDP-43 proteinopathy, five polyglutamine diseases and INIBD, as well as in intranuclear Marinesco bodies in aged normal controls. Cytoplasmic inclusions in neurons and glial cells were unreactive for SIGMAR1. In cultured cells, immunocytofluorescent study showed that leptomycin B and thapsigargin were shown to sequester SIGMAR1 within the nucleus, acting together with p62. This finding was also supported by immunoblot analysis. These results indicate that SIGMAR1 might shuttle between the nucleus and the cytoplasm. Neurodegenerative diseases characterized by neuronal nuclear inclusions might utilize the ER-related degradation machinery as a common pathway for the degradation of aberrant proteins.

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  • ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases 査読

    Tomoya Kon, Fumiaki Mori, Kunikazu Tanji, Yasuo Miki, Yasuko Toyoshima, Mari Yoshida, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    NEUROPATHOLOGY   34 ( 1 )   19 - 26   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    FIG4 is a phosphatase that regulates intracellular vesicle trafficking along the endosomal-lysosomal pathway. Mutations of FIG4 lead to the development of Charcot-Marie-Tooth disease type 4J and amyotrophic lateral sclerosis (ALS). Moreover, ALS-associated proteins (transactivation response DNA protein 43 (TDP-43), fused in sarcoma (FUS), optineurin, ubiquilin-2, charged mutivesicular body protein 2b (CHMP2B) and valosin-containing protein) are involved in inclusion body formation in several neurodegenerative diseases. Using immunohistochemistry, we examined the brains and spinal cords of patients with various neurodegenerative diseases, including sporadic TDP-43 proteinopathy (ALS and frontotemporal lobar degeneration). TDP-43 proteinopathy demonstrated no FIG4 immunoreactivity in neuronal inclusions. However, FIG4 immunoreactivity was present in Pick bodies in Pick's disease, Lewy bodies in Parkinson's disease and dementia with Lewy bodies, neuronal nuclear inclusions in polyglutamine and intranuclear inclusion body diseases, and Marinesco and Hirano bodies in aged control subjects. These findings suggest that FIG4 is not incorporated in TDP-43 inclusions and that it may have a common role in the formation or degradation of neuronal cytoplasmic and nuclear inclusions in several neurodegenerative diseases.

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  • Co-localization of Bunina bodies and TDP-43 inclusions in lower motor neurons in amyotrophic lateral sclerosis 査読

    Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    NEUROPATHOLOGY   34 ( 1 )   71 - 76   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron involvement with Bunina bodies (BBs) and transactivation response DNA protein 43 (TDP-43) inclusions. We examined the spinal cord (n=20), hypoglossal nucleus (n=6) and facial nucleus (n=5) from ALS patients to elucidate the relationship between BBs and TDP-43 inclusions. BBs were found in the anterior horn in 16 of 20 cases, in the hypoglossal nucleus in all six cases and in the facial nucleus in four out of five cases. TDP-43 inclusions were found in each region of all the cases. Co-localization of BBs and TDP-43 inclusions was found in 15.2% of total neurons in the anterior horn, 29.2% in the hypoglossal nucleus and 17.3% in the facial nucleus. The frequency of TDP-43 inclusions was significantly higher in neurons with BBs than in those without in each region. Ultrastructurally, TDP-43-positive filamentous structures were intermingled with BBs. These findings suggest that there is a close relationship in the occurrence between BBs and TDP-43 inclusions.

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  • Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody 査読

    Akiko Yokoseki, Etsuji Saji, Musashi Arakawa, Takayuki Kosaka, Mariko Hokari, Yasuko Toyoshima, Kouichirou Okamoto, Shigeki Takeda, Kazuhiro Sanpei, Hirotoshi Kikuchi, Shunsei Hirohata, Kouhei Akazawa, Akiyoshi Kakita, Hitoshi Takahashi, Masatoyo Nishizawa, Izumi Kawachi

    BRAIN   137 ( Pt 2 )   520 - 536   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting T(H)1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.

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  • Neuronal differentiation associated with Gli3 expression predicts favorable outcome for patients with medulloblastoma 査読

    Hiroaki Miyahara, Manabu Natsumeda, Junichi Yoshimura, Ryosuke Ogura, Kenichi Okazaki, Yasuko Toyoshima, Yukihiko Fujii, Hitoshi Takahashi, Akiyoshi Kakita

    NEUROPATHOLOGY   34 ( 1 )   1 - 10   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Medulloblastoma (MB) is a malignant cerebellar tumor arising in children, and its ontogenesis is regulated by Sonic Hedgehog (Shh) signaling. No data are available regarding the correlation between expression of Gli3, a protein lying downstream of Shh, and neuronal differentiation of MB cells, or the prognostic significance of these features. We re-evaluated the histopathological features of surgical specimens of MB taken from 32 patients, and defined 15 of them as MB with neuronal differentiation (ND), three as MB with both glial and neuronal differentiation (GD), and 14 as differentiation-free (DF) MB. Gli3-immunoreactivity (IR) was evident as a clear circular stain outlining the nuclei of the tumor cells. The difference in the frequency of IR between the ND+GD (94.4%) and DF (0%) groups was significant (P&lt;0.001). The tumor cells with ND showed IR for both Gli3 and neuronal nuclei. Ultrastructurally, Gli3-IR was observed at the nuclear membrane. The overall survival and event-free survival rates of the patients in the ND group were significantly higher than those in the other groups. The expression profile of Gli3 is of considerable significance, and the association of ND with this feature may be prognostically favorable in patients with MB.

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  • The Kick-In System: A Novel Rapid Knock-In Strategy 査読

    Yuko Tomonoh, Masanobu Deshimaru, Kimi Araki, Yasuhiro Miyazaki, Tomoko Arasaki, Yasuyoshi Tanaka, Haruna Kitamura, Fumiaki Mori, Koichi Wakabayashi, Sayaka Yamashita, Ryo Saito, Masayuki Itoh, Taku Uchida, Junko Yamada, Keisuke Migita, Shinya Ueno, Hiroki Kitaura, Akiyoshi Kakita, Christoph Lossin, Yukio Takano, Shinichi Hirose

    PLOS ONE   9 ( 2 )   e88549   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Knock-in mouse models have contributed tremendously to our understanding of human disorders. However, generation of knock-in animals requires a significant investment of time and effort. We addressed this problem by developing a novel knock-in system that circumvents several traditional challenges by establishing stem cells with acceptor elements enveloping a particular genomic target. Once established, these acceptor embryonic stem (ES) cells are efficient at directionally incorporating mutated target DNA using modified Cre/lox technology. This is advantageous, because knock-ins are not restricted to one a priori selected variation. Rather, it is possible to generate several mutant animal lines harboring desired alterations in the targeted area. Acceptor ES cell generation is the rate-limiting step, lasting approximately 2 months. Subsequent manipulations toward animal production require an additional 8 weeks, but this delimits the full period from conception of the genetic alteration to its animal incorporation. We call this system a "kick-in'' to emphasize its unique characteristics of speed and convenience. To demonstrate the functionality of the kick-in methodology, we generated two mouse lines with separate mutant versions of the voltage-dependent potassium channel Kv7.2 (Kcnq2): p. Tyr284Cys (Y284C) and p. Ala306Thr (A306T); both variations have been associated with benign familial neonatal epilepsy. Adult mice homozygous for Y284C, heretofore unexamined in animals, presented with spontaneous seizures, whereas A306T homozygotes died early. Heterozygous mice of both lines showed increased sensitivity to pentylenetetrazole, possibly due to a reduction in M-current in CA1 hippocampal pyramidal neurons. Our observations for the A306T animals match those obtained with traditional knock-in technology, demonstrating that the kick-in system can readily generate mice bearing various mutations, making it a suitable feeder technology toward streamlined phenotyping.

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  • An attempt of non-human primate modeling of schizophrenia with neonatal challenges of epidermal growth factor. 査読

    Sakai M, Kashiwahara M, Kakita A, Nawa H

    J Addict Res Ther   5   170   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.4172/2155-6105.1000170.

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  • Increased l1 retrotransposition in the neuronal genome in schizophrenia. 査読

    Bundo Miki, Toyoshima Manabu, Okada Yohei, Akamatsu Wado, Ueda Junko, Nemoto-Miyauchi Taeko, Sunaga Fumiko, Toritsuka Michihiro, Ikawa Daisuke, Kakita Akiyoshi, Kato Motoichiro, Kasai Kiyoto, Kishimoto Toshifumi, Nawa Hiroyuki, Okano Hideyuki, Yoshikawa Takeo, Kato Tadafumi, Iwamoto Kazuya

    Neuron   81 ( 2 )   306 - 313   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent studies indicate that long interspersed nuclear element-1 (L1) are mobilized in the genome of human neural progenitor cells and enhanced in Rett syndrome and ataxia telangiectasia. However, whether aberrant L1 retrotransposition occurs in mental disorders is unknown. Here, we report high L1 copy number in schizophrenia. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing revealed brain-specific L1 insertion in patients localized preferentially to synapse- and schizophrenia-related genes. To study the mechanism of L1 transposition, we examined perinatal environmental risk factors for schizophrenia in animal models and observed an increased L1 copy number after immune activation by poly-I:C or epidermal growth factor. These findings suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia.

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  • Progressive Neurodegeneration After Experimental Brain Trauma: Association With Chronic Microglial Activation 査読

    Shinsui Tatsumi, Maya Mimuro, Yasushi Iwasaki, Ryosuke Takahashi, Akiyoshi Kakita, Hitoshi Takahashi, Mari Yoshida

    JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY   73 ( 1 )   30 - 38   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Argyrophilic grains are discrete punctate structures that bind to silver stains; they can be observed within the neuropil of the limbic system, particularly in the elderly. It has been reported that argyrophilic grains are more frequent in patients with corticobasal degeneration (CBD) compared with the elderly population in general. To determine the frequency and significance of argyrophilic grains in CBD, we examined the temporal lobes from 35 patients with autopsy-proven CBD (mean age, 69.1 years) and 28 patients with argyrophilic grain disease (mean age, 95.7 years). Grain distributions and densities were evaluated semiquantitatively using Gallyas-Braak stains and immunohistochemistry with AT8 and RD4 antibodies. Argyrophilic grains were observed in all CBD cases (100%) despite a lower average age at death in this population. We also observed the following features that were specific to argyrophilic grains in CBD: 1) grains were likely to be widespread throughout the temporal lobe, 2) grains were consistently found with abundant argyrophilic threads, and 3) the ultrastructure of grains contained paired helical filaments with a periodicity of 120 to 130 nm. In conclusion, we confirm that argyrophilic grains in CBD are specifically related to the 4-repeat tau pathology of CBD and are not simply a result of aging.

    DOI: 10.1097/NEN.0000000000000022

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  • Increased l1 retrotransposition in the neuronal genome in schizophrenia. 査読

    Bundo M, Toyoshima M, Okada Y, Akamatsu W, Ueda J, Nemoto-Miyauchi T, Sunaga F, Toritsuka M, Ikawa D, Kakita A, Kato M, Kasai K, Kishimoto T, Nawa H, Okano H, Yoshikawa T, Kato T, Iwamoto K

    Neuron   81 ( 2 )   306 - 313   2014年1月

  • Haploinsufficiency of CSF-1R and clinicopathologic characterization in patients with HDLS 査読

    Takuya Konno, Masayoshi Tada, Mari Tada, Akihide Koyama, Hiroaki Nozaki, Yasuo Harigaya, Jin Nishimiya, Akiko Matsunaga, Nobuaki Yoshikura, Kenji Ishihara, Musashi Arakawa, Aiko Isami, Kenichi Okazaki, Hideaki Yokoo, Kyoko Itoh, Makoto Yoneda, Mitsuru Kawamura, Takashi Inuzuka, Hitoshi Takahashi, Masatoyo Nishizawa, Osamu Onodera, Akiyoshi Kakita, Takeshi Ikeuchi

    NEUROLOGY   82 ( 2 )   139 - 148   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objective:To clarify the genetic, clinicopathologic, and neuroimaging characteristics of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) with the colony stimulating factor 1 receptor (CSF-1R) mutation.Methods:We performed molecular genetic analysis of CSF-1R in patients with HDLS. Detailed clinical and neuroimaging findings were retrospectively investigated. Five patients were examined neuropathologically.Results:We found 6 different CSF-1R mutations in 7 index patients from unrelated Japanese families. The CSF-1R mutations included 3 novel mutations and 1 known missense mutation at evolutionarily conserved amino acids, and 1 novel splice-site mutation. We identified a novel frameshift mutation. Reverse transcription PCR analysis revealed that the frameshift mutation causes nonsense-mediated mRNA decay by generating a premature stop codon, suggesting that haploinsufficiency of CSF-1R is sufficient to cause HDLS. Western blot analysis revealed that the expression level of CSF-1R in the brain from the patients was lower than from control subjects. The characteristic MRI findings were the involvement of the white matter and thinning of the corpus callosum with signal alteration, and sequential analysis revealed that the white matter lesions and cerebral atrophy relentlessly progressed with disease duration. Spotty calcifications in the white matter were frequently observed by CT. Neuropathologic analysis revealed that microglia in the brains of the patients demonstrated distinct morphology and distribution.Conclusions:These findings suggest that patients with HDLS, irrespective of mutation type in CSF-1R, show characteristic clinical and neuroimaging features, and that perturbation of CSF-1R signaling by haploinsufficiency may play a role in microglial dysfunction leading to the pathogenesis of HDLS.

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  • Argyrophilic grains are reliable disease-specific features of corticobasal degeneration 査読

    Shinsui Tatsumi, Maya Mimuro, Yasushi Iwasaki, Ryosuke Takahashi, Akiyoshi Kakita, Hitoshi Takahashi, Mari Yoshida

    Journal of Neuropathology and Experimental Neurology   73 ( 1 )   30 - 38   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Argyrophilic grains are discrete punctate structures that bind to silver stains
    they can be observed within the neuropil of the limbic system, particularly in the elderly. It has been reported that argyrophilic grains are more frequent in patients with corticobasal degeneration (CBD) compared with the elderly population in general. To determine the frequency and significance of argyrophilic grains in CBD, we examined the temporal lobes from 35 patients with autopsy-proven CBD (mean age, 69.1 years) and 28 patients with argyrophilic grain disease (mean age, 95.7 years). Grain distributions and densities were evaluated semiquantitatively using Gallyas-Braak stains and immunohistochemistry with AT8 and RD4 antibodies. Argyrophilic grains were observed in all CBD cases (100%) despite a lower average age at death in this population. We also observed the following features that were specific to argyrophilic grains in CBD: 1) grains were likely to be widespread throughout the temporal lobe, 2) grains were consistently found with abundant argyrophilic threads, and 3) the ultrastructure of grains contained paired helical filaments with a periodicity of 120 to 130 nm. In conclusion, we confirm that argyrophilic grains in CBD are specifically related to the 4-repeat tau pathology of CBD and are not simply a result of aging. © 2013 by the American Association of Neuropathologists, Inc.

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  • 著明な筋痙攣・線維束性収縮を伴い抗VGKC複合体抗体が高値であった筋萎縮性側索硬化症の1剖検例 査読

    佐藤晶, 酒井直子, 新保淳輔, 橋立英樹, 五十嵐修一, 柿田明美, 山崎元義

    臨床神経   54 ( 1 )   32 - 37   2014年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • FUS colocalizes with polyglutamine, but not with TDP-43 in neuronal intranuclear inclusions in spinocerebellar ataxia type 2 査読

    F. Mori, Y. Toyoshima, K. Tanji, A. Kakita, H. Takahashi, K. Wakabayashi

    Neuropathology and Applied Neurobiology   40 ( 3 )   351 - 355   2014年

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    記述言語:英語   出版者・発行元:Blackwell Publishing Ltd  

    DOI: 10.1111/nan.12075

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  • Histopathologic features of glia in human epileptogenic brain lesions 査読

    Akiyoshi Kakita

    Clinical Neurology   54 ( 12 )   1136 - 1138   2014年

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    記述言語:日本語   掲載種別:研究論文(国際会議プロシーディングス)   出版者・発行元:Societas Neurologica Japonica  

    Focal cortical dysplasia is a common pathologic background observed in surgical specimens taken from patients with intractable epilepsy, where various types and degrees of dysplastic features were observed in various combinations. Prominent astrocytosis in the cortex and white matter was commonly evident. An ultrastructural investigation revealed dilatation of the postsynaptic dendritic spines and shafts in the cortex and features indicating the occurrence in the white matter of demyelination followed by remyelination. Thus, with regard to the epileptogenic lesions, although dysplastic changes constitute the pathogenetic basis, the overlapping subsequent degenerative process involving synapses, dendrites, and axons might contribute to the development of epileptogenic processes. Glia might also actively participate in the development of the pathogenesis of epilepsy.

    DOI: 10.5692/clinicalneurol.54.1136

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  • Hypertrophic pachymeningitis: Significance of myeloperoxidase anti-neutrophil cytoplasmic antibody 査読

    Akiko Yokoseki, Etsuji Saji, Musashi Arakawa, Takayuki Kosaka, Mariko Hokari, Yasuko Toyoshima, Kouichirou Okamoto, Shigeki Takeda, Kazuhiro Sanpei, Hirotoshi Kikuchi, Shunsei Hirohata, Kouhei Akazawa, Akiyoshi Kakita, Hitoshi Takahashi, Masatoyo Nishizawa, Izumi Kawachi

    Brain   137 ( 2 )   520 - 536   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oxford University Press  

    The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance
    (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegenervs granulomatosis) according to Watts' algorithm
    (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis
    (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis
    (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis
    (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting T &lt
    inf&gt
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    1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis
    and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis. © 2013 The Author (2013).

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  • Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population. 査読 国際誌

    Akinori Miyashita, Yanan Wen, Nobutaka Kitamura, Etsuro Matsubara, Takeshi Kawarabayashi, Mikio Shoji, Naoki Tomita, Katsutoshi Furukawa, Hiroyuki Arai, Takashi Asada, Yasuo Harigaya, Masaki Ikeda, Masakuni Amari, Haruo Hanyu, Susumu Higuchi, Masatoyo Nishizawa, Masaichi Suga, Yasuhiro Kawase, Hiroyasu Akatsu, Masaki Imagawa, Tsuyoshi Hamaguchi, Masahito Yamada, Takashi Morihara, Masatoshi Takeda, Takeo Takao, Kenji Nakata, Ken Sasaki, Ken Watanabe, Kenji Nakashima, Katsuya Urakami, Terumi Ooya, Mitsuo Takahashi, Takefumi Yuzuriha, Kayoko Serikawa, Seishi Yoshimoto, Ryuji Nakagawa, Yuko Saito, Hiroyuki Hatsuta, Shigeo Murayama, Akiyoshi Kakita, Hitoshi Takahashi, Haruyasu Yamaguchi, Kohei Akazawa, Ichiro Kanazawa, Yasuo Ihara, Takeshi Ikeuchi, Ryozo Kuwano

    Journal of Alzheimer's disease : JAD   41 ( 4 )   1031 - 8   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimer's disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002-0.0059); however, no significant association with LOAD was observed in these variants. Considering low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese.

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  • An autopsy case of amyotrophic lateral sclerosis with prominent muscle cramps, fasciculation, and high titer of anti-voltage gated potassium channel (VGKC) complex antibody 査読

    Aki Sato, Naoko Sakai, Junsuke Shinbo, Hideki Hashidate, Shuichi Igarashi, Akiyoshi Kakita, Motoyoshi Yamazaki

    Clinical Neurology   54 ( 1 )   32 - 37   2014年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    The patient was a 55-year-old male who had prominent fasciculation and muscle cramps. Muscle weakness and atrophy of the trunk, respiratory system, and extremities gradually progressed. On the basis of these features, we diagnosed this patient as having amyotrophic lateral sclerosis (ALS), however, the upper motor neuron signs were not significant. Following the detection of the anti-voltage gated potassium channel (VGKC) complex antibody at 907.5 pM (normal &lt
    100 pM) and repetitive discharge in a nerve conduction study, immunotherapy with intravenous immuno-globulin, methylprednisolone (mPSL), double filtration plasmapheresis (DFPP), ciclosporin, and rituximab was introduced. mPSL and DFPP showed only tentative effectiveness for fasciculation and muscle cramps, respectively. Thereafter, muscle weakness progressed. The patient died of type II respiratory failure at the age of 57 years, about 2 years after the onset of the disease. At autopsy, a histopathological diagnosis of ALS with lower-motor-predominant degeneration was made. Characteristic cellular features, including Bunina bodies in the remaining lower motor neurons and phosphorylated TAR DNA-binding protein 43-kDa (pTDP-43)-immunopositive inclusions in both upper and lower motor neuron systems, were evident. At present, an immunological role of the anti-VGKC complex antibody in the development of cramp-fasciculation syndrome has been speculated. In this ALS patient, the antibodies might be associated with pathomechanisms underlying the characteristic symptoms.

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  • Phosphorylation of serine 349 of p62 in Alzheimer's disease brain 査読

    Kunikazu Tanji, Yasuo Miki, Taku Ozaki, Atsushi Maruyama, Hidemi Yoshida, Junsei Mimura, Tomoh Matsumiya, Fumiaki Mori, Tadaatsu Imaizumi, Ken Itoh, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    ACTA NEUROPATHOLOGICA COMMUNICATIONS   2 ( 1 )   50   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Extensive research on p62 has established its role in oxidative stress, protein degradation and in several diseases such as Paget's disease of the bone, frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Importantly, previous studies showed that p62 binds directly to Keap1, which is a ubiquitin E3 ligase responsible for degrading Nrf2. Indeed, colocalisation of p62 and Keap1 occurs in tumorigenesis and neurodegeneration. A serine (S) residue in the Keap1-interacting region of p62 is phosphorylated in hepatocellular carcinoma, and this phosphorylation contributes to tumour growth through the higher affinity of p62 to Keap1. However, it remains largely unknown whether p62 is phosphorylated in the Keap1-interacting region under neurodegenerative conditions.
    Results: To answer this question, we generated an antibody against phosphorylated S349 (P-S349) of p62 and showed that S349 is phosphorylated following disruption of protein degradation. In particular, the ratio of P-S349 to total p62 levels was significantly increased in the brains with Alzheimer's disease (AD) compared with controls. We also compared the reactivity of the P-S349 antibody with P-S403 of p62 and showed that these two phosphorylated sites on p62 cause different responses with proteasome inhibition and show distinct localisation patterns in AD brains. In addition to disruption of protein degradation systems, activation of oxidative stress can induce P-S349.
    Conclusion: These results support the hypothesis that disruption of protein degradation systems and sustained activation of the Keap1-Nrf2 system occur in the brains with AD.

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  • Accumulation of 2-hydroxyglutarate in gliomas correlates with survival: a study by 3.0-tesla magnetic resonance spectroscopy 査読

    Manabu Natsumeda, Hironaka Igarashi, Toshiharu Nomura, Ryosuke Ogura, Yoshihiro Tsukamoto, Tsutomu Kobayashi, Hiroshi Aoki, Kouichirou Okamoto, Akiyoshi Kakita, Hitoshi Takahashi, Tsutomu Nakada, Yukihiko Fujii

    ACTA NEUROPATHOLOGICA COMMUNICATIONS   2 ( 1 )   158   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Introduction: Previous magnetic resonance spectroscopy (MRS) and mass spectroscopy studies have shown accumulation of 2-hydroxyglutarate (2HG) in mutant isocitrate dehydrogenase (IDH) gliomas. IDH mutation is known to be a powerful positive prognostic marker in malignant gliomas. Hence, 2HG accumulation in gliomas was assumed to be a positive prognostic factor in gliomas, but this has not yet been proven. Here, we analyzed 52 patients harboring World Health Organization (WHO) grade II and III gliomas utilizing 3.0-tesla MRS.
    Results: Mutant IDH gliomas showed significantly higher accumulation of 2HG (median 5.077 vs. 0.000, p = 0.0002, Mann-Whitney test). 2HG was detectable in all mutant IDH gliomas, whereas in 10 out of 27 (37.0%) wild-type IDH gliomas, 2HG was below the detectable range (2HG = 0) (p = 0.0003, chi-squared test). Screening for IDH mutation by 2HG analysis was highly sensitive (cutoff 2HG = 1.489 mM, sensitivity 100.0%, specificity 72.2%). Gliomas with high 2HG accumulation had better overall survival than gliomas with low 2HG accumulation (p = 0.0401, Kaplan-Meier analysis).
    Discussion: 2HG accumulation detected by 3.0-tesla MRS not only correlates well with IDH status, but also positively correlates with survival in WHO grade II and III gliomas.

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  • Aberration of the spliceosome in amyotrophic lateral sclerosis 査読

    Tomohiko Ishihara, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa

    Clinical Neurology   54 ( 12 )   1155 - 1157   2014年

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    記述言語:日本語   掲載種別:研究論文(国際会議プロシーディングス)   出版者・発行元:Societas Neurologica Japonica  

    TDP-43 is a nuclear protein that plays a role in RNA metabolism, and its dysfunction has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a typical adult-onset motor neuron disease. We investigated RNA metabolism in relation to TDP-43 function in neuronal tissues affected by ALS, and found a decrease in the number of nuclear GEM bodies, as well as reduced expression of minor spliceosomes, which are functional RNA-protein complexes. Similar features have been reported in spinal muscular atrophy (SMA), a motor neuron disease affecting infants. These findings, together with those reported in SMA, strongly suggest that reduction of minor spliceosomes has an important role in the pathomechanism underlying the selective degeneration of motor neurons characteristic of both ALS and SMA.

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  • Analysis of microRNA from archived formalin-fixed paraffin-embedded specimens of amyotrophic lateral sclerosis 査読

    Koichi Wakabayashi, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Jun Utsumi, Hidenao Sasaki

    ACTA NEUROPATHOLOGICA COMMUNICATIONS   2 ( 1 )   173   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: MicroRNAs (miRNAs) are noncoding small RNAs that regulate gene expression. This study investigated whether formalin-fixed paraffin-embedded (FFPE) specimens from postmortem cases of neurodegenerative disorders would be suitable for miRNA profiling.
    Results: Ten FFPE samples from 6 cases of amyotrophic lateral sclerosis (ALS) and 4 neurologically normal controls were selected for miRNA analysis on the basis of the following criteria for RNA quality: (i) a postmortem interval of less than 6 hours, (ii) a formalin fixation time of less than 4 weeks, (iii) an RNA yield per sample of more than 500 ng, and (iv) sufficient quality of the RNA agarose gel image. An overall RNA extraction success rate was 46.2%. For ALS, a total of 364 miRNAs were identified in the motor cortex, 91 being up-regulated and 233 down-regulated. Target genes were predicted using miRNA bioinformatics software, and the data applied to ontology analysis. This indicated that one of the miRNAs up-regulated in ALS (miR-338-3p) had already been identified in leukocytes, serum, cerebrospinal fluid and frozen spinal cord from ALS patients.
    Conclusion: Although analysis was possible for just under half of the specimens examined, we were able to show that informative miRNA data can be derived from archived FFPE samples from postmortem cases of neurodegenerative disorders.

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  • Valosin-containing protein immunoreactivity in tauopathies, synucleinopathies, polyglutamine diseases and intranuclear inclusion body disease 査読

    Fumiaki Mori, Kunikazu Tanji, Yasuko Toyoshima, Hidenao Sasaki, Mari Yoshida, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    NEUROPATHOLOGY   33 ( 6 )   637 - 644   2013年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Valosin-containing protein (VCP) is associated with multiple cellular functions, including ubiquitin-dependent protein degradation. Mutations in VCP are known to cause inclusion body myopathy with Paget's disease and frontotemporal dementia and familial amyotrophic lateral sclerosis (fALS; ALS14), both of which are characterized by trans-activation response DNA protein 43 (TDP-43)-positive neuronal cytoplasmic and nuclear inclusions. Recently, immunoreactivity for fALS-associated proteins (TDP-43, fused in sarcoma (FUS), optineurin and ubiquilin-2) were reported to be present in cytoplasmic and nuclear inclusions in various neurodegenerative diseases. However, the extent and frequency of VCP-immunoreactive structures in these neurodegenerative diseases are uncertain. We immunohistochemically examined the brains of 72 cases with neurodegenerative diseases and five control cases. VCP immunoreactivity was present in Lewy bodies in Parkinson's disease and dementia with Lewy bodies, and neuronal nuclear inclusions in five polyglutamine diseases and intranuclear inclusion body disease, as well as in Marinesco bodies in aged control subjects. However, other neuronal and glial cytoplasmic inclusions in tauopathies and TDP-43 proteinopathies were unstained. These findings suggest that VCP may have common mechanisms in the formation or degradation of cytoplasmic and nuclear inclusions of neurons, but not of glial cells, in several neurodegenerative conditions.

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  • Oligodendroglioma (WHO grade I) in a young epilepsy patient: A specific entity lying within the spectrum of dysembryoplastic neuroepithelial tumor? 査読

    Hitoshi Takahashi, Akiyoshi Kakita, Masaru Tomikawa, Kouichirou Okamoto, Shigeki Kameyama

    NEUROPATHOLOGY   33 ( 6 )   645 - 651   2013年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    We studied a frontal lobe subcortical cystic tumor that had been resected from a 13-year-old girl with a 3-year history of intractable partial seizure. Currently, more than 13 years after surgery, the patient remains recurrence-free and has no neurological deficits. Histological examination showed that the tumor was non-infiltrating and paucicellular with a mucinous matrix, and consisted of fairly uniform small cells with round to oval nuclei. Within the mucinous matrix, the tumor cells were often arranged in pseudorosettes around small blood vessels. Mitotic activity and necrosis were absent, with a Ki-67 labeling index of &lt;1%. Based on the immunohistochemical and ultrastructural findings, the constituent tumor cells were considered to be those of oligodendroglioma, including mini-gemistocytes and gliofibrillary oligodendrocytes. No neuronal elements were identified. Features of cortical dysplasia (FCD Type 1) were evident in the cortex covering the lesion. The surrounding white matter also contained a significant number of ectopic neurons. The entire pathological picture appeared to differ somewhat from that of ordinary oligodendroglioma (WHO grade II). Considering the clinical and pathological features, the present unusual oligodendroglioma appeared to represent a previously undescribed form of oligodendroglioma (WHO grade I) lying within the spectrum of dysembryoplastic neuroepithelial tumor (DNT; WHO grade I). Simultaneously, the present oligodendroglioma also raises the question of whether or not oligodendrocyte-like cells of DNTs truly show neurocytic differentiation.

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  • Malignant peripheral nerve sheath tumor of the trigeminal nerve: Clinicopathologic features in a young adult patient 査読

    Yoko Nakayama, Masatoshi Watanabe, Kenji Suzuki, Hiroyuki Usuda, Iwao Emura, Ryosuke Ogura, Atsushi Shiga, Yasuko Toyoshima, Hitoshi Takahashi, Tadashi Kawaguchi, Akiyoshi Kakita

    Neuropathology   33 ( 5 )   541 - 546   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Malignant peripheral nerve sheath tumors (MPNSTs) arising from cranial nerves are rare and usually affect adults. Here we report the clinicopathologic features of a young adult patient with a trigeminal nerve MPNST, in whom another tumor involving the oculomotor nerve on the contralateral side was evident. The patient, an 18-year-old woman, had suffered recurrent paroxysmal sharp stabbing pain over her cheek and forehead on the right side for 1 month. A brain MRI study disclosed a mass, 35mm in diameter, in the right Meckel's cave, and another mass, 10mm in diameter, involving the intracranial portion of the left oculomotor nerve. Following gadolinium administration, the former and latter tumors exhibited strong and weak enhancement, respectively. The patient had no clinical stigmata characteristic of neurofibromatosis type 1. Following a tentative diagnosis of schwannoma, total resection of the trigeminal nerve tumor was performed. Histologically, the tumor consisted of highly cellular, spindle-shaped cells arranged in a fascicular pattern, with occasional mitotic figures, nuclear pleomorphism and necrosis. Immunohistochemically, the tumor cells showed variable intensities and frequencies of reactivity for S-100 protein, myelin basic protein, CD34, podoplanin and p53, but no reactivity for Smarcb1. Thus, the tumor exhibited features of MPNST. This case appears to provide information that is useful for accurate diagnosis and surgical planning in patients with bilateral or multiple cranial nerve tumors. © 2012 Japanese Society of Neuropathology.

    DOI: 10.1111/neup.12004

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  • Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis 査読

    Tomohiko Ishihara, Yuko Ariizumi, Atsushi Shiga, Taisuke Kato, Chun-Feng Tan, Tatsuya Sato, Yukari Miki, Mariko Yokoo, Takeshi Fujino, Akihide Koyama, Akio Yokoseki, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera

    HUMAN MOLECULAR GENETICS   22 ( 20 )   4136 - 4147   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Disappearance of TAR-DNA-binding protein 43 kDa (TDP-43) from the nucleus contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS), but the nuclear function of TDP-43 is not yet fully understood. TDP-43 associates with nuclear bodies including Gemini of coiled bodies (GEMs). GEMs contribute to the biogenesis of uridine-rich small nuclear RNA (U snRNA), a component of splicing machinery. The number of GEMs and a subset of U snRNAs decrease in spinal muscular atrophy, a lower motor neuron disease, suggesting that alteration of U snRNAs may also underlie the molecular pathogenesis of ALS. Here, we investigated the number of GEMs and U11/12-type small nuclear ribonucleoproteins (snRNP) by immunohistochemistry and the level of U snRNAs using real-time quantitative RT-PCR in ALS tissues. GEMs decreased in both TDP-43-depleted HeLa cells and spinal motor neurons in ALS patients. Levels of several U snRNAs decreased in TDP-43-depleted SH-SY5Y and U87-MG cells. The level of U12 snRNA was decreased in tissues affected by ALS (spinal cord, motor cortex and thalamus) but not in tissues unaffected by ALS (cerebellum, kidney and muscle). Immunohistochemical analysis revealed the decrease in U11/12-type snRNP in spinal motor neurons of ALS patients. These findings suggest that loss of TDP-43 function decreases the number of GEMs, which is followed by a disturbance of pre-mRNA splicing by the U11/U12 spliceosome in tissues affected by ALS.

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  • 晩期発症型アルツハイマー病とTREM2の関連解析 査読

    宮下 哲典, 温 雅楠, 初田 裕幸, 村山 繁雄, 山口 晴保, 赤津 裕康, 柿田 明美, 高橋 均, 井原 康夫, 池内 健, 桑野 良三, JGSCAD(The Japanese Genetic Study Consortium for Alzheimer's Disease)

    Dementia Japan   27 ( 4 )   483 - 483   2013年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • Sporadic ALS with compound heterozygous mutations in the SQSTM1 gene 査読

    Hiroshi Shimizu, Yasuko Toyoshima, Atsushi Shiga, Akio Yokoseki, Keiko Arakawa, Yumi Sekine, Takayoshi Shimohata, Takeshi Ikeuchi, Masatoyo Nishizawa, Akiyoshi Kakita, Osamu Onodera, Hitoshi Takahashi

    Acta Neuropathologica   126 ( 3 )   453 - 459   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Accumulating evidence suggests that heterozygous mutations in the SQSTM1 gene, which encodes p62 protein, are associated with amyotrophic lateral sclerosis (ALS). Here, we report a Japanese patient with sporadic, late-onset ALS who harbored compound heterozygous SQSTM1 mutations (p.[Val90Met]
    [Val153Ile]). Autopsy examination revealed that although TDP-43 pathology was rather widespread, the selective occurrence of p62-positive/TDP-43-negative cytoplasmic inclusions in the lower motor neurons (LMNs) was a characteristic feature. No Bunina bodies were found. Ultrastructurally, p62-positive cytoplasmic inclusions observed in the spinal anterior horn cells were composed of aggregates of ribosome-like granules and intermingled bundles of filamentous structures. Another feature of interest was concomitant Lewy body pathology. The occurrence of distinct p62 pathology in the LMNs in this patient indicates the pathogenic role of SQSTM1 mutations in the development of a subset of ALS. © 2013 Springer-Verlag Berlin Heidelberg.

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  • Surgical pathologic features of cerebral cortical lesions taken from 600 patients with intractable epilepsy 査読

    Akiyoshi Kakita

    BRAIN & DEVELOPMENT   35 ( 8 )   793 - 801   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Objectives: To determine the scope of histopathological variation in lesions responsible for epileptogenesis, I retrospectively reviewed the features of surgical specimens taken consecutively from 600 patients with intractable epilepsy. Methods: The patients were divided into three groups on the basis of age at seizure onset: 94 patients with infantile onset (before 1 year of age), 307 patients with juvenile onset (between 1 and 12 years of age), and 199 patients with adolescent/adult onset (at 13 years of age or beyond). Histological and immunohistochemical evaluations of the surgical specimens were performed. Results: In the infant group, seizure duration was significantly shorter than in the other groups, and malformations caused by abnormalities of cortical development, including focal cortical dysplasia (FCD) type IIa/b, tuberous sclerosis, hemimegalencephaly, and polymicrogyria were predominant, whereas in the juvenile and adolescent/adult groups, other lesions such as hippocampal sclerosis (HS), tumors, FCD type I, and vascular lesions were frequently observed. For patients with HS, seizure duration in the juvenile group was significantly longer than in the adolescent/adult group. FCD type IIIa was noted in nearly half of patient with HS in both juvenile and adolescent/adult groups. The causative tumors included dysembryoplastic neuroepithelial tumors, gangliogliomas, astrocytomas, and other glioneuronal and glial tumors. Conclusion: Various histopathological entities and types, showing clear predominance depending on the age at seizure onset, were observed in patients with epilepsy. These features appear to provide information on the pathomechanisms of the lesions and their clinical relevance in affected patients. (C) 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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  • Epstein-Barr virus-associated primary central nervous system cytotoxic T-cell lymphoma 査読

    Ryosuke Ogura, Hiroshi Aoki, Manabu Natsumeda, Hiroshi Shimizu, Tsutomu Kobayashi, Tomohisa Saito, Jun Takizawa, Kouichirou Okamoto, Go Hasegawa, Hajime Umezu, Kouichi Ohshima, Hitoshi Takahashi, Yukihiko Fujii, Akiyoshi Kakita

    NEUROPATHOLOGY   33 ( 4 )   436 - 441   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Primary central nervous system lymphoma (PCNSL) expressing T-cell markers is rare, among which nasal-type extranodal NK/T-cell lymphoma is an extremely rare subtype associated with Epstein-Barr virus (EBV) infection. Here we report the clinicopathologic features of a case of EBV-associated PCNSL showing a cytotoxic T-cell phenotype. The patient, a 73-year-old woman, presented with rapidly progressive mental deterioration. Brain MRI revealed multiple lesions with swelling in the bilateral cerebral hemispheres, which were hypointense on T1-weighted images, hyperintense on T2-weighted and fluid-attenuated inversion recovery images, and slightly hyperintense on diffusion-weighted images. Biopsy specimens from the temporal region showed many medium-sized anaplastic lymphocytic cells with perivascular and angio-invasive patterns in the cortex. Immunohistochemically, the cells were positive for CD3, CD8, T-cell-restricted intracellular antigen-1 (TIA-1), granzyme B and perforin, but negative for CD56 and CD20. In situ hybridization revealed EBV-encoded RNAs in the tumor cell nuclei. A rearrangement study showed T-cell receptor g-chain gene rearrangement with a clonal appearance. The patient died 6 months after surgery, and a general autopsy revealed no lymphoma cells outside the brain. These cellular profiles are inconsistent with those of extranodal NK/T-cell lymphoma, and have not been previously described. This case appears to represent an unusual CNS manifestation of EBV-associated T-cell lymphoma.

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  • Transportin 1 accumulates in FUS inclusions in adult-onset ALS without FUS mutation 査読

    R. Takeuchi, Y. Toyoshima, M. Tada, A. Shiga, H. Tanaka, M. Shimohata, K. Kimura, T. Morita, A. Kakita, M. Nishizawa, H. Takahashi

    Neuropathology and Applied Neurobiology   39 ( 5 )   580 - 584   2013年8月

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  • Optical imaging of human epileptogenic tissues in vitro 査読

    Hiroki Kitaura, Akiyoshi Kakita

    NEUROPATHOLOGY   33 ( 4 )   469 - 474   2013年8月

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    Epilepsy is a chronic disorder characterized by abnormal spatiotemporal neural activities. To clarify its physiological mechanisms and associated morphological features, we investigated neuronal activities using the flavoprotein fluorescence imaging technique and histopathological changes in epileptogenic tissue resected from patients with epilepsy. We applied an imaging technique suitable for examining human brain slices, and as a consequence achieved sufficient responses with high reproducibility. Moreover, we detected significant alterations in neuronal morphology associated with the acquired responses. Therefore, this strategy is useful for gaining a better understanding of the pathomechanisms underlying intractable epilepsy.

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  • Progressive multifocal leukoencephalopathy developed 26 years after renal transplantation 査読

    Shigemi Nagayama, Yuichiro Gondo, Shin-ichi Araya, Naomi Minato, Michiyo Fujita-Nakata, Muichi Kaito, Megumi Nakanishi, Keiko Tanaka, Hideki Yamaya, Hitoshi Yokoyama, Kazuo Nakamichi, Masayuki Saijo, Kouichirou Okamoto, Yasuko Toyoshima, Akiyoshi Kakita, Makoto Matsui

    CLINICAL NEUROLOGY AND NEUROSURGERY   115 ( 8 )   1482 - 1484   2013年8月

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  • Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia (vol 16, pg 307-320, 2011) 査読

    Kato T, Abe Y, Sotoyama H, Kakita A, Kominami R, Hirokawa S, Ozaki M, Takahashi H, Nawa H

    MOLECULAR PSYCHIATRY   18 ( 8 )   951   2013年8月

  • Mutations of para-hydroxybenzoate-polyprenyltransferase gene (COQ2) are involved in familial and sporadic multiple system atrophy. 査読

    Mitsui J, Matsukawa T, Ishiura H, Fukuda Y, Ichikawa Y, Date H, Ahsan B, Nakahara Y, Momose Y, Takahashi Y, Iwata A, Goto J, Yamamoto Y, Komata M, Shirahige K, Hara K, Kakita A, Yamada M, Takahashi H, Onodera O, Nishizawa M, Takashima H, SatakeW, Toda T, Kuwano R, Watanabe H, Ito M, Sobue G, Soma H, Yabe I, Sasaki H, Aoki M, Ishikawa K, Mizusawa H, Kanai K, Hattori T, Kuwabara S, Arai K, Koyano S, Kuroiwa Y, Hasegawa K, Yuasa T, Yasui K, Nakashima K, Izumi Y, Kaji R, Kato T, Kusunoki S, Osaki Y, Horiuchi M, Kondo T, Murayama S, Dürr A, Brice A, Filla A, Klockgether T, Wüllner U, Nicolson G, Gilman S, Tanner M. C, Kukull A. W, Lee M.-Y. V, Masliah E, Low A. P, Sandroni P, Trojanowski Q. J, Ozelius L, Foroud T, Tsuji S

    The New England Journal of Medicine   369 ( 3 )   233 - 244   2013年7月

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    The multiple-Ststem Atrophy Research Collaboration.

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  • Neurobehavioral deficits of epidermal growth factor-overexpressing transgenic mice: impact on dopamine metabolism. 査読

    Eda Takeyoshi, Mizuno Makoto, Araki Kazuaki, Iwakura Yuriko, Namba Hisaaki, Sotoyama Hidekazu, Kakita Akiyoshi, Takahashi Hitoshi, Satoh Hiroshi, Chan Siu-Yuen, Nawa Hiroyuki

    Neurosci Lett   547   21 - 25   2013年6月

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    Epidermal growth factor (EGF) and its family member neuregulin-1 are implicated in the etiology of schizophrenia. Our recent pharmacological studies indicate that EGF injections to neonatal and adult rats both induce neurobehavioral deficits relevant to schizophrenia. We, however, did not evaluate the genetic impact of EGF transgene on neurobehavioral traits. Here we analyzed transgenic mice carrying the transgene of mouse EGF cDNA. As compared to control littermates, heterozygous EGF transgenic mice had an increase in EGF mRNA levels and showed significant decreases in prepulse inhibition and context-dependent fear learning, but there were no changes in locomotor behaviors and sound startle responses. In addition, these transgenic mice exhibited higher behavioral sensitivity to the repeated cocaine injections. There were neurochemical alterations in metabolic enzymes of dopamine (i.e., tyrosine hydroxylase, dopa decarboxylase, catechol-O-methyl transferase) and monoamine contents in various brain regions of the EGF transgenic mice, but there were no apparent neuropathological signs in the brain. The present findings rule out the indirect influence of anti-EGF antibody production

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  • MRIで髄膜造影を呈し脳生検で診断した脳アミロイドβ関連血管炎の1例 査読

    小池佑佳, 大内東香, 佐藤朋江, 新保淳輔, 佐藤晶, 佐々木修, 渋谷宏行, 岡本浩一郎, 柿田明美, 五十嵐修一

    Brain and Nerve   65 ( 6 )   693 - 697   2013年6月

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  • Cerebral astroblastoma in an adult: An immunohistochemical, ultrastructural and genetic study 査読

    Yong-Juan Fu, Yoshinori Taniguchi, Shigekazu Takeuchi, Atsushi Shiga, Kouichirou Okamoto, Junko Hirato, Sumihito Nobusawa, Yoichi Nakazato, Akiyoshi Kakita, Hitoshi Takahashi

    Neuropathology   33 ( 3 )   312 - 319   2013年6月

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    Astroblastoma is a rare glial tumor of unknown origin, usually affecting the cerebral hemispheres of children and young adults. Here we report an unusual cerebral tumor in a 60-year-old woman. On MRI, the tumor appeared as a well circumscribed lesion in the left frontal lobe. Histopathologically, it was composed of rounded eosinophilic cells, and was divisible into two areas. One area was characterized by a collection of GFAP-positive cells around sclerotic blood vessels (astroblastic pseudorosettes and perivascular hyalinization), and had a Ki-67 labeling index of 2.8%. However, the other area was highly cellular, showing many GFAP-negative cells often with a rhabdoid appearance, mitoses and a Ki-67 index of 15.7%. Thus, a final diagnosis of malignant astroblastoma was made. In both areas of the tumor, nearly all the cells were positive for epithelial membrane antigen, and many were positive for oligodendrocyte transcription factor 2 (Olig2). Focal expression of cytokeratin was also evident. With regard to genetic markers, the tumor cells were positive for INI1 and negative for mutant IDH1. The p53 labeling index was &lt
    1%. Ultrastructurally, the presence of intra- and intercellular lumina with microvilli was a feature. DNA examination of IDH1/2 and TP53 showed no mutations. In conclusion, although ependymal features were evident ultrastructurally in the present tumor, the immunohistochemical expression pattern of Olig2 was that of diffuse astrocytoma. On the other hand, the absence of mutations in both IDH1/2 and TP53 suggested that the present tumor was not a purely astrocytic neoplasm. Further studies, including molecular and genetic analyses, will provide insight into the histogenesis of astroblastoma. © 2012 Japanese Society of Neuropathology.

    DOI: 10.1111/j.1440-1789.2012.01351.x

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  • Amyloid beta-related angiitis: Brain lesions showing leptomeningeal gadolinium enhancement on MRI and characteristic surgical pathologic features 査読

    Yuka Koike, Haruka Ouchi, Tomoe Sato, Junsuke Shimbo, Aki Sato, Osamu Sasaki, Hiroyuki Shibuya, Kouichirou Okamoto, Akiyoshi Kakita, Shuichi Igarashi

    Brain and Nerve   65 ( 6 )   693 - 697   2013年6月

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    Amyloid-β-related angiitis (ABRA) of the CNS occurs in association with vasculitis of small-and medium-sized leptomeningeal arteries. Here, we describe the clinicopathological features of a 76-year-old man with ABRA. The patient suffered progressive truncal oscillation, aphasia, and recent memory disturbance with a subacute disease onset. His cerebrospinal fluid showed a mild increase in protein levels (101 mg/dL) and pleocytosis (8/mm3). High-intensity brain lesion were detected on T2-weighted and FLAIR MRI scans, and prominent spread of gadolinium enhancement spreading was observed through the sulci of the left occipital and temporal lobes and left cerebellar hemisphere. A biopsy of the left temporal lesion showed a granulomatous and angiodestructive inflammation with infiltration of many CD4+ T-lymphocytes and multinucleated giant cells and with fibrinoid necrosis of the arterial walls in the subarachnoid space. Immunolabeling for Aβ1-40 revealed the abundant deposition of this protein in the affected arteries. On the basic of the diagnosis of ABRA, immunosuppressive therapy was conducted, and it ameliorated the clinical course.

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  • Neurobehavioral deficits of epidermal growth factor-overexpressing transgenic mice: Impact on dopamine metabolism 査読

    Takeyoshi Eda, Makoto Mizuno, Kazuaki Araki, Yuriko Iwakura, Hisaaki Namba, Hidekazu Sotoyama, Akiyoshi Kakita, Hitoshi Takahashi, Hiroshi Satoh, Siu-Yuen Chan, Hiroyuki Nawa

    NEUROSCIENCE LETTERS   547   21 - 25   2013年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Epidermal growth factor (EGF) and its family member neuregulin-1 are implicated in the etiology of schizophrenia. Our recent pharmacological studies indicate that EGF injections to neonatal and adult rats both induce neurobehavioral deficits relevant to schizophrenia. We, however, did not evaluate the genetic impact of EGF transgene on neurobehavioral traits. Here we analyzed transgenic mice carrying the transgene of mouse EGF cDNA. As compared to control littermates, heterozygous EGF transgenic mice had an increase in EGF mRNA levels and showed significant decreases in prepulse inhibition and context-dependent fear learning, but there were no changes in locomotor behaviors and sound startle responses. In addition, these transgenic mice exhibited higher behavioral sensitivity to the repeated cocaine injections. There were neurochemical alterations in metabolic enzymes of dopamine (i.e., tyrosine hydroxylase, dopa decarboxylase, catechol-O-methyl transferase) and monoamine contents in various brain regions of the EGF transgenic mice, but there were no apparent neuropathological signs in the brain. The present findings rule out the indirect influence of anti-EGF antibody production on the reported behavioral deficits of EGF-injected mice. These results support the argument that aberrant hyper-signals of EGF have significant impact on mouse behavioral traits and dopamine metabolism. (c) 2013 Elsevier Ireland Ltd. All rights reserved.

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  • てんかん外科病理学の実際 査読

    柿田 明美

    新潟医学会誌   127 ( 5 )   221 - 237   2013年5月

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  • Suppressed expression of autophagosomal protein LC3 in cortical tubers of tuberous sclerosis complex 査読

    Hiroaki Miyahara, Manabu Natsumeda, Atsushi Shiga, Hiroshi Aoki, Yasuko Toyoshima, Yingjun Zheng, Ryoko Takeuchi, Hiroatsu Murakami, Hiroshi Masuda, Shigeki Kameyama, Tatsuro Izumi, Yukihiko Fujii, Hitoshi Takahashi, Akiyoshi Kakita

    Brain Pathology   23 ( 3 )   254 - 262   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tuberous sclerosis complex (TSC) is characterized by benign tumors and hamartomas, including cortical tubers. Hamartin and tuberin, encoded by the TSC 1 and 2 genes, respectively, constitute a functional complex that negatively regulates the mammalian target of rapamycin (mTOR) signaling pathway, eventually promoting the induction of autophagy. In the present study, we assessed the induction of autophagy in cortical tubers surgically removed from seven patients with TSC in comparison with five controls of cortical tissue taken from non-TSC patients with epilepsy. Immunoblotting demonstrated a marked reduction of LC3B-I and LC3B-II in tubers relative to the controls. In tubers, strong, diffuse and dot-like immunoreactivity (IR) for LC3B was observed in dysmorphic neurons and balloon cells, but LC3B-IR in other neurons with normal morphology was significantly weaker than that in neurons in the controls. Immunoelectron microscopy revealed diffuse distribution of LC3B-IR within the cytoplasm of balloon cells. The dot-like pattern may correspond to abnormal aggregation bodies involving LC3. In an autopsy patient with TSC, we observed that LC3B-IR in neurons located outside of the tubers was preserved. Thus, autophagy is suppressed in tubers presumably through the mTOR pathway, and possibly a pathological autophagy reaction occurs in the dysmorphic neurons and balloon cells. © 2012 The Authors
    Brain Pathology © 2012 International Society of Neuropathology.

    DOI: 10.1111/j.1750-3639.2012.00634.x

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  • 脱髄・髄鞘障害性疾患 査読

    柿田 明美

    第9回神経病理コアカリキュラム教育セミナー   86 - 95   2013年4月

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  • Progression of paralysis is the most useful factor for differentiating malignant from benign intramedullary tumors 査読

    T. Ito, K. Sawakami, S. Ishikawa, T. Hirano, N. Endo, A. Kakita, H. Takahashi

    SPINAL CORD   51 ( 4 )   319 - 321   2013年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Study design: Retrospective study.
    Objectives: The purpose of this study was to identify the clinical factors for differentiating malignant from benign intramedullary spinal cord tumors.
    Setting: Niigata, Japan.
    Methods: We conducted a retrospective review of charts and images. Preoperative paralysis including walking ability, urinary function, magnetic resonance imaging (MRI) findings and pathological diagnosis were evaluated in 33 consecutive cases of intramedullary spinal cord tumor, and the clinical factors that were useful for differentiating malignant from benign tumors were identified.
    Results: Early progression of paralysis was the most valuable feature for differentiating malignant from benign tumors. Malignant tumors were suspected in only three of ten cases on the basis of MRI findings.
    Conclusion: Simple assessment of walking ability is easy to perform and is useful for predicting the pathological malignancy of intramedullary tumors of the spinal cord. Spinal Cord (2013) 51, 319-321; doi:10.1038/sc.2012.152; published online 4 December 2012

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  • Plasma matrix metalloproteinase-3 correlates with the clinical severity in men with multiple system atrophy. 査読

    Sasaki H, Matsushima M, Hama Y, Sakushima K, Nakamura M, Yabe I, Oba K, Tanji K, Mori F, Wakabayashi K, Kakita A, Takahashi H, Utsumi J

    Neurology and Clinical Neuroscience   1 ( 2 )   69 - 77   2013年3月

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  • Significance of horizontal propagation of synchronized activities in human epileptic neocortex investigated by optical imaging and immunohistological study 査読

    Tetsuya Hiraishi, Hiroki Kitaura, Makoto Oishi, Masafumi Fukuda, Shigeki Kameyama, Hitoshi Takahashi, Akiyoshi Kakita, Yukihiko Fujii

    Epilepsy Research   104 ( 1-2 )   59 - 67   2013年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To characterize the physiological condition of human epileptic neocortex, we employed flavoprotein fluorescence imaging (FFI), an optical imaging method which detects intrinsic signals accompanying neural activation, and immunohistologically studied human cortical specimens. The experimented materials were cortical tissues surrounding various intracerebral lesions obtained from 5 patients with epilepsy (epileptic patients: EPs) and 5 without epilepsy (non-epileptic patients: NEPs). These tissues were immersed in oxygenated artificial cerebrospinal fluid immediately after removal in the operating room. Signal changes of FFI in the cortical layers subjected to electrical stimulation were observed under bicuculline methiodide perfusion. Immunohistological staining for parvalbumin (PV), calbindin, and calretinin were performed on the same specimens to evaluate expressions of calcium-binding protein positive cells. The FFI study showed the characteristic cortical propagation pattern of elicited activities horizontally along the cortical layers in EPs but not in NEPs. The propagated area with more than 0.5% signal changes was significantly larger in EPs than in NEPs (p=0.008). Only the expression of PV positive neurons was significantly lower in EPs than in NEPs (p=0.006). The propagated area on FFI and the decrease in PV positive neurons correlated significantly (R=-0.78, p=0.04). The present study visualized the unique horizontal propagation of signal changes on FFI and demonstrated a correlation of this propagation with immunohistological decreases in PV positive neurons in human epileptic cortex. Further investigations may elucidate the mechanism of hyper-excitability and hyper-synchronization in epileptic cortical tissue itself. © 2012 Elsevier B.V.

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  • Selenomethionine Protects against Neuronal Degeneration by Methylmercury in the Developing Rat Cerebrum 査読

    Mineshi Sakamoto, Akira Yasutake, Akiyoshi Kakita, Masae Ryufuku, Hing Man Chan, Megumi Yamamoto, Sanae Oumi, Sayaka Kobayashi, Chiho Watanabe

    ENVIRONMENTAL SCIENCE & TECHNOLOGY   47 ( 6 )   2862 - 2868   2013年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    Although many experimental studies have shown that selenium protects against methylmercury (MeHg) toxicity at different end points, the direct interactive effects of selenium and MeHg on neurons in the brain remain unknown. Our goal is to confirm the protective effects of selenium against neuronal degeneration induced by MeHg in the developing postnatal rat brain using a postnatal rat model that is suitable for extrapolating the effects of MeHg to the fetal brain of humans. As an exposure source of selenium, we used selenomethionine (SeMet), a food-originated selenium. Wistar rats of postnatal days 14 were orally administered with vehicle (control), MeHg (8 mg Hg/kg/day), SeMet (2 mg Se/kg/day), or MeHg plus SeMet coexposure for 10 consecutive days. Neuronal degeneration and reactive astrocytosis were observed in the cerebral cortex of the MeHg-group but the symptoms were prevented by coexposure to SeMet. These findings serve as a proof that dietary selenium can directly protect neurons against MeHg toxicity in the mammalian brain, especially in the developing cerebrum.

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  • Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS): Clinical Characteristics and Molecular Analyses of CSF-1R 査読

    Konno Takuya, Tada Masayoshi, Koyama Akihide, Tada Mari, Sugai Akihiro, Nozaki Hiroaki, Matsunaga Akiko, Harigaya Yasuo, Nishimiya Jin, Ishihara Kenji, Yoneda Makoto, Kakita Akiyoshi, Takahashi Hitoshi, Kawamura Mitsuru, Onodera Osamu, Nishizawa Masatoyo, Ikeuchi Takeshi

    NEUROLOGY   80   2013年2月

  • DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia 査読

    S. Tanaka, A. Syu, H. Ishiguro, T. Inada, Y. Horiuchi, M. Ishikawa, M. Koga, E. Noguchi, N. Ozaki, T. Someya, A. Kakita, H. Takahashi, H. Nawa, T. Arinami

    Pharmacogenomics Journal   13 ( 1 )   27 - 34   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a genome-wide (Illumina HumanHapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P=0.008 in the replication sample, allelic P=4.6 × 10-6, odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD. © 2013 Macmillan Publishers Limited All rights reserved.

    DOI: 10.1038/tpj.2011.36

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  • DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia 査読

    S. Tanaka, A. Syu, H. Ishiguro, T. Inada, Y. Horiuchi, M. Ishikawa, M. Koga, E. Noguchi, N. Ozaki, T. Someya, A. Kakita, H. Takahashi, H. Nawa, T. Arinami

    PHARMACOGENOMICS JOURNAL   13 ( 1 )   27 - 34   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a genome-wide (Illumina Human-HapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P = 0.008 in the replication sample, allelic P = 4.6 x 10(-6), odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD. The Pharmacogenomics Journal (2013) 13, 27-34; doi:10.1038/tpj.2011.36; published online 9 August 2011

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  • Brain expression level and activity of HDAC6 protein in neurodegenerative dementia. 査読 国際誌

    Saori Odagiri, Kunikazu Tanji, Fumiaki Mori, Yasuo Miki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    Biochemical and biophysical research communications   430 ( 1 )   394 - 9   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Histone deacetylase 6 (HDAC6) is a multifunctional cytoplasmic protein that plays an especially critical role in the formation of aggresomes, where aggregates of excess protein are deposited. Previous immunohistochemical studies have shown that HDAC6 accumulates in Lewy bodies in Parkinson's disease and dementia with Lewy bodies (DLB) as well as in glial cytoplasmic inclusions in multiple system atrophy (MSA). However, it is uncertain whether the level and activity of HDAC6 are altered in the brains of patients with neurodegenerative dementia. In the present study, we demonstrated that the level of HDAC6 was not altered in the temporal cortex of patients with Alzheimer's disease and DLB in comparison with controls. In contrast, the level of HDAC6 was significantly increased in the temporal cortex of patients with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and in the cerebellar white matter of patients with MSA. However, the level of acetylated α-tubulin, one of the substrates of HDAC6, was not altered in FTLD-TDP and MSA relative to controls. These findings suggest that the induced level of HDAC6 in the brain is insufficient for manifestation of its activity in FTLD-TDP and MSA.

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  • Epilepsy Japan Speaks. てんかんを顕微鏡で診る 査読

    柿田 明美

    International Epilepsy News   183   10 - 11   2013年1月

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  • Phenotypic Spectrum of COL4A1 Mutations: Porencephaly to Schizencephaly 査読

    Yuriko Yoneda, Kazuhiro Haginoya, Mitsuhiro Kato, Hitoshi Osaka, Kenji Yokochi, Hiroshi Arai, Akiyoshi Kakita, Takamichi Yamamoto, Yoshiro Otsuki, Shin-ichi Shimizu, Takahito Wada, Norihisa Koyama, Yoichi Mino, Noriko Kondo, Satoru Takahashi, Shinichi Hirabayashi, Jun-ichi Takanashi, Akihisa Okumura, Toshiyuki Kumagai, Satori Hirai, Makoto Nabetani, Shinji Saitoh, Ayako Hattori, Mami Yamasaki, Akira Kumakura, Yoshinobu Sugo, Kiyomi Nishiyama, Satoko Miyatake, Yoshinori Tsurusaki, Hiroshi Doi, Noriko Miyake, Naomichi Matsumoto, Hirotomo Saitsu

    ANNALS OF NEUROLOGY   73 ( 1 )   48 - 57   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Objective: Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal, and muscular features. In this study, we aimed to clarify the phenotypic spectrum and incidence of COL4A1 mutations. ' Methods: We screened for COL4A1 mutations in 61 patients with porencephaly and 10 patients with schizencephaly, which may be similarly caused by disturbed vascular supply leading to cerebral degeneration, but can be distinguished depending on time of insult.
    Results: COL4A1 mutations were identified in 15 patients (21%, 10 mutations in porencephaly and 5 mutations in schizencephaly), who showed a variety of associated findings, including intracranial calcification, focal cortical dysplasia, pontocerebellar atrophy, ocular abnormalities, myopathy, elevated serum creatine kinase levels, and hemolytic anemia. Mutations include 10 missense, a nonsense, a frameshift, and 3 splice site mutations. Five mutations were confirmed as de novo events. One mutation was cosegregated with familial porencephaly, and 2 mutations were inherited from asymptomatic parents. Aberrant splicing was demonstrated by reverse transcriptase polymerase chain reaction analyses in 2 patients with splice site mutations.
    Interpretation: Our study first confirmed that COL4A1 mutations are associated with schizencephaly and hemolytic anemia. Based on the finding that COL4A1 mutations were frequent in patients with porencephaly and schizencephaly, genetic testing for COL4A1 should be considered for children with these conditions. ANN NEUROL 2013;73:48-57

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  • Alteration of autophagosomal proteins in the brain of multiple system atrophy 査読

    Kunikazu Tanji, Saori Odagiri, Atsushi Maruyama, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    Neurobiology of Disease   49 ( 1 )   190 - 198   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Autophagosomal formation is an initial step for macroautophagy. Similar to the yeast autophagy-related gene 8 (ATG8), mammalian ATG8 is responsible for autophagosomal formation, and categorized into LC3 and GABARAPs/GATE-16. Recent studies have shown that impairment of the autophagy-lysosome system is associated with formation of cytoplasmic inclusions observed in various neurodegenerative disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Although abnormal α-synuclein accumulation is a cardinal neuropathological feature in PD, DLB and multiple system atrophy (MSA), it is unclear whether autophagy is altered in MSA. We here demonstrated that the level of matured GABARAPs was significantly decreased in the cerebellum of MSA relative to controls, and that the higher levels of matured and lipidated LC3 were detected in detergent-insoluble fraction of MSA. Immunohistochemical analysis showed that the vast majority of glial cytoplasmic inclusions, a hallmark of MSA, were positive for LC3, whereas they were unstained or barely stained with anti-GABARAPs or anti-GATE-16 antibodies. Our data suggest that autophagy maturation is impaired through the repressed levels of autophagosomal proteins in MSA. © 2012 Elsevier Inc.

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  • Cognitive impairment and cortical degeneration in neuromyelitis optica 査読

    Etsuji Saji, Musashi Arakawa, Kaori Yanagawa, Yasuko Toyoshima, Akiko Yokoseki, Kouichirou Okamoto, Mika Otsuki, Kohei Akazawa, Akiyoshi Kakita, Hitoshi Takahashi, Masatoyo Nishizawa, Izumi Kawachi

    Annals of Neurology   73 ( 1 )   65 - 76   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objective: Neuromyelitis optica spectrum disorder (NMOsd) is an inflammatory and demyelinating syndrome characterized by optic neuritis and myelitis. Several magnetization transfer magnetic resonance imaging (MRI) studies have revealed abnormalities in normal-appearing gray matter in NMOsd. The aim of this study is to elucidate the characteristics and pathogenesis of cognitive impairment and neurodegeneration in NMOsd brains. Methods: Fourteen Japanese patients with serologically verified NMOsd, 17 patients with multiple sclerosis (MS), and 37 healthy controls were assessed with the Rao's Brief Repeatable Battery of Neuropsychological Tests (BRBN). Using 128 tissue blocks from 6 other cases of NMOsd, 3 cases of MS, and 4 controls without central nervous system involvement, we performed quantitative analysis of cortical neuronal loss and layer-specific changes in NMOsd. Results: In BRBN assessments, 57% of NMOsd patients and 47% of MS patients had impaired performance on at least 3 cognitive tests. Cognitive impairment in NMOsd was common even in the limited form of disease, indicating that NMOsd may progress insidiously from early stages of disease. Neuropathological assessments showed neuronal loss in cortical layers II, III, and IV, with nonlytic reaction of aquaporin-4 (AQP4)-negative astrocytes in layer I, massive activated microglia in layer II, and meningeal inflammation in NMOsd brains. All NMO cases showed no evidence of cortical demyelination. Interpretation: We demonstrate cognitive impairment and substantial cortical neuronal loss with unique AQP4 dynamics in astrocytes in NMOsd. These data indicate pathological processes consisting not only of inflammatory demyelinating events characterized by pattern-specific loss of AQP4 immunoreactivity but also cortical neurodegeneration in NMOsd brains. Copyright © 2012 American Neurological Association.

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  • Cognitive Impairment and Cortical Degeneration in Neuromyelitis Optica 査読

    Etsuji Saji, Musashi Arakawa, Kaori Yanagawa, Yasuko Toyoshima, Akiko Yokoseki, Kouichirou Okamoto, Mika Otsuki, Kohei Akazawa, Akiyoshi Kakita, Hitoshi Takahashi, Masatoyo Nishizawa, Izumi Kawachi

    ANNALS OF NEUROLOGY   73 ( 1 )   65 - 76   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Objective: Neuromyelitis optica spectrum disorder (NMOsd) is an inflammatory and demyelinating syndrome characterized by optic neuritis and myelitis. Several magnetization transfer magnetic resonance imaging (MRI) studies have revealed abnormalities in normal-appearing gray matter in NMOsd. The aim of this study is to elucidate the characteristics and pathogenesis of cognitive impairment and neurodegeneration in NMOsd brains.
    Methods: Fourteen Japanese patients with serologically verified NMOsd, 17 patients with multiple sclerosis (MS), and 37 healthy controls were assessed with the Rao's Brief Repeatable Battery of Neuropsychological Tests (BRBN). Using 128 tissue blocks from 6 other cases of NMOsd, 3 cases of MS, and 4 controls without central nervous system involvement, we performed quantitative analysis of cortical neuronal loss and layer-specific changes in NMOsd.
    Results: In BRBN assessments, 57% of NMOsd patients and 47% of MS patients had impaired performance on at least 3 cognitive tests. Cognitive impairment in NMOsd was common even in the limited form of disease, indicating that NMOsd may progress insidiously from early stages of disease. Neuropathological assessments showed neuronal loss in cortical layers II, III, and IV, with nonlytic reaction of aquaporin-4 (AQP4)-negative astrocytes in layer I, massive activated microglia in layer II, and meningeal inflammation in NMOsd brains. All NMO cases showed no evidence of cortical demyelination.
    Interpretation: We demonstrate cognitive impairment and substantial cortical neuronal loss with unique AQP4 dynamics in astrocytes in NMOsd. These data indicate pathological processes consisting not only of inflammatory demyelinating events characterized by pattern-specific loss of AQP4 immunoreactivity but also cortical neurodegeneration in NMOsd brains. ANN NEUROL 2013;73:65-76

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  • Keap1 Is Localized in Neuronal and Glial Cytoplasmic Inclusions in Various Neurodegenerative Diseases 査読

    Kunikazu Tanji, Atsushi Maruyama, Saori Odagiri, Fumiaki Mori, Ken Itoh, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY   72 ( 1 )   18 - 28   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Oxidative stress has been proposed as a potential mechanism for neurodegenerative diseases, such as Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). In response to oxidative stress, the levels of numerous cytoprotective products are increased via alteration of the Kelch-like ECH-associated protein 1 (Keap1) and NF-E2Yrelated factor 2 (Nrf2) system. One of the Nrf2 targets, p62, has been known to be incorporated into a wide spectrum of cytoplasmic inclusions in neurodegenerative diseases and interact with Keap1. However, it remains unclear whether Keap1 is associated with the pathogenesis of neurodegenerative diseases. In this study, we investigated the relationship between p62 and Keap1 in the brains of patients with AD, PD, dementia with Lewy bodies (DLB), and ALS. Biochemical analyses showed that p62 and Keap1 interacted with each other in AD and DLB brains and were extracted into similar detergent-soluble and -insoluble fractions. Pathologic examination demonstrated that anti-Keap1 antibodies immunostained Lewy bodies in PD and DLB, neurofibrillary tangles in AD, and skeinlike inclusions in ALS. Further analysis showed that the levels of common Nrf2 target genes were increased in AD compared with those in controls. However, there were no statistical significances in the levels of Nrf2 target genes in DLB relative to controls. Our pathologic and biochemical results suggest a molecular basis for stress response to be involved in the formation of cytoplasmic inclusions observed in several neurodegenerative diseases.

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  • Electrocorticographic-histopathologic correlations implying epileptogenicity of dysembryoplastic neuroepithelial tumor 査読

    Kota Kagawa, Koji Iida, Akiyoshi Kakita, Masaya Katagiri, Takeshi Nishimoto, Akira Hashizume, Yoshihiro Kiura, Ryosuke Hanaya, Kazuhiko Sugiyama, Koji Arihiro, Kazunori Arita, Kaoru Kurisu

    Neurologia Medico-Chirurgica   53 ( 10 )   676 - 687   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Based on intracranial-video electroencephalography (EEG), histopathological features, and postoperative seizure outcome, we elucidated the epileptogenicity in patients with dysembryoplastic neuroepithelial tumor (DNT). Five patients (P1-P5) pathologically diagnosed with DNT underwent intracranial-video EEG to identify the ictal onset zone and irritative zone. We evaluated the correlations of ictal onset zone and irritative zone with the magnetic resonance imaging-visible lesion (MRI-lesion) and their histopathological features. Intracranial-video EEG located the ictal onset zone adjacent to the MRI-lesion margin in four patients with complex/simple forms of DNT subcategory, and on the MRI-lesion in P3 with a nonspecific DNT form. The irritative zone extended to surrounding regions of the ictal onset zone in all patients. Histopathologically, MRI-lesions were characterized by specific glioneuronal elements, whereas the ictal onset zone and irritative zone were represented with dysplastic cortex accompanying oligodendroglialike cells in four (P1, P2, P4, and P5) of five patients. Cortical dysplasia was identified with typical histopathologic features in the irritative zone remote from the MRI-lesion in P5. P3, with a nonspecific form, indicated prominent component of dysplastic cortex with oligodendroglia-like cells scattered in the MRIlesion. Lesionectomy of MRI-lesion with additional cortical resections (including the ictal onset zone and irritative zone) yielded postoperative seizure freedom (Engel Class I) in P3, P4, and P5, while P1 and P2 (with only lesionectomy) experienced postoperative residual seizure (Class II and III in each patient). Our results suggest the intrinsic epileptogenicity of DNT. The topographical correlation indicated that the dysplastic cortex accompanying oligodendroglia-like cells was more epileptogenic than the specific glioneuronal elements itself. Meticulous intracranial-video EEG analysis delineating the MRI nonvisible ictal onset zone and the irritative zone may yield better seizure outcome.

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  • SORL1 is Genetically Associated with Neuropathologically Characterized Late-Onset Alzheimer's Disease 査読

    Yanan Wen, Akinori Miyashita, Nobutaka Kitamura, Tamao Tsukie, Yuko Saito, Hiroyuki Hatsuta, Shigeo Murayama, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyasu Akatsu, Takayuki Yamamoto, Kenji Kosaka, Haruyasu Yamaguchi, Kohei Akazawa, Yasuo Ihara, Ryozo Kuwano

    JOURNAL OF ALZHEIMERS DISEASE   35 ( 2 )   387 - 394   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IOS PRESS  

    SORL1 was shown to be genetically associated with late-onset Alzheimer's disease (LOAD) in a large-scale genome-wide association study (GWAS) involving clinically verified subjects. Here, we attempted to replicate the association of SORL1 in Japanese neuropathologically characterized brain donor subjects (LOAD, 213; control, 370) through a single-nucleotide polymorphism (SNP)-based genetic study involving 19 SNPs: 11 SNPs were selected from the initial study reported by Rogaeva et al. (2007), and the other eight were from our GWAS. Among these SNPs, five exhibited a significant association with LOAD after multiple test correction (p &lt; 2.63E-03 [=0.05/19]), which was supported by means of multiple logistic regression analysis with adjustment for age, gender, and carrier status of the APOE epsilon 4 allele. Three of these SNPs (rs985421, rs12364988 [Rogaeva's SNP 7], and rs4598682) were encompassed by a 5' linkage disequilibrium (LD) region, and the remaining two (rs3781834 and rs3781836) by a 3' LD region. Strong LD among SNPs was observed within each LD region, implying that there are two genomic regions showing association with LOAD in SORL1. Case-control haplotype analysis demonstrated that some haplotypes are associated with LOAD in both LD regions. Our replication study strongly supports the preceding evidence that SORL1 is likely one of the genes associated with LOAD.

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  • Phagocytized corpora amylacea as a histological hallmark of astrocytic injury in neuromyelitis optica 査読

    Aya Suzuki, Hideaki Yokoo, Akiyoshi Kakita, Hitoshi Takahashi, Yasuo Harigaya, Hayato Ikota, Yoichi Nakazato

    NEUROPATHOLOGY   32 ( 6 )   587 - 594   2012年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Neuromyelitis optica (NMO) is an inflammatory demyelinating and necrotizing disorder of the CNS that mainly affects the optic nerve and spinal cord. The etiology is still uncertain; however, the discovery of serum anti-aquaporin-4 (AQP4) autoantibody is becoming the center of attention, and a new hypothesis is emerging that NMO is essentially astrocytopathy provoked by this autoantibody. In this study, we focused on corpora amylacea (CA), glycoproteinaceous inclusions in astrocytic processes. We examined 57 lesions in nine cases of NMO spectrum disorder, and demonstrated that CA were phagocytized by macrophages in 42 lesions (74%) of eight cases, while phagocytized figures were not seen in unaffected areas. Phagocytized CA were frequently encountered in early-phase lesions still retaining myelin structures, while fewer or none were found in chronic destructive lesions. Moreover, phagocytized CA were significantly smaller in diameter than intact ones, and CA were decreased or absent in most lesions assessed. These findings suggest the following pathophysiological process: the astrocytes are affected at an early phase in NMO, CA are expelled from the astrocytes and phagocytized by macrophages finally leading to clearance. A phagocytized figure and subsequent loss of CA can be a histological hallmark of astrocytic injury of NMO.

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  • Involvement of the γ-secretase-mediated EphA4 signaling pathway in synaptic pathogenesis of Alzheimer's disease. 査読

    Matsui C, Inoue E, Kakita A, Arita K, Deguchi-Tawarada M, Togawa A, Yamada A, Takai Y, Takahashi H

    Brain pathology (Zurich, Switzerland)   22 ( 6 )   776 - 787   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Coexistence of Huntington's disease and amyotrophic lateral sclerosis: a clinicopathologic study 査読

    Mari Tada, Elizabeth A. Coon, Alexander P. Osmand, Patricia A. Kirby, Wayne Martin, Marguerite Wieler, Atsushi Shiga, Hiroe Shirasaki, Masayoshi Tada, Takao Makifuchi, Mitsunori Yamada, Akiyoshi Kakita, Masatoyo Nishizawa, Hitoshi Takahashi, Henry L. Paulson

    ACTA NEUROPATHOLOGICA   124 ( 5 )   749 - 760   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    We report a retrospective case series of four patients with genetically confirmed Huntington's disease (HD) and sporadic amyotrophic lateral sclerosis (ALS), examining the brain and spinal cord in two cases. Neuropathological assessment included a polyglutamine recruitment method to detect sites of active polyglutamine aggregation, and biochemical and immunohistochemical assessment of TDP-43 pathology. The clinical sequence of HD and ALS varied, with the onset of ALS occurring after the mid-50's in all cases. Neuropathologic features of HD and ALS coexisted in both cases examined pathologically: neuronal loss and gliosis in the neostriatum and upper and lower motor neurons, with Bunina bodies and ubiquitin-immunoreactive skein-like inclusions in remaining lower motor neurons. One case showed relatively early HD pathology while the other was advanced. Expanded polyglutamine-immunoreactive inclusions and TDP-43-immunoreactive inclusions were widespread in many regions of the CNS, including the motor cortex and spinal anterior horn. Although these two different proteinaceous inclusions coexisted in a small number of neurons, the two proteins did not co-localize within inclusions. The regional distribution of TDP-43-immunoreactive inclusions in the cerebral cortex partly overlapped with that of expanded polyglutamine-immunoreactive inclusions. In the one case examined by TDP-43 immunoblotting, similar TDP-43 isoforms were observed as in ALS. Our findings suggest the possibility that a rare subset of older HD patients is prone to develop features of ALS with an atypical TDP-43 distribution that resembles that of aggregated mutant huntingtin. Age-dependent neuronal dysfunction induced by mutant polyglutamine protein expression may contribute to later-life development of TDP-43 associated motor neuron disease in a small subset of patients with HD.

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  • p62/sequestosome 1 binds to TDP-43 in brains with frontotemporal lobar degeneration with TDP-43 inclusions 査読

    Kunikazu Tanji, Hai-Xin Zhang, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    JOURNAL OF NEUROSCIENCE RESEARCH   90 ( 10 )   2034 - 2042   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Ubiquitin-positive cytoplasmic inclusions are consistently found in various neurodegenerative diseases. As with ubiquitin, anti-p62/SQSTM1 (referred to as p62) antibody clearly immunostains these inclusions. p62 has a ubiquitin-associated domain at the carboxyl terminus and thereby interacts with ubiquitinated and misfolded proteins. Here we immunoprecipitated endogenous p62 in the cerebral cortex from patients with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and found that p62 coimmunoprecipitated several proteins, including TDP-43, which is a major disease protein in FTLD-TDP. Unexpectedly, p62 immunoprecipitated a smaller amount of TDP-43 in FTLD-TDP compared with controls. Further analyses showed that p62 physiologically binds to TDP-43 and likely is involved in degradation of TDP-43 with 35-kDa, but not full-length TDP-43. Our results suggest that the interaction of TDP-43 and p62 is disrupted and may participate in the pathogenesis of TDP-43 proteinopathy. (c) 2012 Wiley Periodicals, Inc.

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  • Endosomal sorting related protein CHMP2B is localized in Lewy bodies and glial cytoplasmic inclusions in α-synucleinopathy. 査読

    Tanikawa S, Mori F, Tanji K, Kakita A, Takahashi H, Wakabayashi K

    Neuroscience letters   527 ( 1 )   16 - 21   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Analysis of Chromosome 19q13.42 Amplification in Embryonal Brain Tumors with Ependymoblastic Multilayered Rosettes 査読

    Sumihito Nobusawa, Hideaki Yokoo, Junko Hirato, Akiyoshi Kakita, Hitoshi Takahashi, Takashi Sugino, Kazuhiro Tasaki, Hideaki Itoh, Tsutomu Hatori, Yoshie Shimoyama, Atsuko Nakazawa, Shigeru Nishizawa, Hiroshi Kishimoto, Keiko Matsuoka, Masahiro Nakayama, Naoki Okura, Yoichi Nakazato

    BRAIN PATHOLOGY   22 ( 5 )   689 - 697   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Recently, it was reported that ependymoblastoma and embryonal tumor with abundant neuropil and true rosettes (ETANTR) show 19q13.42 amplification at a high frequency, suggesting that these tumors may constitute a single entity. As ependymoblastic rosettes are the most prominent features in both subtypes, embryonal tumor with multilayered rosettes (ETMR) was proposed, for which 19q13.42 amplification represents a specific molecular hallmark. However, ependymoblastic rosettes are not specific to ependymoblastoma and ETANTR, and are also found in a few other embryonal tumors as well as immature teratomas, and knowledge on 19q13.42 amplification in these tumors is limited. In this study, we performed fluorescence in situ hybridazation (FISH) analysis and differential polymerase chain reaction (PCR), and detected 19q13.42 amplification in three out of four ETANTR, one ependymoblastoma and one medulloepithelioma with ETANTR components, whereas none of the two atypical teratoid/rhabdoid tumors (AT/RT) with ependymoblastic rosettes nor two immature teratomas with developing neuroectodermal structures showed such amplification, suggesting that medulloepitheliomas would possibly be included in ETMR, and ependymoblastic rosettes in AT/RT do not signify that these tumors constitute ETMR. Also, we found C19MC rather than miR-371-373 was amplified in one ETANTR, suggesting that C19MC miRNA cluster seems to be more closely linked to the pathogenesis of ETMR.

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  • ブレインバンク:ローカルな活動からグローバルな役割を.―新潟大学脳研究所の取り組み― 査読

    柿田 明美

    新潟県医師会報   ( 750 )   2 - 7   2012年9月

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  • Novel pathological abnormalities of deep brain structures including dysplastic neurons in anterior striatum associated with focal cortical dysplasia in epilepsy Clinical article 査読

    Takanobu Kaido, Taisuke Otsuki, Akiyoshi Kakita, Kenji Sugai, Yoshiaki Saito, Takafumi Sakakibara, Akio Takahashi, Yuu Kaneko, Yuko Saito, Hitoshi Takahashi, Ryoko Honda, Eiji Nakagawa, Masayuki Sasaki, Masayuki Itoh

    JOURNAL OF NEUROSURGERY-PEDIATRICS   10 ( 3 )   217 - 225   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC NEUROLOGICAL SURGEONS  

    Object. Some patients are not seizure free even after epileptogenic cortical resection. The authors recently described a case of frontal lobe epilepsy cured after the resection of periventricular white matter and striatum, in which dysplastic neurons were revealed. The authors attempted to confirm similar cases.
    Methods. They reviewed the records of 8 children with frontal lobe epilepsy who had daily (7) or monthly (1) seizures and underwent resections including deep brain structures.
    Results. Five patients undenvent multiple resections. Neuroimaging of the deep structures showed the transmantle sign in 3 patients, ictal hyperperfusion in 6, reduced iomazenil uptake in 2, and spike dipole clustering in 6. All patients became seizure free postoperatively. Focal cortical dysplasia of various types was diagnosed in all patients. Dysmorphic neurons were found in the cortex and subcortical white matter of 5 patients. The striatum was verified in 3 patients in whom dysmorphic neurons were scattered. In the periventricular white matter, prominent astrocytosis was evident in all cases.
    Conclusions. Pathological abnormalities such as dysmorphic neurons and astrocytosis in deep brain structures would play a key role in epileptogenesis. (http://thejns.org/doi/abs/10.3171/2012.6.PEDS11325)

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  • Autophagic adapter protein NBR1 is localized in Lewy bodies and glial cytoplasmic inclusions and is involved in aggregate formation in α-synucleinopathy. 査読

    Odagiri S, Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K

    Acta neuropathologica   124 ( 2 )   173 - 186   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Primary lateral sclerosis: Upper-motor-predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration - immunohistochemical and biochemical analyses of TDP-43 査読

    Takayuki Kosaka, Yong-Juan Fu, Atsushi Shiga, Haruka Ishidaira, Chun-Feng Tan, Takashi Tani, Ryoko Koike, Osamu Onodera, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    NEUROPATHOLOGY   32 ( 4 )   373 - 384   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Primary lateral sclerosis (PLS) is clinically defined as a disorder selectively affecting the upper motor neuron (UMN) system. However, recently it has also been considered that PLS is heterogeneous in its clinical presentation. To elucidate the association of PLS, or disorders mimicking PLS, with 43-kDa TAR DNA-binding protein (TDP-43) abnormality, we examined two adult patients with motor neuron disease, which clinically was limited almost entirely to the UMN system, and was followed by progressive frontotemporal atrophy. In the present study, the distribution and severity, and biochemical profile of phosphorylated TDP-43 (pTDP-43) in the brains and spinal cords were examined immunohistochemically and biochemically. Pathologically, in both cases, frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) was evident, with the most severe degeneration in the motor cortex. An important feature in both cases was the presence of Bunina bodies and/or ubiquitin inclusions, albeit very rarely, in the well preserved lower motor neurons. The amygdala and neostriatum were also affected. pTDP-43 immunohistochemistry revealed the presence of many positively stained neuronal cytoplamic inclusions (NCIs) and dystrophic neurites/neuropil threads in the affected frontotemporal cortex and subcortical gray matter. By contrast, such pTDP-43 lesions, including NCIs, were observed in only a few lower motor neurons. pTDP-43 immunoblotting revealed that fragments of similar to 25-kDa were present in the cortices, but not in the spinal cord in both cases. Genetically, neither of the patients had any mutation in the TDP-43 gene. In conclusion, we consider that although PLS may be a clinically significant disease entity, at autopsy, the majority of such clinical cases would present as upper-motor-predominant amyotrophic lateral sclerosis with FTLD-TDP.

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  • Autophagy-related proteins (p62, NBR1 and LC3) in intranuclear inclusions in neurodegenerative diseases 査読

    Fumiaki Mori, Kunikazu Tanji, Saori Odagiri, Yasuko Toyoshima, Mari Yoshida, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    NEUROSCIENCE LETTERS   522 ( 2 )   134 - 138   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Incorporation of ubiquitin and ubiquitin-related proteins including p62 into neuronal intranuclear inclusions (NIIs) has been reported in a variety of neurodegenerative diseases. However, involvement of autophagy-specific proteins (NBR1 and LC3) in NIIs has not been mentioned. We immunohistochemically examined the brain of patients with Machado-Joseph disease (MJD; n = 5), dentatorubral-pallidoluysian atrophy (DRPLA; n = 5) and intranuclear inclusion body disease (INIBD; n = 5), using antibodies against ubiquitin, p62, NBR1 and LC3. The proportion of p62-, NBR1- and LC3-positive inclusions relative to the number of ubiquitin-positive inclusions was calculated in each case. NIIs were positive for p62 in MJD (19.3%), DRPLA (49.7%) and INIBD (99.8%). As for autophagy-specific proteins, NIIs were positive for NBR1 in MID (4.2%), DRPLA (5.5%) and INIBD (13.2%) and negative for LC3 in MJD. DRPLA and INIBD, except for one case of INIBD. These findings suggest that autophagy-lysosome pathway is not involved in the formation/degradation of NIIs. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

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  • Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS 査読

    Atsushi Shiga, Tomohiko Ishihara, Akinori Miyashita, Misaki Kuwabara, Taisuke Kato, Norihiro Watanabe, Akie Yamahira, Chigusa Kondo, Akio Yokoseki, Masuhiro Takahashi, Ryozo Kuwano, Akiyoshi Kakita, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

    PLOS ONE   7 ( 8 )   e43120   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in the polymerase delta interacting protein 3 (POLDIP3) as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type POLDIP3 (variant-1) decreased and POLDIP3 lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment of POLDIP3 variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons collected by laser capture microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS.

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  • Characteristics of Aquaporin Expression Surrounding Senile Plaques and Cerebral Amyloid Angiopathy in Alzheimer Disease 査読

    Akihiko Hoshi, Teiji Yamamoto, Keiko Shimizu, Yoshikazu Ugawa, Masatoyo Nishizawa, Hitoshi Takahashi, Akiyoshi Kakita

    JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY   71 ( 8 )   750 - 759   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Senile plaques (SPs) containing amyloid beta peptide (A beta) 1-42 are the major species present in Alzheimer disease (AD), whereas A beta 1-40 is the major constituent of arteriolar walls affected by cerebral amyloid angiopathy. The water channel proteins astrocytic aquaporin 1 (AQP1) and aquaporin 4 (AQP4) are known to be abnormally expressed in AD brains, but the expression of AQPs surrounding SPs and cerebral amyloid angiopathy has not been described in detail. Here, we investigated whether AQP expression is associated with each species of A beta deposited in human brains affected by either sporadic or familial AD. Immunohistochemical analysis demonstrated more numerous AQP1-positive reactive astrocytes in the AD cerebral cortex than in controls, located close to A beta 42- or A beta 40-positive SPs. In AD cases, however, AQP1-positive astrocytes were not often observed in AA-rich areas, and there was a significant negative correlation between the levels of AQP1 and A beta 42 assessed semiquantitatively. We also found that AA plaque-like AQP4 was distributed in association with A beta 42- or A beta 40-positive SPs and that the degree of AQP4 expression around A beta 40-positive vessels was variable. These findings suggest that a defined population of AQP1-positive reactive astrocytes may modify A beta deposition in the AD brain, whereas the A beta deposition process might alter astrocytic expression of AQP4.

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  • Periventricular nodular heterotopia functionally couples with the overlying hippocampus 査読

    Hiroki Kitaura, Makoto Oishi, Nobuyuki Takei, Yong-Juan Fu, Tetsuya Hiraishi, Masafumi Fukuda, Hitoshi Takahashi, Katsuei Shibuki, Yukihiko Fujii, Akiyoshi Kakita

    EPILEPSIA   53 ( 7 )   e127 - e131   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Patients with periventricular nodular heterotopia (PVNH) often have severe epilepsy. However, it is unclear how the heterotopia contributes to epileptogenesis. Recently, electrophysiologic studies using intraoperative depth electrodes have indicated that interaction between the heterotopia and overlying cortex is crucial for seizure onset. We performed an in vitro physiologic study using slices of resected brain from a 22-year-old man with PVNH, who manifested medically refractory mesial temporal lobe epilepsy. Preoperative evaluation indicated that the right mesial temporal structure and PVNH were the epileptogenic focus. The resected tissue was immediately immersed in cold artificial cerebrospinal fluid, and then slices of the brain tissue including the heterotopic nodules and overlying hippocampus were prepared. We electrically stimulated the incubated slices, and the elicited neural activities were analyzed as changes in the flavoprotein fluorescence signals. When we stimulated either the heterotopic nodule or the overlying hippocampus, clear functional coupling of neural activities between these structures was observed. The coupling response evoked by stimulation of the subiculum and developing within the heterotopic nodule was enhanced by application of bicuculline. Therefore, activities of the hippocampus and the nodule are closely correlated.

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  • Periventricular nodular heterotopia functionally couples with the overlying hippocampus

    Hiroki Kitaura, Makoto Oishi, Nobuyuki Takei, Yong-Juan Fu, Tetsuya Hiraishi, Masafumi Fukuda, Hitoshi Takahashi, Katsuei Shibuki, Yukihiko Fujii, Akiyoshi Kakita

    Epilepsia   53 ( 7 )   e127 - e131   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Patients with periventricular nodular heterotopia (PVNH) often have severe epilepsy. However, it is unclear how the heterotopia contributes to epileptogenesis. Recently, electrophysiologic studies using intraoperative depth electrodes have indicated that interaction between the heterotopia and overlying cortex is crucial for seizure onset. We performed an in vitro physiologic study using slices of resected brain from a 22-year-old man with PVNH, who manifested medically refractory mesial temporal lobe epilepsy. Preoperative evaluation indicated that the right mesial temporal structure and PVNH were the epileptogenic focus. The resected tissue was immediately immersed in cold artificial cerebrospinal fluid, and then slices of the brain tissue including the heterotopic nodules and overlying hippocampus were prepared. We electrically stimulated the incubated slices, and the elicited neural activities were analyzed as changes in the flavoprotein fluorescence signals. When we stimulated either the heterotopic nodule or the overlying hippocampus, clear functional coupling of neural activities between these structures was observed. The coupling response evoked by stimulation of the subiculum and developing within the heterotopic nodule was enhanced by application of bicuculline. Therefore, activities of the hippocampus and the nodule are closely correlated. © Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

    DOI: 10.1111/j.1528-1167.2012.03509.x

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  • Dynein and dynactin components modulate neurodegeneration induced by excitotoxicity 査読

    Takeshi Fujiwara, Koji Morimoto, Akiyoshi Kakita, Hitoshi Takahashi

    JOURNAL OF NEUROCHEMISTRY   122 ( 1 )   162 - 174   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    J. Neurochem. (2012) 122, 162174. Abstract Glutamate excitotoxicity causes neuronal dysfunction and degeneration. It is implicated in chronic disorders, including Alzheimers disease, and in acute CNS insults such as ischemia. These disorders share prominent morphological features, including axon degeneration and cell body death. However, the molecular mechanism underlying excitotoxicity-induced neurodegeneration remains poorly understood. A key molecular feature of neurodegeneration is deficits in microtubule-based cargo transport that plays a pivotal role in maintaining the balance of survival and stress signaling in the axon. We developed an excitotoxicity-induced neurodegeneration system in primary neuronal cultures. We find that excitotoxicity generates a C-terminal truncated form of p150Glued, a major component of the dynactin complex, which exacerbates axon degeneration. This p150Glued truncated form was identified in brain tissues of patients with Alzheimers disease. Overexpression of wild-type (WT) dynein intermediate chain (DIC), a dynein component that interacts with p150Glued and links dynein and dynactin complexes, DIC (S84D) mutant, and WT p150Glued suppressed axon degeneration. These modulating effects of p150Glued and DIC on excitotoxicity-induced axon degeneration are also observed in apoptosis and cell body death. Thus, our findings identify retrograde transport proteins, p150Glued and DIC, as novel modulators of neurodegeneration induced by glutamate excitotoxicity.

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  • Ubiquilin immunoreactivity in cytoplasmic and nuclear inclusions in synucleinopathies, polyglutamine diseases and intranuclear inclusion body disease 査読

    Fumiaki Mori, Kunikazu Tanji, Saori Odagiri, Yasuko Toyoshima, Mari Yoshida, Teruaki Ikeda, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    ACTA NEUROPATHOLOGICA   124 ( 1 )   149 - 151   2012年7月

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    記述言語:英語   出版者・発行元:SPRINGER  

    DOI: 10.1007/s00401-012-0999-z

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  • Immunohistochemical analysis of Marinesco bodies, using antibodies against proteins implicated in the ubiquitin-proteasome system, autophagy and aggresome formation 査読

    Saori Odagiri, Kunikazu Tanji, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Tetsu Kamitani, Koichi Wakabayashi

    NEUROPATHOLOGY   32 ( 3 )   261 - 266   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Marinesco bodies (MBs) are spherical eosinophilic intranuclear inclusions in pigmented neurons in the substantia nigra and locus ceruleus. Previous immunohistochemical studies have shown that MBs are positive for ubiquitin, p62 and SUMO-1, suggesting the involvement of ubiquitination and related proteins in the formation or disaggregation of MBs. However, the involvement is not thoroughly understood. Therefore, we immunohistochemically examined the midbrain from five control subjects ranged from 53 to 84 years old. MBs were positive for various proteins implicated in the ubiquitin-proteasome system (ubiquitin, p62, EDD1, NEDD8, NUB1, SUMO-1 and SUMO-2), aggresome formation (HDAC6) and autophagy (ubiquitin, p62, LC3, GABARAP and GATE-16). These findings suggest that proteins related to ubiquitination, proteasomal degradation and autophagy are involved in the formation or disaggregation of MBs.

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  • Optineurin immunoreactivity in neuronal nuclear inclusions of polyglutamine diseases (Huntington's, DRPLA, SCA2, SCA3) and intranuclear inclusion body disease 査読

    Fumiaki Mori, Kunikazu Tanji, Yasuko Toyoshima, Mari Yoshida, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    ACTA NEUROPATHOLOGICA   123 ( 5 )   747 - 749   2012年5月

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    記述言語:英語   出版者・発行元:SPRINGER  

    DOI: 10.1007/s00401-012-0956-x

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  • Lymphoplasmacyte-rich meningioma: A convexity mass with regional enhancement in the adjacent brain parenchyma 査読

    Yoko Nakayama, Masatoshi Watanabe, Kenji Suzuki, Hiroyuki Usuda, Iwao Emura, Yasuko Toyoshima, Hitoshi Takahashi, Tadashi Kawaguchi, Akiyoshi Kakita

    NEUROPATHOLOGY   32 ( 2 )   174 - 179   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Lymphoplasmacyte-rich meningioma (LPM) is a rare, benign variant of meningioma, characterized by massive inflammatory cell infiltration and a variable proportion of meningothelial tumorous elements. Here we report the clinicopathological features of an LPM located at the right frontal convexity in a 37-year-old woman. The patient had suffered an initial generalized tonic-clonic seizure when she was 32 weeks pregnant. The lesion exhibited low intensity on T1-weighted MRI and high intensity on T2-weighted images, with surrounding parenchymal edema. The mass exhibited gadolinium enhancement with dural tail signs. Moreover, multiple foci of linear enhancement spreading through the sulci and into the nearby brain parenchyma were evident. At 1 month after parturition, en bloc removal of the mass, the attached dura mater and adjacent brain tissue was performed. Histologically, the mass located in the subdural space was composed of a mixture of B- and T-lymphocytes and plasma cells. Within the mass, multiple small lobules of meningothelial cells showing immunoreactivity for epithelial membrane antigen and vimentin were observed. The inflammatory cells had also infiltrated the subarachnoid and Virchow-Robin spaces, and the dura mater. The cerebral cortex showed ischemic changes, but no tumor cell invasion. On the basis of these histological features, the lesion appeared to be LPM with an inconspicuous meningothelial component and extensive inflammatory infiltration. This case appears to provide useful information on the pathogenesis of this variant.

    DOI: 10.1111/j.1440-1789.2011.01236.x

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  • Epidermoid cyst involving the medial temporal lobe: Surgical pathologic features of the epileptogenic lesion 査読

    Tetsuya Hiraishi, Makoto Oishi, Hiroki Kitaura, Masae Ryufuku, Yong-Juan Fu, Masafumi Fukuda, Hitoshi Takahashi, Yukihiko Fujii, Akiyoshi Kakita

    NEUROPATHOLOGY   32 ( 2 )   196 - 201   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Epidermoid cysts in the middle fossa are rare and may involve the temporal lobe and lateral ventricle. Affected patients often suffer from seizures, but the pathomechanisms underlying the epileptogenic lesions have remained unclear. Here we report the surgical pathological features of the hippocampus in a 31-year-old woman with mesial temporal lobe epilepsy (mTLE), in whom an epidermoid cyst involving the right basal cistern and inferior horn of the lateral ventricle was evident. The ictal electrocorticogram indicated seizure onset at the parahippocampal gyrus. An anterior temporal lobectomy and amygdalohippocampectomy were performed. Histologically, the hippocampus showed marked atrophy with severe loss of pyramidal neurons in the cornu Ammonis subfields and granule cell loss in the dentate gyrus. At the ventricular surface of the hippocampus, there were small granulomatous lesions with spicularly anchored keratin substance. These features indicated multiple and chronic stab wounds by the cyst contents and consequent local inflammatory responses within the parenchyma. The predisposition to adhesion between the tumor and hippocampus may have caused neurons to develop abnormal irritability to certain chemical mediators present in the cyst. Epileptogenicity involving the atrophic hippocampus and medial temporal lobes nearby may have developed in association with these processes. This case appears to provide information that is useful for surgical planning in patients with mTLE and epidermoid cysts involving the medial temporal lobe.

    DOI: 10.1111/j.1440-1789.2011.01243.x

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  • Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons 査読

    Takuto Hideyama, Takenari Yamashita, Hitoshi Aizawa, Shoji Tsuji, Akiyoshi Kakita, Hitoshi Takahashi, Shin Kwak

    NEUROBIOLOGY OF DISEASE   45 ( 3 )   1121 - 1128   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Amyotrophic lateral sclerosis (ALS) is the most common adult-onset fatal motor neuron disease. In spinal motor neurons of patients with sporadic ALS, normal RNA editing of GluA2, a subunit of the L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, is inefficient. Adenosine deaminase acting on RNA 2 (ADAR2) specifically mediates RNA editing at the glutamine/arginine (Q/R) site of GluA2 and motor neurons expressing Q/R site-unedited GluA2 undergo slow death in conditional ADAR2 knockout mice. Therefore, investigation into whether inefficient ADAR2-mediated GluA2 Q/R site-editing occurs universally in motor neurons of patients with ALS would provide insight into the pathogenesis of ALS. We analyzed the extents of GluA2 Q/R site-editing in an individual laser-captured motor neuron of 29 ALS patients compared with those of normal and disease control subjects. In addition, we analyzed the enzymatic activity of three members of the ADAR family (ADAR1, ADAR2 and ADAR3) in ALS motor neurons expressing unedited GluA2 mRNA and those expressing only edited GluA2 mRNA. Q/R site-unedited-GluA2 mRNA was expressed in a significant proportion of motor neurons from all of the ALS cases examined. Conversely, motor neurons of the normal and disease control subjects expressed only edited GluA2 mRNA. ADAR2, but not ADAR1 or ADAR3, was significantly downregulated in all the motor neurons of ALS patients, more extensively in those expressing Q/R site-unedited GluA2 mRNA than those expressing only Q/R site-edited GluA2 mRNA. These results indicate that ADAR2 downregulation is a profound pathological change relevant to death of motor neurons in ALS. (C) 2011 Elsevier Inc. All rights reserved.

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  • Co-occurrence of argyrophilic grain disease in sporadic amyotrophic lateral sclerosis 査読

    K. Soma, Y. -J. Fu, K. Wakabayashi, O. Onodera, A. Kakita, H. Takahashi

    NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY   38 ( 1 )   54 - 60   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    K. Soma, Y.-J. Fu, K. Wakabayashi, O. Onodera, A. Kakita and H. Takahashi (2012) Neuropathology and Applied Neurobiology38, 5460

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  • Vertebral basilar system dolichoectasia with marked infiltration of IgG4-containing plasma cells: A manifestation of IgG4-related disease? 査読

    Yasuko Toyoshima, Iwao Emura, Yoshitake Umeda, Nobuya Fujita, Akiyoshi Kakita, Hitoshi Takahashi

    NEUROPATHOLOGY   32 ( 1 )   100 - 104   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    We report the histopathological features of vertebral basilar system dolichoectasia (VBD) in a 68-year-old man who died as a result of accompanying infarction of the medulla oblongata on day 6 of admission. During hospitalization, the patient was also found to have an elevated serum IgG level and tumors of the renal pelvis. A possible clinical diagnosis of VBD associated with IgG4-related disease was considered postmortem. Autopsy examination, limited to the intracranial tissues, revealed marked infiltration of IgG4-containing plasma cells in the adventitia and media of the vertebral and basilar arteries. Multiple fibrous nodules forming pseudotumors were also evident on the outer surface of the affected arteries. These histological features were very similar to those of arteriopathy, such as inflammatory aortic aneurysm, which has been described in patients with IgG4-related disease, suggesting that autoimmune mechanisms, known to be involved in the pathogenesis of visceral lesions in the disease, also played a role in the etiology of VBD in the present patient. In conclusion, we consider that the present case may represent VBD as a manifestation of IgG4-related disease.

    DOI: 10.1111/j.1440-1789.2011.01227.x

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  • Association of SNPs linked to increased expression of SLC1A1 with schizophrenia. 査読 国際誌

    Yasue Horiuchi, Syuhei Iida, Minori Koga, Hiroki Ishiguro, Yoshimi Iijima, Toshiya Inada, Yuichiro Watanabe, Toshiyuki Someya, Hiroshi Ujike, Nakao Iwata, Norio Ozaki, Hiroshi Kunugi, Mamoru Tochigi, Masanari Itokawa, Makoto Arai, Kazuhiro Niizato, Shuji Iritani, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki Nawa, Tadao Arinami

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics   159B ( 1 )   30 - 7   2012年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Glutamate is one of the key molecules involved in signal transduction in the brain, and dysfunction of glutamate signaling could be linked to schizophrenia. The SLC1A1 gene located at 9p24 encodes the glutamate transporter EAAT3/EAAC1. To investigate the association between the SLC1A1 gene and schizophrenia in the Japanese population, we genotyped 19 tagging single nucleotide polymorphisms (tagSNPs) in the SLC1A1 gene in 576 unrelated individuals with schizophrenia and 576 control subjects followed by replication in an independent case-control study of 1,344 individuals with schizophrenia and 1,344 control subjects. In addition, we determined the boundaries of the copy number variation (CNV) region in the first intron (Database of Genomic Variants, chr9:4516796-4520549) and directly genotyped the CNV because of significant deviation from the Hardy-Weinberg equilibrium. The CNV was not associated with schizophrenia. Four SNPs showed a possible association with schizophrenia in the screening subjects and the associations were replicated in the same direction (nominal allelic P < 0.05), and, among them, an association with rs7022369 was replicated even after Bonferroni correction (allelic nominal P = 5 × 10(-5) , allelic corrected P = 2.5 × 10(-4) , allelic odds ratio, 1.30; 95% CI: 1.14-1.47 in the combined subjects). Expression analysis quantified by the real-time quantitative polymerase chain reaction in the postmortem prefrontal cortex of 43 Japanese individuals with schizophrenia and 11 Japanese control subjects revealed increased SLC1A1 expression levels in individuals homozygous for the rs7022369 risk allele (P = 0.003). Our findings suggest the involvement of SLC1A1 in the pathogenesis of schizophrenia.

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  • 脳神経疾患の診断に必須な組織染色 査読

    柿田 明美

    新潟県臨床検査技師会誌   52 ( 1 )   2 - 5   2012年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Association of SNPs linked to increased expression of SLC1A1 with schizophrenia. 査読

    Horiuchi Y, Iida S, Koga M, Ishiguro H, Iijima Y, Inada T, Watanabe Y, Someya T, Ujike H, Iwata N, Ozaki N, Kunugi H, Tochigi M, Itokawa M, Arai M, Niizato K, Iritani S, Kakita A, Takahashi H, Nawa H, Arinami T

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics   159B ( 1 )   30 - 37   2012年1月

  • Difference in MSA Phenotype Distribution Between Populations: Genetics or Environment? 査読

    Tetsutaro Ozawa, Tamas Revesz, Dominic Paviour, Andrew J. Lees, Niall Quinn, Mari Tada, Akiyoshi Kakita, Osamu Onodera, Koichi Wakabayashi, Hitoshi Takahashi, Masatoyo Nishizawa, Janice L. Holton

    JOURNAL OF PARKINSONS DISEASE   2 ( 1 )   7 - 18   2012年

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    記述言語:英語   出版者・発行元:IOS PRESS  

    The reasons for the differences in emphasis on striatonigral or olivopontocerebellar involvement in multiple system atrophy (MSA) remain to be determined. Semi-quantitative pathological analyses carried out in the United Kingdom and Japan demonstrated that olivopontocerebellar-predominant pathology was more frequent in Japanese MSA than British MSA. This observation provides evidence for a difference in phenotype distribution between British and Japanese patients with definite MSA. Studies of the natural history and epidemiology of MSA carried out in various populations have revealed that the relative prevalences of clinical subtypes of MSA probably differ among populations; the majority of MSA patients diagnosed in Europe have predominant parkinsonism (MSA-P), while the majority of MSA patients diagnosed in Asia have predominant cerebellar ataxia (MSA-C). Although potential drawbacks to the published frequencies of clinical subtypes and pathological subtypes should be considered because of selection biases, the difference demonstrated in pathological subtype is also consistent with the differences in clinical subtype of MSA demonstrated between Europe and Asia. Modest alterations in susceptibility factors may contribute to the difference in MSA phenotype distribution between populations. Synergistic interactions between genetic risk variants and environmental toxins responsible for parkinsonism or cerebellar dysfunction should therefore be explored. Further investigations are needed to determine the environmental, genetic, and epigenetic factors that account for the differences in clinicopathological phenotype of MSA among different populations.

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  • Unmyelinated axons are more vulnerable to degeneration than myelinated axons of the cardiac nerve in Parkinson&apos;s disease 査読

    S. Orimo, T. Uchihara, T. Kanazawa, Y. Itoh, K. Wakabayashi, A. Kakita, H. Takahashi

    NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY   37 ( 7 )   791 - 802   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Aims: We recently demonstrated accumulation of alpha-synuclein aggregates of the cardiac sympathetic nerve in Parkinson&apos;s disease (PD) and a possible relationship between degeneration of the cardiac sympathetic nerve and alpha-synuclein aggregates. The aim of this study is to determine whether there is a difference in the degenerative process between unmyelinated and myelinated axons of the cardiac nerve. Methods: We immunohistochemically examined cardiac tissues from four pathologically verified PD patients, nine patients with incidental Lewy body disease (ILBD) and five control subjects, using antibodies against neurofilament, myelin basic protein (MBP) and alpha-synuclein. First, we counted the number of neurofilament-immunoreactive axons not surrounded by MBP (unmyelinated axons) and those surrounded by MBP (myelinated axons). Next, we counted the number of unmyelinated and myelinated axons with alpha-synuclein aggregates. Results: (i) The percentage of unmyelinated axons in PD (77.5 +/- 9.14%) was significantly lower compared to that in control subjects (92.2 +/- 2.40%). (ii) The ratio of unmyelinated axons with alpha-synuclein aggregates to total axons with a-synuclein aggregates in ILBD ranged from 94.4 to 100 (98.2 +/- 2.18%). Among axons with alpha-synuclein aggregates, unmyelinated axons were the overwhelming majority, comprising 98.2%. Conclusion: These findings suggest that in PD unmyelinated axons are more vulnerable to degeneration than myelinated axons of the cardiac nerve, because alpha-synuclein aggregates accumulate much more abundantly in unmyelinated axons.

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  • Immunohistochemical expression of fibroblast growth factor-2 in developing human cerebrum and epilepsy-associated malformations of cortical development 査読

    Manami Ueda, Chitose Sugiura, Kousaku Ohno, Akiyoshi Kakita, Akira Hori, Eisaku Ohama, Harry V. Vinters, Hajime Miyata

    NEUROPATHOLOGY   31 ( 6 )   589 - 598   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    To elucidate the biological significance of fibroblast growth factor-2 (FGF-2) expression in epilepsy-associated malformations of cortical development, immunohistochemical expression of FGF-2 was investigated in the developing human cerebral mantles obtained from 30 autopsy cases of fetuses, stillborn infants and children ranging from 12 weeks gestation to 15 years old, and 70 surgically-resected corticectomy specimens from patients with medically intractable epilepsy, including: group I, 12 tubers of tuberous sclerosis; group II, 24 cases of focal cortical dysplasia (FCD) with balloon cells (BC); group III, 11 FCD without BC; group IV, 23 histologically normal-appearing neocortices from patients with Rasmussen encephalitis, cystic-gliotic encephalopathy, temporal lobe epilepsy; and group V, 14 normal-appearing neocortices adjacent to dysplastic lesions from groups I and II. FGF-2 expression was detected in a population of matrix cells and/or neuroblasts within the ventricular zone in fetuses younger than 19 weeks gestation. Nuclei of glioblasts and immature astrocytes were also positive for FGF-2 in cases older than 18 weeks gestation. FGF-2 expression was not detected in immature cortical plate neurons. Astrocytes and ependymal cells were positive for FGF-2 in the postnatal brains. Choroid plexus epithelium was strongly positive for FGF-2 in all cases examined. Among the corticectomy specimens, the cytoplasms and/or nuclei of dysmorphic neurons (DNs) and BCs in groups I and II were variably positive for FGF-2. The proportions of FGF-2 immunoreactive cells (FGF-2-IR%) was significantly higher in groups I (36.9 +/- 9.6) and II (45.1 +/- 7.0) than in groups III (21.0 +/- 5.7), IV (14.4 +/- 4.7) and V (24.3 +/- 10.3), and that in group V was higher than in group IV (P &lt; 0.01). These results indicate that FGF-2 upregulation in DNs and BCs is an important feature common to groups I and II, and suggest that BCs and DNs in these groups represent disturbed gliogenesis from matrix cells and disturbed maturation of cortical neurons from migrating neuroblasts, respectively.

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  • Accumulation of histone deacetylase 6, an aggresome-related protein, is specific to Lewy bodies and glial cytoplasmic inclusions 査読

    Yasuo Miki, Fumiaki Mori, Kunikazu Tanji, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    NEUROPATHOLOGY   31 ( 6 )   561 - 568   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Histone deacetylase 6 (HDAC6) plays a crucial role in aggresome formation, resulting in the clearance of misfolded proteins. Previous studies have shown that HDAC6 is concentrated in Lewy bodies (LBs) in Parkinson's disease (PD) and dementia with LBs (DLB) (Cell 115: 727-738, 2003). We performed immunohistochemical and ultrastructural investigations on the brains of patients with various neurodegenerative disorders. Anti-HDAC6 antibody faintly immunostained the cytoplasm of neuronal and glial cells in control subjects. In PD and DLB, almost all of the cortical, brainstem-type and peripheral LBs were intensely immunolabeled with anti-HDAC6. In multiple system atrophy (MSA), the vast majority of glial cytoplasmic inclusions (GCIs) were also positive for HDAC6. Immunoelectron microscopy revealed that the reaction product was localized to the filamentous structures in LBs and GCIs. Various neuronal and glial inclusions in neurodegenerative disorders other than LB disease and MSA were HDAC6-negative. These findings suggest that accumulation of HDAC6 is specific to alpha-synucleinopathy and that both LBs and GCIs may represent cytoprotective responses to sequester toxic proteins.

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  • Routine aspiration method during filter-protected carotid stenting: histological evaluation of captured debris and predictors for debris amount 査読

    Takatoshi Sorimachi, Akiyoshi Kakita, Kenichi Morita, Kazuhiko Nishino, Osamu Sasaki, Tetsuo Koike, Takashi Kumagai, Yasushi Ito, Yukihiko Fujii

    ACTA NEUROCHIRURGICA   153 ( 11 )   2159 - 2167   2011年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER WIEN  

    A routine aspiration method in filter-protected carotid artery stenting (CAS) has been reported recently in which the proximal internal carotid artery (ICA) blood column was aspirated using an aspiration catheter after postdilatation regardless of flow state on digital subtraction angiography. We examined the debris particles captured by this method.
    The routine aspiration method was used in 71 CAS procedures. In two procedures, captured debris particles were examined histologically. In the remaining 69 procedures, the size and number of debris particles were measured under a stereoscopic microscope, and then relationships between the amount of debris particles and clinical variables were evaluated using multivariate regression analysis.
    Histologically, the captured debris contained platelet-precipitating, thrombotic, lipid-rich fibrous and calcified material. The number of debris particles a parts per thousand yen1 mm was 19.6 +/- 12.1 (mean +/- SD) in 60 procedures with normal flow and 25.9 +/- 17.2 (mean +/- SD) in 9 procedures with slow/stop flow. Multivariate regression analysis demonstrated that extension of a proximal ICA angulation was an independent predictor of the amount of debris particles with a maximum diameter of either a parts per thousand yen1 mm or &lt; 1 mm but a parts per thousand yen0.5 mm (p &lt; 0.05).
    The captured debris appeared to originate from atheromatous plaques. If the routine aspiration method had not been used in the present series, the debris might have migrated into intracerebral arteries. Restriction of the extension of a proximal ICA angulation might reduce the amount of debris associated with CAS, especially when the proximal ICA angulation is pronounced.

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  • Hypertrophy of hippocampal end folium neurons in patients with mesial temporal lobe epilepsy 査読

    Masae Ryufuku, Yasuko Toyoshima, Hiroki Kitaura, Yingjun Zheng, Yong-Juan Fu, Hiroaki Miyahara, Hiroatsu Murakami, Hiroshi Masuda, Shigeki Kameyama, Hitoshi Takahashi, Akiyoshi Kakita

    NEUROPATHOLOGY   31 ( 5 )   476 - 485   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Hypertrophic and dysmorphic neurons have been identified in the hippocampal end folium of patients with mesial temporal lobe epilepsy (mTLE). No data are available regarding the correlation between these cellular alterations and the severity of hippocampal sclerosis (HS), and the significance of this phenomenon has been unclear. We evaluated both the perikaryon and nuclear areas of residual neurons in the hippocampal end folium of 47 patients with mTLE, seven with lesional neocortical temporal lobe epilepsy (LTLE), and 10 controls without seizure episodes. According to the severity of neuron loss in the end folium, we defined mTLE cases showing slight (&lt;10%) or no, moderate (10-50%) and severe (&gt;50%) loss as groups A, B and C, respectively. We also performed immunohistochemistry with antibodies against heat shock protein 70 and the phosphorylated epitope of neurofilament. In both mTLE and LTLE cases, the perikaryon and nuclear areas of the end folium neurons were significantly greater than those in the controls (P&lt;0.0001), and those in mTLE were significantly greater than those in LTLE. There were no differences in areas between groups A and B, but the areas in group C were significantly greater than those of both groups A and B. Neurons with large, bizarre morphology were labeled with both antibodies. Neuronal hypertrophy is evident in patients with epilepsy, and appears to advance gradually as the hippocampal sclerosis becomes more severe. This alteration may be a consequence of cellular stress incurred by neurons.

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  • Synphilin-1-binding protein NUB1 is colocalized with nonfibrillar, proteinase K-resistant α-synuclein in presynapses in Lewy body disease. 査読

    Tanji K, Mori F, Kito K, Kakita A, Mimura J, Itoh K, Takahashi H, Kamitani T, Wakabayashi K

    Journal of neuropathology and experimental neurology   70 ( 10 )   879 - 889   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Induction of autophagy in temozolomide treated malignant gliomas 査読

    Manabu Natsumeda, Hiroshi Aoki, Hiroaki Miyahara, Naoki Yajima, Takeo Uzuka, Yasuko Toyoshima, Akiyoshi Kakita, Hitoshi Takahashi, Yukihiko Fujii

    NEUROPATHOLOGY   31 ( 5 )   486 - 493   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Autophagy is a dynamic process of protein degradation. Induction of autophagy by temozolomide (TMZ) has been noted in glioma cell lines. Twenty-eight specimens, obtained from 14 patients before and after TMZ treatment, were analyzed to investigate whether induction of autophagy could be detected in surgical specimens by immunohistochemical analysis. Macroautophagy was monitored by immunohistochemical analysis employing anti-light chain 3 isoform B (LC3B) and anti-lysosome-associated membrane protein 1 (LAMP1) antibodies; chaperone-mediated autophagy was monitored by anti-LAMP2A antibody immunostaining. Furthermore, detection of LC3B protein by Western blotting was performed on six specimens obtained from the preserved frozen tissues of three patients. All specimens showed dot-like staining for each immunostain in the cytoplasm of glioma cells, indicating induction of autophagy. LC3B, LAMP1 and LAMP2A immunostains were semiquantitatively scored from 1 to 3 points. Combination of the three scores after TMZ treatment (6.4 +/- 1.2) showed a significant increase (P = 0.020) compared to pre-treatment scores (5.2 +/- 1.5). Western blotting for LC3B showed increased LC3B-I and LC3B-II expression after TMZ treatment. The present study proved that autophagy monitoring by immunohistochemical staining of surgical specimens was feasible. These results suggest that autophagy is induced by TMZ.

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  • Spatiotemporal dynamics of epileptiform propagations: Imaging of human brain slices

    Hiroki Kitaura, Tetsuya Hiraishi, Hiroatsu Murakami, Hiroshi Masuda, Masafumi Fukuda, Makoto Oishi, Masae Ryufuku, Yong-Juan Fu, Hitoshi Takahashi, Shigeki Kameyama, Yukihiko Fujii, Katsuei Shibuki, Akiyoshi Kakita

    NeuroImage   58 ( 1 )   50 - 59   2011年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Seizure activities often originate from a localized region of the cerebral cortex and spread across large areas of the brain. The properties of these spreading abnormal discharges may account for clinical phenotypes in epilepsy patients, although the manner of their propagation and the underlying mechanisms are not well understood. In the present study we performed flavoprotein fluorescence imaging of cortical brain slices surgically resected from patients with partial epilepsy caused by various symptomatic lesions. Elicited neural activities in the epileptogenic tissue spread horizontally over the cortex momentarily, but those in control tissue taken from patients with brain tumors who had no history of epilepsy demonstrated only localized responses. Characteristically, the epileptiform propagation comprised early and late phases. When the stimulus intensity was changed gradually, the early phase showed an all-or-none behavior, whereas the late phase showed a gradual increase in the response. Moreover, the two phases were propagated through different cortical layers, suggesting that they are derived from distinct neural circuits. Morphological investigation revealed the presence of hypertrophic neurons and loss of dendritic spines, which might participate in the aberrant activities observed by flavoprotein fluorescence imaging. These findings indicate that synchronized activities of the early phase may play a key role in spreading abnormal discharges in human cortical epilepsies. © 2011 Elsevier Inc.

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  • Spatiotemporal dynamics of epileptiform propagations: Imaging of human brain slices 査読

    Hiroki Kitaura, Tetsuya Hiraishi, Hiroatsu Murakami, Hiroshi Masuda, Masafumi Fukuda, Makoto Oishi, Masae Ryufuku, Yong-Juan Fu, Hitoshi Takahashi, Shigeki Kameyama, Yukihiko Fujii, Katsuei Shibuki, Akiyoshi Kakita

    NEUROIMAGE   58 ( 1 )   50 - 59   2011年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Seizure activities often originate from a localized region of the cerebral cortex and spread across large areas of the brain. The properties of these spreading abnormal discharges may account for clinical phenotypes in epilepsy patients, although the manner of their propagation and the underlying mechanisms are not well understood. In the present study we performed flavoprotein fluorescence imaging of cortical brain slices surgically resected from patients with partial epilepsy caused by various symptomatic lesions. Elicited neural activities in the epileptogenic tissue spread horizontally over the cortex momentarily, but those in control tissue taken from patients with brain tumors who had no history of epilepsy demonstrated only localized responses. Characteristically, the epileptiform propagation comprised early and late phases. When the stimulus intensity was changed gradually, the early phase showed an all-or-none behavior, whereas the late phase showed a gradual increase in the response. Moreover, the two phases were propagated through different cortical layers, suggesting that they are derived from distinct neural circuits. Morphological investigation revealed the presence of hypertrophic neurons and loss of dendritic spines, which might participate in the aberrant activities observed by flavoprotein fluorescence imaging. These findings indicate that synchronized activities of the early phase may play a key role in spreading abnormal discharges in human cortical epilepsies. (C) 2011 Elsevier Inc. All rights reserved.

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  • Spinocerebellar ataxia type 2 (SCA2) is associated with TDP-43 pathology 査読

    Yasuko Toyoshima, Hajime Tanaka, Mitsuteru Shimohata, Kakuhei Kimura, Takashi Morita, Akiyoshi Kakita, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA   122 ( 3 )   375 - 378   2011年9月

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    記述言語:英語   出版者・発行元:SPRINGER  

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  • Alteration of autophagosomal proteins (LC3, GABARAP and GATE-16) in Lewy body disease 査読

    Kunikazu Tanji, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    NEUROBIOLOGY OF DISEASE   43 ( 3 )   690 - 697   2011年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Macroautophagy is a dynamic process whereby cytoplasmic molecules are sequestered within autophagosomes. Based on amino acid similarity, there exist two groups of mammalian autophagy-related gene (Atg) 8 homologues [microtubule-associated protein 1 light chain 3 (LC3) and gamma-aminobutyric-acid type A receptor associated proteins (GABARAPs)], which play essential role in autophagosomal formation. Despite recent progress in studies on LC3, the other Atg8 homologues remain to be poorly understood, especially in pathological condition. In this study, we determined whether Atg8 homologues are affected in Lewy body disease, including Parkinson&apos;s disease (PD) and dementia with Lewy bodies (DLB). Our findings indicated that biochemical and pathological properties of LC3 were altered and that the level of LC3 was increased in an insoluble fraction from the brain of patients with DLB, whereas the level of GABARAPs was decreased in DLB. Furthermore, immunohistochemical staining revealed that both LC3 and GABARAPs were localized in Lewy bodies in PD and DLB. These findings suggest that autophagic function is impaired through alteration of Atg8 homologues in Lewy body disease. (C) 2011 Elsevier Inc. All rights reserved.

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  • Enhancement of native and phosphorylated TDP-43 immunoreactivity by proteinase K treatment following autoclave heating 査読

    Fumiaki Mori, Kunikazu Tanji, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    NEUROPATHOLOGY   31 ( 4 )   401 - 404   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    TDP-43 is a major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). To evaluate the effectiveness of proteinase K (PK) treatment in antigen retrieval for native and phosphorylated TDP-43 protein, we examined the temporal cortex and spinal cord from patients with sporadic ALS and FTLD-TDP and control subjects. PK treatment following heat retrieval enhanced the immunoreactivity for native TDP-43 in controls as well as for native and phosphorylated TDP-43 in ALS and FTLD-TDP. A significant number of TDP-43-positive neuropil threads were demonstrated in lesions, in which routine immunohistochemistry revealed that the predominant inclusions are cytoplasmic. This retrieval method is the best of immunohistochemical techniques for demonstrating TDP-43 pathology, especially in the neuropil.

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  • Prenatal Stress Inhibits Neuronal Maturation through Downregulation of Mineralocorticoid Receptors 査読

    Makoto Tamura, Mari Sajo, Akiyoshi Kakita, Norio Matsuki, Ryuta Koyama

    JOURNAL OF NEUROSCIENCE   31 ( 32 )   11505 - 11514   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Prenatal stress (PS) increases the risk of depressive disorders in adult offspring. The pathophysiology of depressive disorders has been linked to hippocampal dysfunction; however, whether and how PS attenuates the development and function of hippocampal networks remains unknown. Using a rat model of PS, in which pregnant mothers receive daily restraint stress during late gestation and their offspring exhibit depressive-like behavior later in life, we show that PS impairs the morphological and functional maturation of hippocampal granule cells in adult offspring via the downregulated expression of mineralocorticoid receptors. PS reduced the dendritic complexity and spine density of neonatal-generated granule cells, which persists into adulthood. These granule cells exhibited depressed synaptic responses to stimulation of the medial perforant path. We further revealed that the expression of mineralocorticoid receptors, which we found is necessary for proper dendritic maturation in this study, was significantly downregulated in granule cells after PS. These results suggest that PS-induced downregulation of mineralocorticoid receptors attenuates neuronal maturation, which results in dysfunction of neuronal network in adulthood.

    DOI: 10.1523/JNEUROSCI.3447-10.2011

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  • Indication of intraoperative immunohistochemistry for accurate pathological diagnosis of brain tumors 査読

    Takeo Uzuka, Hiroshi Aoki, Manabu Natsumeda, Akiyoshi Kakita, Hitoshi Takahashi, Yukihiko Fujii

    BRAIN TUMOR PATHOLOGY   28 ( 3 )   239 - 246   2011年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER TOKYO  

    Immunohistochemical staining is important for histological diagnosis of brain tumors; however, its intraoperative application has rarely been reported. Herein, we describe our methods and four successfully diagnosed cases. Between January 2008 and April 2010, intraoperative immunohistochemical analysis was performed in 43 patients undergoing brain tumor surgery at our institute. The time for rapid histological diagnosis was 70 min. MIB-1 immunostaining was performed; staining index (SI) was 0.8-76.2% (median, 2.5%) in rapid diagnoses and 0.6-83.9% (median, 7.7%) in permanent diagnoses. There was no discrepancy in low- or high-grade tumors between intraoperative and final pathological diagnosis. The antibodies used for staining were MIB-1 in all cases, L26 in 8 cases, UCHL-1 in 6 cases, GFAP in 4 cases, AFP in 3 cases, and PLAP in 5 cases. The staining patterns were similar between rapid and permanent diagnoses. We think that immunohistochemical examination is indicated under the following conditions: (1) preoperative radiologic differential diagnosis includes both high- and low-grade tumors, (2) intraoperative assessment is necessary to determine the extent of excision, and (3) quick and accurate pathological diagnosis is necessary for early initiation of treatment after surgery.

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  • Inhibition of VEGF signaling pathway attenuates hemorrhage after tPA treatment 査読

    Masato Kanazawa, Hironaka Igarashi, Kunio Kawamura, Tetsuya Takahashi, Akiyoshi Kakita, Hitoshi Takahashi, Tsutomu Nakada, Masatoyo Nishizawa, Takayoshi Shimohata

    JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM   31 ( 6 )   1461 - 1474   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    An angiogenic factor, vascular endothelial growth factor (VEGF), might be associated with the blood-brain barrier (BBB) disruption after focal cerebral ischemia; however, it remains unknown whether hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment is related to the activation of VEGF signaling pathway in BBB. Here, we hypothesized that inhibition of VEGF signaling pathway can attenuate HT after tPA treatment. Rats subjected to thromboembolic focal cerebral ischemia were assigned to a permanent ischemia group and groups treated with tPA at 1 or 4 hours after ischemia. Anti-VEGF neutralizing antibody or control antibody was administered simultaneously with tPA. At 24 hours after ischemia, we evaluated the effects of the antibody on the VEGF expression, matrix metalloproteinase-9 (MMP-9) activation, degradation of BBB components, and HT. Delayed tPA treatment at 4 hours after ischemia promoted expression of VEGF in BBB, MMP-9 activation, degradation of BBB components, and HT. Compared with tPA and control antibody, combination treatment with tPA and the anti-VEGF neutralizing antibody significantly attenuated VEGF expression in BBB, MMP-9 activation, degradation of BBB components, and HT. It also improved motor outcome and mortality. Inhibition of VEGF signaling pathway may be a promising therapeutic strategy for attenuating HT after tPA treatment. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1461-1474; doi:10.1038/jcbfm.2011.9; published online 9 February 2011

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  • 脱髄・髄鞘障害性疾患 査読

    柿田 明美

    第7回 神経病理コアカリキュラム教育セミナー ハンドアウト   77 - 85   2011年6月

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    記述言語:日本語   掲載種別:研究論文(研究会,シンポジウム資料等)  

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  • Anaplastic astrocytoma with angiocentric ependymal differentiation 査読

    Hiroaki Miyahara, Yasuko Toyoshima, Manabu Natsumeda, Takeo Uzuka, Hiroshi Aoki, Yoko Nakayama, Kouichiou Okamoto, Yukihiko Fujii, Akiyoshi Kakita, Hitoshi Takahashi

    NEUROPATHOLOGY   31 ( 3 )   292 - 298   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Angiocentric glioma (AG) is an epileptogenic benign cerebral tumor primarily affecting children and young adults, and characterized histopathologically by an angiocentric pattern of growth of monomorphous bipolar cells with features of ependymal differentiation (WHO grade I). We report an unusual cerebral glial tumor in a 66-year-old woman with generalized tonic-clonic seizure; the patient also had a 6-year history of headache. On MRI, the tumor appeared as a large T2-hyperintense lesion involving the right insular gyri-anterior temporal lobe, with post-contrast enhancement in the insula region. Histopathologically, the tumor involving the insular cortex-subcortical white matter was composed of GFAP-positive glial cells showing two different morphologies: one type had monomorphous bipolar cytoplasm and was angiocentric with circumferential alignment to the blood vessels, with dot-like structures positive for epithelial membrane antigen and a Ki-67 labeling index of &lt; 1%, and the other was apparently astrocytic, being diffusely and more widely distributed in the parenchyma, showing mitoses and a Ki-67 labeling index of &gt; 5%. In the anterior temporal lobe, a diffuse increase in the number of astrocytic cells was evident in part of the cortex and subcortical white matter. On the basis of these findings, we considered whether the present tumor may represent an unusual example of AG with infiltrating astrocytic cells showing primary anaplastic features (AG with anaplastic features), or anaplastic astrocytoma showing primary vascular-associated ependymal differentiation (anaplastic astrocytoma with angiocentric ependymal differentiation). At present, the latter appears to be the more appropriate interpretation.

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  • Microglial Cystatin F Expression Is a Sensitive Indicator for Ongoing Demyelination With Concurrent Remyelination 査読

    Jianmei Ma, Kenji F. Tanaka, Takahiro Shimizu, Claude C. A. Bernard, Akiyoshi Kakita, Hitoshi Takahashi, Steven E. Pfeiffer, Kazuhiro Ikenaka

    JOURNAL OF NEUROSCIENCE RESEARCH   89 ( 5 )   639 - 649   2011年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Demyelination coincides with numerous changes of gene expression in the central nervous system (CNS). Cystatin F, which is a papain-like lysosomal cysteine proteinase inhibitor that is normally expressed by immune cells and not in the brain, is massively induced in the CNS during acute demyelination. We found that microglia, which are monocyte/macrophage-lineage cells in the CNS, express cystatin F only during demyelination. By using several demyelinating animal models and the spinal cord tissues from multiple sclerosis (MS) patients, we examined spatiotemporal expression pattern of cystatin F by in situ hybridization and immunohistochemistry. We found that the timing of cystatin F induction matches with ongoing demyelination, and the places with cystatin F expression overlapped with the remyelinating area. Most interestingly, cystatin F induction ceased in chronic demyelination, in which remyelinating ability was lost. These findings demonstrate that the expression of cystatin F indicates the occurrence of ongoing demyelination/remyelination and the absence of cystatin F expression indicates the cessation of remyelination in the demyelinating area. (C) 2011 Wiley-Liss, Inc.

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  • Biochemical and histopathological alterations in TAR DNA-binding protein-43 after acute ischemic stroke in rats 査読

    Masato Kanazawa, Akiyoshi Kakita, Hironaka Igarashi, Tetsuya Takahashi, Kunio Kawamura, Hitoshi Takahashi, Tsutomu Nakada, Masatoyo Nishizawa, Takayoshi Shimohata

    JOURNAL OF NEUROCHEMISTRY   116 ( 6 )   957 - 965   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    P&gt;Nuclear factor TAR DNA-binding protein-43 (TDP-43) is considered to play roles in pathogenesis of human neurodegenerative diseases, so-called TDP-43 proteinopathy, via its proteolytic cleavage, abnormal phosphorylation, subcellular redistribution, and insolubilization generating TDP-43-positive neuronal intracellular inclusions. The purpose of this study was to elucidate biochemical and histopathological alternations in TDP-43 specific to acute ischemic stroke. Adult male rats were subjected to a 90-min middle cerebral artery occlusion. We examined the proteolytic cleavage, phosphorylation, subcellular localization, and solubility of TDP-43 by immunoblottings and histopathological examinations using the ischemic and sham-operated cortex. The level of full-length TDP-43 (43 kDa) decreased and that of the 25-kDa C-terminal fragment increased after acute ischemic stroke, which can be explained by proteolytic cleavage of TDP-43. Cytoplasmic redistribution and altered nuclear distribution of TDP-43 was observed after acute ischemic stroke, whereas abnormal phosphorylation and insolubilization of TDP-43 as well as formation of intracellular inclusions were not observed. Ischemic neurons with the cytoplasmic redistribution of TDP-43 expressed ubiquitin and activated caspase 3 and were terminal deoxynucleotidyl transferase-mediated uridine 5&apos;-triphosphate-biotin nick end labeling-positive. In conclusion, biochemical and histopathological alterations in TDP-43 were identified in rats after acute ischemic stroke, although there was very less similarity between TDP-43 alterations observed in acute ischemic stroke and those observed in TDP-43 proteinopathy.

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  • Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: Implication in neurodevelopmental hypothesis for schizophrenia 査読

    T. Kato, Y. Abe, H. Sotoyama, A. Kakita, R. Kominami, S. Hirokawa, M. Ozaki, H. Takahashi, H. Nawa

    Molecular Psychiatry   16 ( 3 )   307 - 320   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuregulin-1 (NRG1) is implicated in the etiology or pathology of schizophrenia, although its biological roles in this illness are not fully understood. Human midbrain dopaminergic neurons highly express NRG1 receptors (ErbB4). To test its neuropathological role in the neurodevelopmental hypothesis of schizophrenia, we administered type-1 NRG1 protein to neonatal mice and evaluated the immediate and subsequent effects on dopaminergic neurons and their associated behaviors. Peripheral NRG1 administration activated midbrain ErbB4 and elevated the expression, phosphorylation and enzyme activity of tyrosine hydroxylase (TH), which ultimately increased dopamine levels. The hyperdopaminergic state was sustained in the medial prefrontal cortex after puberty. There were marked increases in dopaminergic terminals and TH levels. In agreement, higher amounts of dopamine were released from this brain region of NRG1-treated mice following high potassium stimulation. Furthermore, NRG1-treated mice exhibited behavioral impairments in prepulse inhibition, latent inhibition, social behaviors and hypersensitivity to methamphetamine. However, there were no gross abnormalities in brain structures or other phenotypic features of neurons and glial cells. Collectively, our findings provide novel insights into neurotrophic contribution of NRG1 to dopaminergic maldevelopment and schizophrenia pathogenesis. © 2011 Macmillan Publishers Limited.

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  • Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia 査読

    T. Kato, Y. Abe, H. Sotoyama, A. Kakita, R. Kominami, S. Hirokawa, M. Ozaki, H. Takahashi, H. Nawa

    MOLECULAR PSYCHIATRY   16 ( 3 )   307 - 320   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Neuregulin-1 (NRG1) is implicated in the etiology or pathology of schizophrenia, although its biological roles in this illness are not fully understood. Human midbrain dopaminergic neurons highly express NRG1 receptors (ErbB4). To test its neuropathological role in the neurodevelopmental hypothesis of schizophrenia, we administered type-1 NRG1 protein to neonatal mice and evaluated the immediate and subsequent effects on dopaminergic neurons and their associated behaviors. Peripheral NRG1 administration activated midbrain ErbB4 and elevated the expression, phosphorylation and enzyme activity of tyrosine hydroxylase (TH), which ultimately increased dopamine levels. The hyperdopaminergic state was sustained in the medial prefrontal cortex after puberty. There were marked increases in dopaminergic terminals and TH levels. In agreement, higher amounts of dopamine were released from this brain region of NRG1-treated mice following high potassium stimulation. Furthermore, NRG1-treated mice exhibited behavioral impairments in prepulse inhibition, latent inhibition, social behaviors and hypersensitivity to methamphetamine. However, there were no gross abnormalities in brain structures or other phenotypic features of neurons and glial cells. Collectively, our findings provide novel insights into neurotrophic contribution of NRG1 to dopaminergic maldevelopment and schizophrenia pathogenesis. Molecular Psychiatry (2011) 16, 307-320; doi:10.1038/mp.2010.10; published online 9 February 2010

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  • Inhibition of VEGF Signaling Pathway Attenuates Hemorrhagic Transformation after tPA Treatment 査読

    Takayoshi Shimohata, Niigata Japan, Masato Kanazawa, Hironaka Igarashi, Tetsuya Takahashi, Kunio Kawamura, Akiyoshi Kakita, Hitoshi Takahashi, Tsutomu Nakada, Masatoyo Nishizawa

    NEUROLOGY   76 ( 9 )   A447 - A448   2011年3月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Survival motor neuron (SMN) protein in the spinal anterior horn cells of patients with sporadic amyotrophic lateral sclerosis 査読

    Yingshan Piao, Tomoyo Hashimoto, Sachiko Takahama, Akiyoshi Kakita, Takashi Komori, Takashi Morita, Hitoshi Takahashi, Toshio Mizutani, Kiyomitsu Oyanagi

    BRAIN RESEARCH   1372   152 - 159   2011年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving mainly the upper and lower motor neurons of adult humans. With regard to the pathomechanism of spinal anterior horn cell (AHC) degeneration in ALS, copy number abnormalities of the survival motor neuron (SMN) genes have been reported in sporadic (s) ALS. SMN protein is the protein responsible for the pathogenesis of spinal muscular atrophy (SMA), an autosomal recessive disease characterized by lower motor neuron loss and muscle atrophy. The disease is caused by deficiency of SMN protein induced by mutation of one of the SMA-associated genes, SMN1. To clarify the role of SMN protein in the degeneration of spinal AHCs in sALS, we examined the amount of cytoplasmic SMN protein in individual AHCs using cytofluorophotometry in 9 patients with sALS and 10 control subjects. It was found that: 1) SMN protein was present in the cytoplasm, nucleus and nucleolus of AHCs and in the nucleus of glial cells, 2) expression of SMN protein in AHCs was significantly associated with cell size in both sALS patients and controls, 3) expression of SMN protein per unit area in AHCs was similar in sALS patients and controls. These findings suggest that: 1) the amount of SMN protein in the cytoplasm of AHCs is strictly controlled in accordance with cell size, in both sALS patients and controls, 2) the amount of SMN protein in the AHCs of sALS patients may be reduced when the AHCs are atrophic, and 3) decrease of SMN protein in the AHCs of sALS patients may be a secondary, and not primary, phenomenon according to their sizes. (C) 2010 Elsevier B.V. All rights reserved.

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  • Balloon cells in the dentate gyrus in hippocampal sclerosis associated with non-herpetic acute limbic encephalitis 査読

    Hiroaki Miyahara, Masae Ryufuku, Yong-Juan Fu, Hiroki Kitaura, Hiroatsu Murakami, Hiroshi Masuda, Shigeki Kameyama, Hitoshi Takahashi, Akiyoshi Kakita

    SEIZURE-EUROPEAN JOURNAL OF EPILEPSY   20 ( 1 )   87 - 89   2011年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO LTD  

    The presence of balloon cells, a pathognomonic cellular feature of focal cortical dysplasia type BB, in a background of hippocampal sclerosis is rare. Here we report the surgical pathologic features of the hippocampus resected from a 32-year-old woman with mesial temporal lobe epilepsy and a precipitating history of non-herpetic acute limbic encephalitis. Histologically, the resected specimen showed features of hippocampal sclerosis with granule cell dispersion. Characteristically, many balloon cells, immunoreactive for nestin, vimentin, glial fibrillary acidic protein (GFAP), GFAP-delta and CD34, were observed in the molecular and granule cell layers of the dentate gyrus. In the present case hippocampal sclerosis was an apparently acquired alteration, rather than a result of maldevelopment. The appearance of balloon cells raises questions regarding their origin and morphogenesis. (C) 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.seizure.2010.09.013

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  • てんかん原性病巣における細胞内情報伝達経路関連蛋白の発現解析 査読

    柿田明美, 鄭 英君, 龍福雅恵, 北浦弘樹, 村上博淳, 増田 浩, 亀山茂樹, 高橋 均, 武井延之

    てんかん治療研究振興財団研究年報 2011   22   31 - 38   2011年

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    記述言語:日本語   掲載種別:研究論文(大学,研究機関等紀要)  

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  • 急性脳虚血によるTDP-43の生化学的・組織学的変化の検討 査読

    下畑亨良, 金澤雅人, 柿田明美, 五十嵐博中, 高橋哲哉, 川村邦雄, 高橋 均, 中田 力, 西澤正豊

    脳循環代謝   22 ( 2 )   40 - 45   2011年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Widespread ischemic brain lesions caused by vasculopathy associated with neurofibromatosis type 1 査読

    Kenichi Okazaki, Akiyoshi Kakita, Hajime Tanaka, Kakuhei Kimura, Makoto Minagawa, Takashi Morita, Hitoshi Takahashi

    NEUROPATHOLOGY   30 ( 6 )   627 - 633   2010年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    We report the autopsy findings of a 63-year-old man with neurofibromatosis type 1 (NF1), in whom widespread ischemic brain lesions caused by vasculopathy associated with the disorder were observed. The patient, who had cafe au lait macules, axillary freckling, and neurofibromas, was inarticulate of speech, had difficulty in maintaining a sitting position, and was hyporeactive at the age of 57 years. He then developed autonomic dysfunction, followed by consciousness disturbance and status epilepticus. Repeated MRI studies disclosed multiple, ill-defined lesions in the brain and progressive cerebral atrophy. The histopathological features of the lesions were those of ischemia that had occurred with spatiotemporal variability in the brain. Characteristically, many arteries in the subarachnoid space manifested accumulation of cells in the intimal layer: this hyperplasia had resulted in narrowing and occlusion of the lumen. Immunoblotting demonstrated a marked decrease of neurofibromin, the NF1 product, which is known to act as a functional molecule in the normal process of vascular maintenance and repair. This case provides useful information about the pathomechanisms underlying central nervous system manifestations in patients with NF1.

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  • The phenotype spectrum of Japanese multiple system atrophy 査読

    T. Ozawa, M. Tada, A. Kakita, O. Onodera, M. Tada, T. Ishihara, T. Morita, T. Shimohata, K. Wakabayashi, H. Takahashi, M. Nishizawa

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY   81 ( 11 )   1253 - 1255   2010年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:B M J PUBLISHING GROUP  

    Objective This study aimed to determine the spectrum of pathological involvement of the striatonigral (StrN) and olivopontocerebellar (OPC) systems in Japanese patients with multiple system atrophy (MSA). This study also aimed to compare the pathological spectrum of Japanese MSA patients with the previously reported results in British MSA patients.
    Methods A semiquantitative pathological analysis of 50 MSA patients&apos; brains that were referred to the Brain Research Institute, Niigata University, Japan, was performed. The severity of neuronal cell loss was determined as previously described by the study from the Queen Square Brain Bank (QSBB), UK.
    Results The mean neuronal cell loss score was significantly higher in the OPC area than in the basal ganglia sites examined, except the dorsolateral putamen. The relative prevalence of pathological phenotypes showed that 40% of cases had OPC-predominant pathology, 18% had StrN-predominant pathology and the remaining (42%) had equivalent StrN and OPC pathology. None of the MSA cases had coexistent Lewy bodies in the dorsal motor nucleus of the vagus and the substantia nigra.
    Conclusions In contrast to the previously reported results involving British patients&apos; brains from the QSBB (OPC-predominant pathology 17%, StrN-predominant pathology 34%, equivalent StrN and OPC pathology 49%), the results of the present study showed more pathological involvement of the OPC system than of the StrN system. The rarity of Lewy bodies may underlie the phenotypic expression of Japanese MSA. The present observations reflect the disequilibrium in the phenotype distribution between the two populations.

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  • TDP-43/ALSの臨床と病理 査読

    小野寺理, 横関明男, 譚 春鳳, 石原智彦, 西平 靖, 豊島靖子, 柿田明美, 西澤正豊, 高橋 均

    臨床神経   50 ( 11 )   940 - 942   2010年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.5692/clinicalneurol.50.940

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  • [FTLD/ALS as TDP-43 proteinopathies]. 査読

    Ishihara T, Ariizumi Y, Shiga A, Yokoseki A, Sato T, Toyoshima Y, Kakita A, Takahashi H, Nishizawa M, Onodera O

    Rinsho shinkeigaku = Clinical neurology   50 ( 11 )   1022 - 1024   2010年11月

  • てんかん焦点の外科病理2 査読

    柿田 明美

    Epilepsy   4 ( 2 )   80 - 83   2010年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • TDP-43プロテイノパチーとしてのFTLD/ALS 査読

    石原智彦, 有泉優子, 志賀 篤, 横関明男, 佐藤達哉, 豊島靖子, 柿田明美, 高橋 均, 西澤正豊, 小野寺理

    臨床神経   50 ( 11 )   1022 - 1024   2010年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.5692/clinicalneurol.50.1022

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  • [Human brain resource--experience at the Brain Research Institute,University of Niigata]. 査読

    Kakita A, Takahashi H

    Brain and nerve = Shinkei kenkyu no shinpo   62 ( 10 )   1019 - 1024   2010年10月

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  • ブレインリソースの現状.―新潟大学脳研究所のとりくみ 査読

    柿田明美, 高橋 均

    Brain Nerve   62 ( 10 )   1019 - 1024   2010年10月

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  • Foix-Alajouanine症候群の病理 査読

    松尾宏俊, 柿田明美, 高橋 均

    神経内科   73 ( 3 )   246 - 250   2010年9月

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  • Proteinase K-resistant alpha-synuclein is deposited in presynapses in human Lewy body disease and A53T alpha-synuclein transgenic mice 査読

    Kunikazu Tanji, Fumiaki Mori, Junsei Mimura, Ken Itoh, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    ACTA NEUROPATHOLOGICA   120 ( 2 )   145 - 154   2010年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Abnormally modified alpha-synuclein is a pathological hallmark of Parkinson&apos;s disease and the other alpha-synucleinopathies. Since proteinase K (PK) treatment is known to enhance the immunoreactivity of abnormal alpha-synuclein, we immunohistochemically examined the brain of transgenic (Tg) mice expressing human mutant A53T alpha-synuclein using this retrieval method. PK treatment abolished the immunoreactivity of alpha-synuclein in abnormal inclusions as well as of endogenous alpha-synuclein in Tg mice, whereas PK-resistant alpha-synuclein was found in the presynaptic nerve terminals, especially in the hippocampus and temporal cortex. In human Lewy body disease, PK-resistant alpha-synuclein was deposited in Lewy bodies and Lewy neurites, as well as in the presynapses in distinct brain regions, including the hippocampus, temporal cortex and substantia nigra. Biochemical analysis revealed that PK-resistant alpha-synuclein was detected in the presynaptic fraction in Tg mice and human Lewy body disease. Although PK-resistant alpha-synuclein was found in the presynapse in Tg mice even at 1 week of age, it was not phosphorylated until at least 8 months of age. Moreover, PK-resistant alpha-synuclein in the presynapse was not phosphorylated in human Lewy body disease. These findings suggest that phosphorylation is not necessary to cause the conversion of soluble form to PK-resistant alpha-synuclein. Considering that native alpha-synuclein is a soluble protein localized to the presynaptic terminals, our findings suggest that PK-resistant alpha-synuclein may disturb the neurotransmission in alpha-synucleinopathies.

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  • Renal sclerosing peritubular nodules in a patient with neurofibromatosis type 2: A case report with immunohistochemical and electron microscopic studies. 査読

    Morita T, Kimura K, Kakita A

    Human pathology   41 ( 7 )   1051 - 2; author reply 1052   2010年7月

  • Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity 査読

    Yong-Juan Fu, Yasushi Nishihira, Shigetoshi Kuroda, Yasuko Toyoshima, Tomohiko Ishihara, Makoto Shinozaki, Akinori Miyashita, Yue-Shan Piao, Chun-Feng Tan, Takashi Tani, Ryoko Koike, Keisuke Iwanaga, Mitsuhiro Tsujihata, Osamu Onodera, Ryozo Kuwano, Masatoyo Nishizawa, Akiyoshi Kakita, Takeshi Ikeuchi, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA   120 ( 1 )   21 - 32   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Tau is the pathological protein in several neurodegenerative disorders classified as frontotemporal lobar degeneration (FTLD), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). We report an unusual tauopathy in three Japanese patients presenting with Parkinsonism and motor neuron disease (neuroimaging revealed frontotemporal cerebral atrophy in two patients who were examined). At autopsy, all cases showed FTLD with the most severe neuronal loss and gliosis evident in the premotor and precentral gyri. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. In the spinal cord, loss of anterior horn cells and degeneration of the corticospinal tract were evident. In addition, the affected regions exhibited neuronal cytoplasmic inclusions resembling neurofibrillary tangles. Immunostaining using antibodies against hyperphosphorylated tau and 4-repeat tau revealed widespread occurrence of neuronal and glial cytoplasmic inclusions in the central nervous system; the astrocytic tau lesions were unique, and different in morphology from astrocytic plaques in CBD, or tufted astrocytes in PSP. However, immunoblotting of frozen brain samples available in two cases revealed predominantly 4R tau, with the approximately 37-kDa and 33-kDa low-molecular mass tau fragments characteristic of CBD and PSP, respectively. No mutations were found in the tau gene in either of the two cases. Based on these clinicopathological, biochemical, and genetic findings, we consider that the present three patients form a distinct 4R tauopathy associated with sporadic FTLD.

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  • Neurocutaneous melanosis: surgical pathological features of an apparently hamartomatous lesion in the amygdala Case report 査読

    Yong-Juan Fu, Nobuhito Morota, Atsuko Nakagawa, Hitoshi Takahashi, Akiyoshi Kakita

    JOURNAL OF NEUROSURGERY-PEDIATRICS   6 ( 1 )   82 - 86   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC NEUROLOGICAL SURGEONS  

    Neurocutaneous melanosis (NCM) is a rare, congenital phakomatosis characterized by the presence of congenital melanocytic nevi and a benign or malignant pigmented cell tumor of the leptomeninges of the CNS. Here the authors report the surgical pathological features of a lesion in the left amygdala in a 10-year-old girl with giant congenital pigmented nevi and mesial temporal lobe epilepsy. The lesion exhibited high intensity on T1-weighted MR images and low intensity to isointensity on T2-weighted images. A left anterior temporal lobectomy and hippocampectomy were performed. Histologically, the lesion was composed of melanin-containing polygonal cells arranged in solid alveolar or multiple lobular patterns. Immunohistochemically, the cells were immunoreactive for HMB45, S100 protein, and vimentin, the profiles being consistent with those of melanocytes. Bundles of astrocytic processes surrounded the nests of melanocytes. Melanin-containing and dysmorphic neurons were also scattered near the nests. In the temporal neocortex adjacent to the amygdaloid melanocytic lesion, cortical dysplasia with cortical laminar disorganization was evident. Based on the histopathological features, the parenchymal lesion appeared to be hamartomatous in nature rather than a neoplasm, involving aberrant migration of melanocytes into the developing neuroepithelial tissue. This case appears to represent an unusual CNS manifestation of NCM. (DOI: 10.3171/2010.3.PEDS1025)

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  • Supportive evidence for reduced expression of GNB1L in schizophrenia. 査読

    Ishiguro Hiroki, Koga Minori, Horiuchi Yasue, Noguchi Emiko, Morikawa Miyuki, Suzuki Yoshimi, Arai Makoto, Niizato Kazuhiro, Iritani Shyuji, Itokawa Masanari, Inada Toshiya, Iwata Nakao, Ozaki Norio, Ujike Hiroshi, Kunugi Hiroshi, Sasaki Tsukasa, Takahashi Makoto, Watanabe Yuichiro, Someya Toshiyuki, Kakita Akiyoshi, Takahashi Hitoshi, Nawa Hiroyuki, Arinami Tadao

    Schizophr Bull   36 ( 4 )   756 - 765   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Chromosome 22q11 deletion syndrome (22q11DS) increases the risk of development of schizophrenia more than 10 times compared with that of the general population, indicating that haploinsufficiency of a subset of the more than 20 genes contained in the 22q11DS region could increase the risk of schizophrenia. In the present study, we screened for genes located in the 22q11DS region that are expressed at lower levels in postmortem prefrontal cortex of patients with schizophrenia than in those of controls. METHODS: Gene expression was screened by Illumina Human-6 Expression BeadChip arrays and confirmed by real-time reverse transcription-polymerase chain reaction assays and Western blot analysis. RESULTS: Expression of GNB1L was lower in patients with schizophrenia than in control subjects in both Australian (10 schizophrenia cases and 10 controls) and Japanese (43 schizophrenia cases and 11 controls) brain samples. TBX1 could not be evaluated due to its low expression levels. Expression levels of the other genes were not significantly lower in patients with schizophrenia than in control subjects. Association analysis of tag single-nucleotide polymorphisms in the GNB1L gene

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  • Supportive evidence for reduced expression of GNB1L in schizophrenia 査読

    Hiroki Ishiguro, Minori Koga, Yasue Horiuchi, Emiko Noguchi, Miyuki Morikawa, Yoshimi Suzuki, Makoto Arai, Kazuhiro Niizato, Shyuji Iritani, Masanari Itokawa, Toshiya Inada, Nakao Iwata, Norio Ozaki, Hiroshi Ujike, Hiroshi Kunugi, Tsukasa Sasaki, Makoto Takahashi, Yuichiro Watanabe, Toshiyuki Someya, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki Nawa, Tadao Arinami

    Schizophrenia Bulletin   36 ( 4 )   756 - 765   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Chromosome 22q11 deletion syndrome (22q11DS) increases the risk of development of schizophrenia more than 10 times compared with that of the general population, indicating that haploinsufficiency of a subset of the more than 20 genes contained in the 22q11DS region could increase the risk of schizophrenia. In the present study, we screened for genes located in the 22q11DS region that are expressed at lower levels in postmortem prefrontal cortex of patients with schizophrenia than in those of controls. Methods: Gene expression was screened by Illumina Human-6 Expression BeadChip arrays and confirmed by real-time reverse transcription-polymerase chain reaction assays and Western blot analysis. Results: Expression of GNB1L was lower in patients with schizophrenia than in control subjects in both Australian (10 schizophrenia cases and 10 controls) and Japanese (43 schizophrenia cases and 11 controls) brain samples. TBX1 could not be evaluated due to its low expression levels. Expression levels of the other genes were not significantly lower in patients with schizophrenia than in control subjects. Association analysis of tag single-nucleotide polymorphisms in the GNB1L gene region did not confirm excess homozygosity in 1918 Japanese schizophrenia cases and 1909 Japanese controls. Haloperidol treatment for 50 weeks increased Gnb1l gene expression in prefrontal cortex of mice. Conclusions: Taken together with the impaired prepulse inhibition observed in heterozygous Gnb1l knockout mice reported by the previous study, the present findings support assertions that GNB1L is one of the genes in the 22q11DS region responsible for increasing the risk of schizophrenia. © The Author 2010. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

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  • Relationship between Bunina bodies and TDP-43 inclusions in spinal anterior horn in amyotrophic lateral sclerosis 査読

    F. Mori, K. Tanji, Y. Miki, A. Kakita, H. Takahashi, K. Wakabayashi

    NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY   36 ( 4 )   345 - 352   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Aims: Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neurone involvement with Bunina bodies (BBs) and TDP-43 inclusions. To elucidate the relationship between BBs and TDP-43 inclusions, we examined the spinal cord from 18 patients with ALS. Methods: Five serial sections from lumbar cord were first stained with haematoxylin and eosin to detect BBs and subsequently immunostained with anti-TDP-43 antibody. Immunoelectron microscopy was performed on vibratome sections from two cases of ALS. Results: BBs were found in 15 out of 18 cases. TDP-43 inclusions were found in all the cases. The average incidence of anterior horn cells with BBs and TDP-43 inclusions relative to the total number of neurones was 17.1% and 46.4%, respectively. The concurrence of both inclusions in the same neurones was found in 15 cases. The incidence of co-localization of BBs and TDP-43 inclusions was 15.7% of total neurones. The frequency of TDP-43 inclusions was significantly higher in neurones with BBs than in those without. Ultrastructurally, TDP-43-immunoreactive filamentous structures were intermingled with early-stage BBs, but not associated with advanced-stage BBs. Conclusion: These findings suggest that there is a close relationship in the occurrence between BBs and TDP-43 inclusions.

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  • Brain cannabinoid CB2 receptor in schizophrenia. 査読

    Ishiguro Hiroki, Horiuchi Yasue, Ishikawa Maya, Koga Minori, Imai Keiko, Suzuki Yoshimi, Morikawa Miyuki, Inada Toshiya, Watanabe Yuichiro, Takahashi Makoto, Someya Toshiyuki, Ujike Hiroshi, Iwata Nakao, Ozaki Norio, Onaivi Emmanuel S, Kunugi Hiroshi, Sasaki Tsukasa, Itokawa Masanari, Arai Makoto, Niizato Kazuhiro, Iritani Shyuji, Naka Izumi, Ohashi Jun, Kakita Akiyoshi, Takahashi Hitoshi, Nawa Hiroyuki, Arinami Tadao

    Biol Psychiatry   67 ( 10 )   974 - 982   2010年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Neural endocannabinoid function appears to be involved in schizophrenia. Two endocannabinoid receptors, CB1 and CB2, are found in the brain and elsewhere in the body. We investigated roles of CB2 in schizophrenia. MATERIALS AND METHODS: An association study was performed between tag single nucleotide polymorphisms (SNPs) in the CNR2 gene encoding the CB2 receptor and schizophrenia in two independent case-control populations. Allelic differences of associated SNPs were analyzed in human postmortem brain tissues and in cultured cells. Prepulse inhibition and locomotor activity in C57BL/6JJmsSlc mice with CB2 receptor antagonist AM630 administration was examined. RESULTS: The analysis in the first population revealed nominally significant associations between schizophrenia and two SNPs, and the associations were replicated in the second population. The R63 allele of rs2501432 (R63Q) (p = .001), the C allele of rs12744386 (p = .005) and the haplotype of the R63-C allele (p = 5 x 10(-6)) were significantly increased among 1920 patients with schizophrenia compared with 1920 control subjects in the combined population. A significantly lower response to CB2 ligands in cultured

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  • Brain Cannabinoid CB2 Receptor in Schizophrenia 査読

    Hiroki Ishiguro, Yasue Horiuchi, Maya Ishikawa, Minori Koga, Keiko Imai, Yoshimi Suzuki, Miyuki Morikawa, Toshiya Inada, Yuichiro Watanabe, Makoto Takahashi, Toshiyuki Someya, Hiroshi Ujike, Nakao Iwata, Norio Ozaki, Emmanuel S. Onaivi, Hiroshi Kunugi, Tsukasa Sasaki, Masanari Itokawa, Makoto Arai, Kazuhiro Niizato, Shyuji Iritani, Izumi Naka, Jun Ohashi, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki Nawa, Tadao Arinami

    Biological Psychiatry   67 ( 10 )   974 - 982   2010年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Neural endocannabinoid function appears to be involved in schizophrenia. Two endocannabinoid receptors, CB1 and CB2, are found in the brain and elsewhere in the body. We investigated roles of CB2 in schizophrenia. Materials and Methods: An association study was performed between tag single nucleotide polymorphisms (SNPs) in the CNR2 gene encoding the CB2 receptor and schizophrenia in two independent case-control populations. Allelic differences of associated SNPs were analyzed in human postmortem brain tissues and in cultured cells. Prepulse inhibition and locomotor activity in C57BL/6JJmsSlc mice with CB2 receptor antagonist AM630 administration was examined. Results: The analysis in the first population revealed nominally significant associations between schizophrenia and two SNPs, and the associations were replicated in the second population. The R63 allele of rs2501432 (R63Q) (p = .001), the C allele of rs12744386 (p = .005) and the haplotype of the R63-C allele (p = 5 × 10-6) were significantly increased among 1920 patients with schizophrenia compared with 1920 control subjects in the combined population. A significantly lower response to CB2 ligands in cultured CHO cells transfected with the R63 allele compared with those with Q63, and significantly lower CB2 receptor mRNA and protein levels found in human brain with the CC and CT genotypes of rs12744386 compared with TT genotype were observed. AM630 exacerbated MK-801- or methamphetamine-induced disturbance of prepulse inhibition and hyperactivity in C57BL/6JJmsSlc mice. Conclusions: These findings indicate an increased risk of schizophrenia for people with low CB2 receptor function. © 2010 Society of Biological Psychiatry.

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  • てんかん焦点の外科病理 1 査読

    柿田 明美

    Epilepsy   4 ( 1 )   4 - 6   2010年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the brain of Parkinson&apos;s disease and dementia with Lewy bodies 査読

    Kunikazu Tanji, Tetsu Kamitani, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

    NEUROBIOLOGY OF DISEASE   38 ( 2 )   210 - 218   2010年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    TRIM family proteins are involved in a broad range of biological processes, and their alteration results in many diverse pathological conditions found in genetic diseases, viral infections, and cancers. However, the spatial and temporal expression and function of TRIM9, one of TRIM family proteins, remain obscure. Our results here showed that TRIM9 protein is mainly expressed in the cerebral cortex, and functions as an E3 ubiquitin ligase collaborating with an E2 ubiquitin conjugating enzyme UbcH5b. Immunohistochemical examination revealed that TRIM9 is localized to the neurons in the normal mouse and human brain and that TRIM9 immunoreactivity is severely decreased in the affected brain areas in Parkinson&apos;s disease and dementia with Lewy bodies. This repressed level of TRIM9 protein was supported by immunoblotting analysis. Intriguingly, cortical and brainstem-type Lewy bodies were immunopositive for TRIM9. These results suggest that TRIM9 plays an important role in the regulation of neuronal functions and participates in pathological process of Lewy body disease through its ligase activity. (C) 2010 Elsevier Inc. All rights reserved.

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  • Anterior striatum with dysmorphic neurons associated with the epileptogenesis of focal cortical dysplasia 査読

    Takanobu Kaido, Taisuke Otsuki, Yuu Kaneko, Akio Takahashi, Akiyoshi Kakita, Hitoshi Takahashi, Yoshiaki Saito, Eiji Nakagawa, Kenji Sugai, Masayuki Sasaki

    SEIZURE-EUROPEAN JOURNAL OF EPILEPSY   19 ( 4 )   256 - 259   2010年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO LTD  

    The epileptogenesis of the striatum is unknown. We describe the case of a 12-year-old girl with intractable epilepsy who was treated by surgical interventions. Magnetic resonance imaging (MRI) showed ambiguous corticomedullary boundary in the left frontal lobe, and magnetoencephalography (MEG) revealed spike dipoles in the vicinity of the left ventral striatum. The epileptic seizures disappeared after partial resection of the frontal lobe, but recurred within 2 months and remained intractable. Neuropathological examination confirmed the presence of focal cortical dysplasia in the resected brain tissue. Ictal single photon emission computed tomography at this period displayed hyperperfusion of the left anterior striatum. At the second surgery, intraoperative electrocorticography exhibited spike discharges from the anterior striatum. After the removal of this structure and adjacent brain tissues, the patient remains seizure-free for 33 months, without any neurological deficits. Histopathological examination of the resected tissue revealed a large number of dysmorphic neurons distributed widely in the cerebral cortex, subcortical white matter, striatum, and insular cortex. These findings suggest that microscopic dysplasia of basal ganglia can accompany certain cases of focal cortical malformations, and may play a critical role in the epileptogenesis through their interaction with cortical structures. (C) 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

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  • Association of the HSPG2 gene with neuroleptic-induced tardive dyskinesia. 査読

    Syu Aoi, Ishiguro Hiroki, Inada Toshiya, Horiuchi Yasue, Tanaka Syunsuke, Ishikawa Maya, Arai Makoto, Itokawa Masanari, Niizato Kazuhiro, Iritani Shuji, Ozaki Norio, Takahashi Makoto, Kakita Akiyoshi, Takahashi Hitoshi, Nawa Hiroyuki, Keino-Masu Kazuko, Arikawa-Hirasawa Eri, Arinami Tadao

    Neuropsychopharmacology   35 ( 5 )   1155 - 1164   2010年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tardive dyskinesia (TD) is characterized by repetitive, involuntary, and purposeless movements that develop in patients treated with long-term dopaminergic antagonists, usually antipsychotics. By a genome-wide association screening of TD in 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD (non-TD group) and subsequent confirmation in independent samples of 36 treatment-resistant TD and 136 non-TD subjects, we identified association of a single nucleotide polymorphism, rs2445142, (allelic p=2 x 10(-5)) in the HSPG2 (heparan sulfate proteoglycan 2, perlecan) gene with TD. The risk allele was significantly associated with higher expression of HSPG2 in postmortem human prefrontal brain (p&lt;0.01). Administration of daily injection of haloperidol (HDL) for 50 weeks significantly reduced Hspg2 expression in mouse brains (p&lt;0.001). Vacuous chewing movements (VCMs) induced by 7-week injection of haloperidol-reserpine were significantly infrequent in adult Hspg2 hetero-knockout mice compared with wild-type littermates (p&lt;0.001). Treatment by the acetylcholinesterase inhibitor, physostigmine, was significantly effective for red

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  • Association of the HSPG2 Gene with Neuroleptic-Induced Tardive Dyskinesia 査読

    Aoi Syu, Hiroki Ishiguro, Toshiya Inada, Yasue Horiuchi, Syunsuke Tanaka, Maya Ishikawa, Makoto Arai, Masanari Itokawa, Kazuhiro Niizato, Shuji Iritani, Norio Ozaki, Makoto Takahashi, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki Nawa, Kazuko Keino-Masu, Eri Arikawa-Hirasawa, Tadao Arinami

    NEUROPSYCHOPHARMACOLOGY   35 ( 5 )   1155 - 1164   2010年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Tardive dyskinesia (TD) is characterized by repetitive, involuntary, and purposeless movements that develop in patients treated with long-term dopaminergic antagonists, usually antipsychotics. By a genome-wide association screening of TD in 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD (non-TD group) and subsequent confirmation in independent samples of 36 treatment-resistant TD and 136 non-TD subjects, we identified association of a single nucleotide polymorphism, rs2445142, (allelic p = 2 x 10(-5)) in the HSPG2 (heparan sulfate proteoglycan 2, perlecan) gene with TD. The risk allele was significantly associated with higher expression of HSPG2 in postmortem human prefrontal brain (p&lt;0.01). Administration of daily injection of haloperidol (HDL) for 50 weeks significantly reduced Hspg2 expression in mouse brains (p&lt;0.001). Vacuous chewing movements (VCMs) induced by 7-week injection of haloperidol-reserpine were significantly infrequent in adult Hspg2 hetero-knockout mice compared with wild-type littermates (p&lt;0.001). Treatment by the acetylcholinesterase inhibitor, physostigmine, was significantly effective for reduction of VCMs in wild-type mice but not in Hspg2 hetero-knockout mice. These findings suggest that the HSPG2 gene is involved in neuroleptic-induced TD and higher expression of HSPG2, probably even after antipsychotic treatment, and may be associated with TD susceptibility. Neuropsychopharmacology (2010) 35, 1155-1164; doi: 10.1038/npp.2009.220; published online 13 January 2010

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  • Increased expression and activation of cytosolic phospholipase A(2) in the spinal cord of patients with sporadic amyotrophic lateral sclerosis 査読

    Noriyuki Shibata, Akiyoshi Kakita, Hitoshi Takahashi, Yuetsu Ihara, Keigo Nobukuni, Harutoshi Fujimura, Saburo Sakoda, Makio Kobayashi

    ACTA NEUROPATHOLOGICA   119 ( 3 )   345 - 354   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Compelling evidence identifies a link between cytotoxic effects of cytosolic phospholipase A(2) (cPLA(2)) activity and neuron death in cell cultures. cPLA(2) catalyzes the hydrolysis of membrane phospholipids to produce and release arachidonate, leading to plasma membrane injury, inflammatory response and subsequent cell death. To assess a role for cPLA(2) in the pathomechanism of amyotrophic lateral sclerosis (ALS), we performed immunohistochemical, immunoblot, and densitometric analyses of cPLA(2) and its active form phosphorylated at S-505 (p-cPLA(2)) on spinal cords obtained at autopsy from ten sporadic ALS patients and ten age-matched controls. On sections, immunoreactivities for cPLA(2) and p-cPLA(2) were distinct and localized in almost all of the motor neurons, reactive astrocytes, and activated microglia in the ALS cases, while immunoreactivities were only weak or not at all observed in neurons and glia in the control cases. On immunoblots, both the cPLA(2)/beta-actin density ratio and the p-cPLA(2)/cPLA(2) density ratio were significantly increased in the ALS group compared to the control group. There was no significant link between the densitometric data and the clinical phenotypes, age at death or disease duration of the ALS patients. These results provide in vivo evidence for increased expression and activation of cPLA(2) in motor neurons, reactive astrocytes, and activated microglia in ALS, suggesting occurrence of arachidonate cascade-induced motor neuron death via cell-autonomous and/or non-cell-autonomous mechanisms.

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  • Molecular characterization and gene disruption of a novel zinc-finger protein, HIT-4, expressed in rodent brain 査読

    Yasutaka Tanabe, Akiko Hirano, Takuji Iwasato, Shigeyoshi Itohara, Kazuaki Araki, Tsuyoshi Yamaguchi, Tomio Ichikawa, Toshiro Kumanishi, Yoshifusa Aizawa, Hitoshi Takahashi, Akiyoshi Kakita, Hiroyuki Nawa

    Journal of Neurochemistry   112 ( 4 )   1035 - 1044   2010年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To identify a novel regulatory factor involved in brain development or synaptic plasticity, we applied the differential display PCR method to mRNA samples from NMDA-stimulated and un-stimulated neocortical cultures. Among 64 cDNA clones isolated, eight clones were novel genes and one of them encodes a novel zinc-finger protein, HIT-4, which is 317 amino acid residues (36-38 kDa) in length and contains seven C2H2 zinc-finger motifs. Rat HIT-4 cDNA exhibits strong homology to human ZNF597 (57% amino acid identity and 72% homology) and identity to rat ZNF597 at the carboxyl region. Furthermore, genomic alignment of HIT-4 cDNA indicates that the alternative use of distinct promoters and exons produces HIT-4 and ZNF597 mRNAs. Northern blotting revealed that HIT-4 mRNA (∼6 kb) is expressed in various tissues such as the lung, heart, and liver, but enriched in the brain, while ZNF597 mRNA (∼1.5 kb) is found only in the testis. To evaluate biological roles of HIT-4/ZNF597, targeted mutagenesis of this gene was performed in mice. Homozygous (-/-) mutation was embryonic lethal, ceasing embryonic organization before cardiogenesis at embryonic day 7.5. Heterozygous (+/-) mice were able to survive but showing cell degeneration and vacuolization of the striatum, cingulate cortex, and their surrounding white matter. These results reveal novel biological and pathological roles of HIT-4 in brain development and/or maintenance. © 2010 International Society for Neurochemistry.

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  • Molecular characterization and gene disruption of a novel zinc-finger protein, HIT-4, expressed in rodent brain 査読

    Yasutaka Tanabe, Akiko Hirano, Takuji Iwasato, Shigeyoshi Itohara, Kazuaki Araki, Tsuyoshi Yamaguchi, Tomio Ichikawa, Toshiro Kumanishi, Yoshifusa Aizawa, Hitoshi Takahashi, Akiyoshi Kakita, Hiroyuki Nawa

    JOURNAL OF NEUROCHEMISTRY   112 ( 4 )   1035 - 1044   2010年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    To identify a novel regulatory factor involved in brain development or synaptic plasticity, we applied the differential display PCR method to mRNA samples from NMDA-stimulated and un-stimulated neocortical cultures. Among 64 cDNA clones isolated, eight clones were novel genes and one of them encodes a novel zinc-finger protein, HIT-4, which is 317 amino acid residues (36-38 kDa) in length and contains seven C(2)H(2) zinc-finger motifs. Rat HIT-4 cDNA exhibits strong homology to human ZNF597 (57% amino acid identity and 72% homology) and identity to rat ZNF597 at the carboxyl region. Furthermore, genomic alignment of HIT-4 cDNA indicates that the alternative use of distinct promoters and exons produces HIT-4 and ZNF597 mRNAs. Northern blotting revealed that HIT-4 mRNA (similar to 6 kb) is expressed in various tissues such as the lung, heart, and liver, but enriched in the brain, while ZNF597 mRNA (similar to 1.5kb) is found only in the testis. To evaluate biological roles of HIT-4/ZNF597, targeted mutagenesis of this gene was performed in mice. Homozygous (-/-) mutation was embryonic lethal, ceasing embryonic organization before cardiogenesis at embryonic day 7.5. Heterozygous (+/-) mice were able to survive but showing cell degeneration and vacuolization of the striatum, cingulate cortex, and their surrounding white matter. These results reveal novel biological and pathological roles of HIT-4 in brain development and/or maintenance.

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  • Ictal bradycardia in an infant following surgical treatment for hemimegalencephaly 査読

    Hiroaki Miyahara, Kouji Sonoda, Naho Okazaki, Kazuhito Sekiguchi, Tatsuya Kawano, Kensuke Akiyoshi, Tomoki Maeda, Tatsuro Izumi

    PEDIATRICS INTERNATIONAL   52 ( 1 )   156 - 157   2010年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

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  • Increased Levels of Soluble LR11 in Cerebrospinal Fluid of Patients with Alzheimer Disease 査読

    Takeshi Ikeuchi, Satoshi Hirayama, Takashi Miida, Isamu Fukamachi, Takayoshi Tokutake, Hiroyuki Ebinuma, Kohei Takubo, Hiroyuki Kaneko, Kensaku Kasuga, Akiyoshi Kakita, Hitoshi Takahashi, Hideaki Bujo, Yasushi Saito, Masatoyo Nishizawa

    DEMENTIA AND GERIATRIC COGNITIVE DISORDERS   30 ( 1 )   28 - 32   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    Background: Recent genetic and pathological studies have suggested that a lipoprotein receptor, LR11, is intricately implicated in the pathogenesis of Alzheimer disease (AD). We have recently established a novel sandwich ELISA, which enabled the sensitive quantification of a soluble LR11 (sLR11). By this ELISA, we attempted to determine the difference in the levels of CSF sLR11 in AD patients. Methods: We examined CSF from 29 AD patients, 20 frontotemporal lobar degeneration patients and 27 age-matched control subjects. The CSF sLR11 level as well as the levels of tau and beta-amyloid42 (A beta 42) were determined by sandwich ELISA. Results: The CSF tau level and tau/A beta 42 ratio were significantly increased (p &lt; 0.01) in the AD patients. The CSF sLR11 level in the AD patients was significantly higher (p &lt; 0.01) than that of the frontotemporal lobar degeneration patients and the controls. The APOE-epsilon 4-positive AD patients have higher sLR11 levels than the APOE-epsilon 4-negative patients (p &lt; 0.01). Conclusions: These results suggest that the quantification of CSF sLR11 may serve as a biomarker of AD, although the diagnostic value for individual patients is limited. An elevated CSF sLR11 level in AD patients may be relevant to AD pathogenesis. Copyright (C) 2010 S. Karger AG, Basel

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  • The clinical and pathological spectrum of TDP-43 associated ALS 査読

    Osamu Onodera, AMo Yokoseki, Chun-Feng Tan, Tomohiko Ishihara, Yasushi Nishiira, Yasuko Toyoshima, AMyoshi Kakita, Masatoyo Nishizawa, Hitoshi Takahashi

    Clinical Neurology   50 ( 11 )   940 - 942   2010年

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    記述言語:日本語   掲載種別:研究論文(国際会議プロシーディングス)  

    The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) is unclear. TAR DNA-binding proteins of 43 KDa (TDP43) immunopositive cytoplasmic inclusions have been found in glia and neurons of ALS patients. The discovery of TDP-43 mutations in ALS patients indicates a direct role of TDP43 in ALS. More than 30 mutations in the TDP-43 gene have been identified in patients with familial and sporadic ALS. ALS with a TDP43 mutation is classified as ALS-10. The clinical features of ALS-10 are quite similar to those of sporadic ALS. Furthermore, the neuropathological findings for ALS-10, including TDP-43 immunopositive inclusions and Bunina bodies, are identical to those in sporadic ALS. Most of the mutations are located in the C-terminus of TDP43, which may function as a binding domain of heterogeneous nuclear ribonucleoprotein. Frontotemporal lobar degeneration: FTLD and FTLD/MND (motor neuron disease) also have TDP-43 immunopositive inclusions. These disorders have been named as TDP43 proteinopathy. However, patients with TDP-43 mutations rarely develop FTLD. Causative genes for familial FTLD and FTLD/MND are not linked to the TDP-43 gene. Thus, other factors may contribute to the TDP-43 pathology in these diseases. Further analysis is required to elucidate the molecular mechanism of ALS-10 and TDP-43 proteinopathy.

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  • Persistent cleavage and nuclear translocation of apoptosis-inducing factor in motor neurons in the spinal cord of sporadic amyotrophic lateral sclerosis patients 査読

    Noriyuki Shibata, Akiyoshi Kakita, Hitoshi Takahashi, Yuetsu Ihara, Keigo Nobukuni, Harutoshi Fujimura, Saburo Sakoda, Shoichi Sasaki, Tomoko Yamamoto, Makio Kobayashi

    ACTA NEUROPATHOLOGICA   118 ( 6 )   755 - 762   2009年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Mounting evidence suggests that glutamate excitotoxicity induces both enzymatic cleavage and nuclear translocation of apoptosis-inducing factor (AIF), which is involved in apoptosis-like programed cell death characterized by nuclear condensation without appearance of apoptotic bodies. Given the lack of apoptotic bodies in motor neurons in the spinal cord of patients with amyotrophic lateral sclerosis (ALS), the aim of the present study was to determine the role for AIF in this disease. We investigated the expression of AIF in spinal cords obtained at autopsy from ten sporadic ALS patients and ten age-matched, control subjects, using morphological and quantitative techniques. Immunohistochemical analysis showed that AIF immunoreactivity was localized in the nucleus as well as the cytoplasm of a subset of affected motor neurons and reactive astrocytes in the ALS cases, while it was restricted to the cytoplasm of these cells in the control cases. Immunoblot analysis disclosed immunoreactivity for cleaved AIF in both cytoplasmic and nuclear protein extracts at a 57-kDa mobility. Densitometric analysis revealed significant increases in the cytoplasmic cleaved AIF/cytoplasmic beta-actin ratio and the nuclear cleaved AIF/nuclear histone H1 ratio in the ALS group compared with the control group. There was no significant link between the cytoplasmic and nuclear cleaved AIF levels in the ALS spinal cords and the clinical features such as phenotypes, age at death, and disease duration. Our results provide evidence for persistent cleavage and nuclear translocation of AIF in ALS spinal cord, suggesting implications for the AIF-mediated motor neuron death in this disease.

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  • Isolation and Characterization of Patient-derived, Toxic, High Mass Amyloid beta-Protein (A beta) Assembly from Alzheimer Disease Brains 査読

    Akihiko Noguchi, Satoko Matsumura, Mari Dezawa, Mari Tada, Masako Yanazawa, Akane Ito, Manami Akioka, Satoru Kikuchi, Michio Sato, Shouji Ideno, Munehiro Noda, Atsushi Fukunari, Shin-ichi Muramatsu, Yutaka Itokazu, Kazuki Sato, Hitoshi Takahashi, David B. Teplow, Yo-ichi Nabeshima, Akiyoshi Kakita, Kazutomo Imahori, Minako Hoshi

    JOURNAL OF BIOLOGICAL CHEMISTRY   284 ( 47 )   32895 - 32905   2009年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Amyloid beta-protein (A beta) assemblies are thought to play primary roles in Alzheimer disease (AD). They are considered to acquire surface tertiary structures, not present in physiologic monomers, that are responsible for exerting toxicity, probably through abnormal interactions with their target(s). Therefore, A beta assemblies having distinct surface tertiary structures should cause neurotoxicity through distinct mechanisms. Aiming to clarify the molecular basis of neuronal loss, which is a central phenotype in neurodegenerative diseases such as AD, we report here the selective immunoisolation of neurotoxic 10-15-nm spherical A beta assemblies termed native amylospheroids (native ASPDs) from AD and dementia with Lewy bodies brains, using ASPD tertiary structure-dependent antibodies. In AD patients, the amount of native ASPDs was correlated with the pathologic severity of disease. Native ASPDs are anti-pan oligomer A11 antibody-negative, high mass (&gt; 100 kDa) assemblies that induce degeneration particularly of mature neurons, including those of human origin, in vitro. Importantly, their immuno-specificity strongly suggests that native ASPDs have a distinct surface tertiary structure from other reported assemblies such as dimers, A beta-derived diffusible ligands, and A11-positive assemblies. Only ASPD tertiary structure-dependent antibodies could block ASPD-induced neurodegeneration. ASPDs bind presynaptic target(s) on mature neurons and have a mode of toxicity different from those of other assemblies, which have been reported to exert their toxicity through binding postsynaptic targets and probably perturbing glutamatergic synaptic transmission. Thus, our findings indicate that native ASPDs with a distinct toxic surface induce neuronal loss through a different mechanism from other A beta assemblies.

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  • Neuropathological similarities and differences between frontotemporal lobar degeneration with ubiquitin inclusions and amyotrophic lateral sclerosis with dementia 査読

    Chun-Feng Tan, Yasuko Toyoshima, Akiyoshi Kakita, Hitoshi Takahashi

    Brain and Nerve   61 ( 11 )   1319 - 1327   2009年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Findings of clinical, neuropathological and biochemical studies have supported the idea that frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) are part of a neurological disease spectrum. This concept is now further strengthened by the recent discovery of a 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) as a key component of the underlying neuropathology of FTLD-U, ALS with dementia (ALS-D) and ALS. Here we describe the clinicopathological features of selected autopsy cases belonging to this disease spectrum, and discuss the neuropathological similarities and differences between FTLD-U and ALS-D, with special reference to the morphology, distribution and density of ubiquitin/TDP-43-positive abnormal structures, along with a review of the literature.

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  • Pathologic and immunologic profiles of a limited form of neuromyelitis optica with myelitis 査読

    K. Yanagawa, I. Kawachi, Y. Toyoshima, A. Yokoseki, M. Arakawa, A. Hasegawa, T. Ito, N. Kojima, R. Koike, K. Tanaka, T. Kosaka, C. -F. Tan, A. Kakita, K. Okamoto, M. Tsujita, K. Sakimura, H. Takahashi, M. Nishizawa

    NEUROLOGY   73 ( 20 )   1628 - 1637   2009年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Background: Neuromyelitis optica (NMO) is a demyelinating syndrome characterized by myelitis and optic neuritis. Detection of anti-NMO immunoglobulin G antibody that binds to aquaporin-4 (AQP4) water channels allows the diagnosis of a limited form of NMO in the early stage with myelitis, but not optic neuritis. However, the detailed clinicopathologic features and long-term course of this limited form remain elusive.
    Methods: We investigated 8 patients with the limited form of NMO with myelitis in comparison with 9 patients with the definite form.
    Result: All patients with limited and definite form showed uniform relapsing-remitting courses, with no secondary progressive courses. Pathologic findings of biopsy specimens from the limited form were identical to those of autopsy from the definite form, demonstrating extremely active demyelination of plaques, extensive loss of AQP4 immunoreactivity in plaques, and diffuse infiltration by macrophages containing myelin basic proteins with thickened hyalinized blood vessels. Moreover, the definite form at the nadir of relapses displayed significantly higher amounts of the inflammatory cytokines interleukin (IL)-1 beta and IL-6 in CSF than the limited form and multiple sclerosis.
    Conclusion: This consistency of pathologic findings and uniformity of courses indicates that aquaporin 4-specific autoantibodies as the initiator of the neuromyelitis optica (NMO) lesion consistently play an important common role in the pathogenicity through the entire course, consisting of both limited and definite forms, and NMO continuously displays homogeneity of pathogenic effector immune mechanisms through terminal stages, whereas multiple sclerosis should be recognized as the heterogeneous 2-stage disease that could switch from inflammatory to degenerative phase. This report is a significant description comparing the pathologic and immunologic data of limited NMO with those of definite NMO. Neurology (R) 2009; 73: 1628-1637

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  • Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph disease 査読

    Chun-Feng Tan, Mitsunori Yamada, Yasuko Toyoshima, Akio Yokoseki, Yukari Miki, Yasuhiro Hoshi, Hiroyuki Kaneko, Takeshi Ikeuchi, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA   118 ( 4 )   553 - 560   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Pathological transactivation-responsive DNA-binding protein 43 (TDP-43) has been identified as a component of ubiquitinated inclusions in frontotemporal lobar degeneration with motor neuron disease, as well as in sporadic and some forms of familial amyotrophic lateral sclerosis. To clarify whether pathological TDP-43 is present in other neurodegenerative diseases involving the motor neuron system, we immunohistochemically examined the brain and spinal cord affected by two CAG repeat (polyglutamine) diseases, Machado-Joseph disease (MJD) and spinal and bulbar muscular atrophy (SBMA), using polyclonal antibody against TDP-43. In all the MJD cases, TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs), although few in number, were found only in the lower motor neurons in the brainstem and spinal cord. TDP-43-ir NCIs appeared as linear wisp-like, skein-like, or thick, somewhat rod-like bodies. These inclusions were also visualized with antibodies against phosphoserines 409 and 410 of TDP-43, and ubiquitin, but were not recognized by antibody against expanded polyglutamine stretches or ataxin-3. The ultrastructure of the TDP-43-ir NCIs was similar to that of the inclusions seen in sporadic ALS, consisting of bundles of parallel filaments. None of the SBMA cases showed abnormal TDP-43 immunoreactivity in any of the regions examined. Immunoblot analysis failed to recognize hyperphosphorylated TDP-43 at similar to 23 kDa in two MJD cases examined. However, the immunohistochemical findings strongly suggested that in MJD, in addition to the polyglutamine-dependent disease process, TDP-43-related pathogenesis is associated with degeneration and death of the lower motor neurons.

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  • Cerebellar Involvement in Progressive Supranuclear Palsy: A Clinicopathological Study 査読

    Masato Kanazawa, Takayoshi Shimohata, Yasuko Toyoshima, Mari Tada, Akiyoshi Kakita, Takashi Morita, Tetsutaro Ozawa, Hitoshi Takahashi, Masatoyo Nishizawa

    MOVEMENT DISORDERS   24 ( 9 )   1312 - 1318   2009年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    The clinical heterogeneity of progressive supranuclear palsy (PSP), which is classified as classic Richardson&apos;s syndrome (RS) and PSP-Parkinsonism (PSP-P), has been previously discussed. We retrospectively analyzed 22 consecutive Japanese patients with pathologically proven PSP to investigate the clinicopathological heterogeneity. We investigated the clinical features both early in and at any time during the disease course. The pathological severities of neuronal loss with gliosis and tau pathology were also evaluated. On the basis of the clinical features, 10 patients were categorized as having RS, and 8 were categorized as having PSP-P. Four patients presenting with cerebellar ataxia or cerebral cortical signs were categorized as having unclassifiable PSP. Among them, 3 developed cerebellar ataxia as the initial and principal symptom. Notably, tau-positive inclusion bodies in Purkinje cells were significantly more frequently observed in the patients with cerebellar ataxia than in those without cerebellar ataxia. All the patients with cerebellar ataxia exhibited more neuronal loss with gliosis and higher densities of coiled bodies in the cerebellar dentate nucleus than those without cerebellar ataxia. This study confirms the wide spectrum of clinicopathological manifestations associated with PSP regardless of different ethnic origin, and demonstrates that PSP patients manifest cerebellar ataxia. (C) 2009 Movement Disorder Society

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  • Depletion of medullary serotonergic neurons in patients with multiple system atrophy who succumbed to sudden death 査読

    Mari Tada, Akiyoshi Kakita, Yasuko Toyoshima, Osamu Onodera, Tetsutaro Ozawa, Takashi Morita, Masatoyo Nishizawa, Hitoshi Takahashi

    BRAIN   132 ( Pt 7 )   1810 - 1819   2009年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by prominent autonomic failure with ataxia and/or parkinsonism. The leading cause of death in MSA is sudden death. We have shown that the early development of autonomic failure is an independent risk factor for sudden death. The depletion of sympathetic preganglionic neurons in the spinal intermediolateral cell column (IML) and its afferent medullary catecholaminergic and serotonergic neurons has been proposed to be partly responsible for autonomic failure in MSA. In this study, we investigated whether the depletion of neurons in any of these autonomic neuron groups contributes to sudden death in MSA. Out of 52 autopsy-proven patients with MSA, we selected 12 individuals who had died within 3.5 years after disease onset to define the accurate levels of slices and identify early neuropathological changes of autonomic nuclei in MSA. Four patients succumbed to sudden death and eight patients died through established causes. Serial 10 mu m sections were obtained from the 8th segment of the thoracic cord and the rostral medulla oblongata. Sections from the medulla oblongata were immunostained for thyrosine hydroxylase and tryptophan hydroxylase. The total cell number in the five sections was computed for comparison. Compared with the control, the MSA group showed a marked depletion of neurons in the IML (38.0 +/- 7.1 versus 75.2 +/- 7.6 cells, P &lt; 0.001), thyrosine hydroxylase-immunoreactive neurons in the ventrolateral medulla (VLM) (17.4 +/- 5.1 versus 72.8 +/- 13.6 cells, P &lt; 0.01) and tryptophan hydroxylase-immunoreactive neurons in the VLM (15.6 +/- 9.2 versus 60.8 +/- 17.0 cells, P &lt; 0.01), nucleus raphe obscurus (19.3 +/- 4.4 versus 75.3 +/- 8.6 cells, P &lt; 0.001), nucleus raphe pallidus (2.1 +/- 2.7 versus 9.0 +/- 3.4 cells, P &lt; 0.03), and arcuate nucleus (0.4 +/- 0.8 versus 2.3 +/- 1.5 cells, P &lt; 0.05). Moreover, in patients who succumbed to sudden death, when compared with patients who had established causes of death, we found a marked depletion of tryptophan hydroxylase-immunoreactive neurons in the VLM (7.3 +/- 3.5 versus 21.8 +/- 6.5 cells, P &lt; 0.02) and nucleus raphe obscurus (15.0 +/- 2.0 versus 22.5 +/- 2.1 cells, P &lt; 0.01). The results indicate that the spinal IML and medullary catecholaminergic and serotonergic systems are involved even in the early stages of MSA, and the dysfunction of the medullary serotonergic system regulating cardiovascular and respiratory systems could be responsible for sudden death in patients with MSA.

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  • Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia 査読

    Minori Koga, Hiroki Ishiguro, Saori Yazaki, Yasue Horiuchi, Makoto Arai, Kazuhiro Niizato, Shuji Iritani, Masanari Itokawa, Toshiya Inada, Nakao Iwata, Norio Ozaki, Hiroshi Ujike, Hiroshi Kunugi, Tsukasa Sasaki, Makoto Takahashi, Yuichiro Watanabe, Toshiyuki Someya, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki Nawa, Christian Muchardt, Moshe Yaniv, Tadao Arinami

    HUMAN MOLECULAR GENETICS   18 ( 13 )   2483 - 2494   2009年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Chromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212; overall allelic P = 5.8 x 10(-5)) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490; overall allelic P = 2.0 x 10(-6)) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of Smarca2 knockout mice. Smarca2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered Smarca2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia.

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  • Expression of ErbB4 in substantia nigra dopamine neurons of monkeys and humans 査読

    Yingjun Zheng, Akiya Watakabe, Masahiko Takada, Akiyoshi Kakita, Hisaaki Namba, Hitoshi Takahashi, Tetsuo Yamamori, Hiroyuki Nawa

    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY   33 ( 4 )   701 - 706   2009年6月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Abnormal neuregulin-1 signaling through its receptor (ErbR4) might be associated with schizophrenia, although their neuropathological contribution remains controversial. To assess the role of neuregulin-1 in the dopamine hypothesis of schizophrenia, we used in situ hybridization and immunoblotting to investigate the cellular distribution of ErbB4 mRNA in the substantia nigra of Japanese monkeys (Macaca fuscata) and human postmortem brains. In both monkeys and humans, significant signal for ErbR4 mRNA was detected in substantia nigra dopamine neurons, which were identified by melanin deposits. The expression of ErbB4 mRNA in nigral dopamine neurons was confirmed with an independent RNA probe, as well as with combined tyrosine hydroxylase immunostaining. Immunoblotting appeared to support the observation of in situ hybridization. Immunoreactivity for ErbB4 protein was much more enriched in substantia nigra pars compacta containing dopamine neurons than in neighboring substantia nigra pars reticulata. These observations suggest that ErbR4 is expressed in the dopaminergic neurons of primate substantia nigra and ErbB4 abnormality might contribute to the dopaminergic pathology associated with schizophrenia or other brain diseases. (C) 2009 Elsevier Inc. All rights reserved.

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  • Activity-dependent glial swelling is impaired in aquaporin-4 knockout mice 査読

    Hiroki Kitaura, Mika Tsujita, Vincent J. Huber, Akiyoshi Kakita, Katsuei Shibuki, Kenji Sakimura, Ingrid L. Kwee, Tsutomu Nakada

    NEUROSCIENCE RESEARCH   64 ( 2 )   208 - 212   2009年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    We investigated the role of aquaporin-4 (AQP4), a water channel expressed in glial cells, in neural activity mediated morphological changes observed in brain slice preparation. Changes in flavoprotein fluorescence (FF) and infrared light scattering (LS) signals were measured before and after repetitive stimulation of layer VI in rostral somatosensory cortical slices taken from AQP4 knockout(KO)and wildtype (WT) mice. Changes in FF, which reflect neural aerobic activities, were comparable for the two groups in all cortical layers. However, changes in LS signals, which are indicative of cell swelling, were significantly decreased in layer 1 of AQP4 KO mice compared to that of WT mice. We conclude that AQP4 likely plays a significant role in neural activity-dependent glial swelling. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

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  • Activity-dependent glial swelling is impaired in aquaporin-4 knockout mice.

    Kitaura Hiroki, Tsujita Mika, Huber Vincent J, Kakita Akiyoshi, Shibuki Katsuei, Sakimura Kenji, Kwee Ingrid L, Nakada Tsutomu

    Neurosci Res   64 ( 2 )   208 - 212   2009年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We investigated the role of aquaporin-4 (AQP4), a water channel expressed in glial cells, in neural activity mediated morphological changes observed in brain slice preparation. Changes in flavoprotein fluorescence (FF) and infrared light scattering (LS) signals were measured before and after repetitive stimulation of layer VI in rostral somatosensory cortical slices taken from AQP4 knockout (KO) and wild-type (WT) mice. Changes in FF, which reflect neural aerobic activities, were comparable for the two groups in all cortical layers. However, changes in LS signals, which are indicative of cell swelling, were significantly decreased in layer I of AQP4 KO mice compared to that of WT mice. We conclude that AQP4 likely plays a significant role in neural activity-dependent glial swelling.

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  • Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese 査読

    Norihiro Takei, Akinori Miyashita, Tarriao Tsukie, Hiroyuki Arai, Takashi Asada, Masaki Imagawa, Mikio Shoji, Susumu Higuchi, Katsuya Urakami, Hideo Kimura, Akiyoshi Kakita, Hitoshi Takahashi, Shoji Tsuji, Ichiro Kanazawa, Yasuo Ihara, Shoji Odani, Ryozo Kuwano

    GENOMICS   93 ( 5 )   441 - 448   2009年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

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  • TDP-43 May Contribute To The Protective Effects Of Hypothermia Against Rat Focal Cerebral Ischemia 査読

    Masato Kanazawa, Akiyoshi Kakita, Hironaka Igarashi, Tetsuya Takahashi, Hitoshi Takahashi, Masatoyo Nishizawa, Tsutomu Nakada, Takayoshi Shimohata

    STROKE   40 ( 4 )   E223 - E223   2009年4月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Caspase 3-Dependent Proteolytic Cleavage of TDP-43 in a Model of Transient Middle Cerebral Artery Occlusion 査読

    Masato Kanazawa, Akiyoshi Kakita, Hironaka Igarashi, Tetsuya Takahashi, Hitoshi Takahashi, Masatoyo Nishizawa, Tsutomu Nakada, Takayoshi Shimohata

    NEUROLOGY   72 ( 11 )   A401 - A401   2009年3月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology 査読

    Yasushi Nishihira, Chun-Feng Tan, Yasuhiro Hoshi, Keisuke Iwanaga, Megumi Yamada, Izumi Kawachi, Mitsuhiro Tsujihata, Isao Hozumi, Takashi Morita, Osamu Onodera, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA   117 ( 1 )   45 - 53   2009年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (&lt; 5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10-20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule cells). The number of neurons displaying NCIs in each region was very small (1-3 per region, except the dentate gyrus). On the other hand, the occurrence of TDP-43-ir glial cytoplasmic inclusions (GCIs) was more widespread in the central nervous system, including the cerebral white matter. Again, however, the number of glial cells displaying GCIs in each region was very small (1-3 per region). In conclusion, compared to the usual form of SALS, TDP-43 pathology shown in SALS of long duration was apparently mild in degree and limited in distribution, corresponding to the relatively benign clinical courses observed. It is now apparent that SALS of long duration is actually part of a TDP-43 proteinopathy spectrum.

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  • Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology. 査読

    Nishihira Yasushi, Tan Chun-Feng, Hoshi Yasuhiro, Iwanaga Keisuke, Yamada Megumi, Kawachi Izumi, Tsujihata Mitsuhiro, Hozumi Isao, Morita Takashi, Onodera Osamu, Nishizawa Masatoyo, Kakita Akiyoshi, Takahashi Hitoshi

    Acta Neuropathol   117 ( 1 )   45 - 53   2009年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (&lt;5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10-20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule c

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  • 皮質形成異常の診断と治療 査読

    増田 浩, 村上博淳, 亀山茂樹, 柿田明美

    脳神経外科ジャーナル   18 ( 8 )   577 - 585   2009年

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    記述言語:日本語   掲載種別:研究論文(国際会議プロシーディングス)  

    DOI: 10.7887/jcns.18.577

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  • Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia 査読

    Minori Koga, Hiroki Ishiguro, Saori Yazaki, Yasue Horiuchi, Makoto Arai, Kazuhiro Niizato, Shuji Iritani, Masanari Itokawa, Toshiya Inada, Nakao Iwata, Norio Ozaki, Hiroshi Ujike, Hiroshi Kunugi, Tsukasa Sasaki, Makoto Takahashi, Yuichiro Watanabe, Toshiyuki Someya, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki Nawa, Christian Muchardt, Moshe Yaniv, Tadao Arinami

    Human Molecular Genetics   18 ( 13 )   2483 - 2494   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Chromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212
    overall allelic P = 5.8 × 10-5) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490
    overall allelic P = 2.0 × 10-6) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of Smarca2 knockout mice. Smarca2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered Smarca2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia. © The Author 2009. Published by Oxford University Press. All rights reserved.

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  • Activation of Signal Transducer and Activator of Transcription-3 in the Spinal Cord of Sporadic Amyotrophic Lateral Sclerosis Patients 査読

    Noriyuki Shibata, Akiyoshi Kakita, Hitoshi Takahashi, Yuetsu Ihara, Keigo Nobukuni, Harutoshi Fujimura, Saburo Sakoda, Shoichi Sasaki, Makoto Iwata, Shunichi Morikawa, Asao Hirano, Makio Kobayashi

    NEURODEGENERATIVE DISEASES   6 ( 3 )   118 - 126   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    Background: Neuroinflammation has been implicated in the pathomechanism of amyotrophic lateral sclerosis (ALS). It is known that signal transducer and activator of transcription-3 (STAT3) is a proinflammatory transcription factor. However, it remains to be determined whether STAT3 is involved in ALS. Objective: To test the hypothesis that STAT3 may be upregulated, activated, or both in the spinal cord of ALS patients. Methods: We performed immunohistochemical, immunoblot and densitometric analyses of total STAT3 (t-STAT3) or phosphorylated active form of STAT3 (p-STAT3) in spinal cords obtained at autopsy from 10 sporadic ALS patients and 10 age-matched control subjects. Results: On sections, p-STAT3 immunoreactivity was localized in the nucleus as well as the cytoplasm of almost all activated microglia in the ALS cases, while it was detectable in a few resting microglia in the control cases. On blots, densitometric p-STAT3 levels in nuclear protein extracts significantly increased in the ALS group compared with the control group, although there was no significant difference in densitometric t-STAT3 levels in cytosolic protein extracts between the two groups. Additionally, there was no significant relationship between the nuclear p-STAT3 levels in the ALS cases and the clinical phenotypes, age at death, or disease duration. Conclusion: The present results suggest that persistent activation and nuclear translocation but not upregulation of STAT3 occurs in ALS spinal cord microglia, which may regulate inflammatory activity. Copyright (C) 2009 S. Karger AG, Basel

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  • Cardiac sympathetic denervation in Parkinson's disease linked to SNCA duplication 査読

    Satoshi Orimo, Toshiki Uchihara, Ayako Nakamura, Fumiaki Mori, Takeshi Ikeuchi, Osamu Onodera, Masatoyo Nishizawa, Atsushi Ishikawa, Akiyoshi Kakita, Koichi Wakabayashi, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA   116 ( 5 )   575 - 577   2008年11月

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    記述言語:英語   出版者・発行元:SPRINGER  

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  • Marinesco-Sjögren syndrome with atrophy of the brain stem tegmentum and dysplastic cytoarchitecture in the cerebral cortex. 査読

    Sakai K, Tada M, Yonemochi Y, Nakajima T, Onodera O, Takahashi H, Kakita A

    Neuropathology : official journal of the Japanese Society of Neuropathology   28 ( 5 )   541 - 546   2008年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1440-1789.2008.00884.x

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  • Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions 査読

    Yasushi Nishihira, Chun-Feng Tan, Osamu Onodera, Yasuko Toyoshima, Mitsunori Yamada, Takashi Morita, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA   116 ( 2 )   169 - 182   2008年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    A nuclear protein, 43-kDa TAR DNA-binding protein (TDP-43), was recently identified as a component of the ubiquitinated inclusions (UIs) in frontotemporal lobar degeneration (FTLD-U) and sporadic amyotrophic lateral sclerosis (SALS). In the present study using immunohistochemistry, we examined various regions of the nervous system in a series of 35 SALS cases using a polyclonal antibody against TDP-43. Seven of the 35 cases had disease durations of more than 10 years with artificial respiratory support (ARS; duration: 69-156 months). In all cases, TDP-43-immunoreactive (ir) neuronal and glial cytoplasmic inclusions (NCIs and GCIs) were found together in many regions, including the histologically affected lower motor neuron nuclei. Cluster analysis of the distribution pattern of TDP-43-ir NCIs for cases without ARS (n = 28) identified two types (type 1, n = 16; type 2, n = 12). Type 2 was distinguished from type 1 by the presence of TDP-43-ir NCIs in the frontotemporal cortex, hippocampal formation, neostriatum and substantia nigra, and was significantly associated with dementia. Eleven of the 28 cases showed UIs in the hippocampal dentate granule cells, all of which had type-2 distribution pattern. Cases with ARS (n = 7) were also classified into the same types (type 1, n = 5; type 2, n = 2). Cases having type-1 distribution pattern (n = 21) showed no evident neuronal loss in most of the non-motor neuron nuclei where TDP-43-ir NCIs were present, whereas cases having type-2 distribution pattern (n = 14) often showed evident neuronal loss in the frontotemporal cortices, amygdaloid nuclei and substantia nigra. These findings indicate that SALS is a multisystem degenerative disease widely affecting both neurons and glial cells with a heterogeneous pattern of TDP-43-ir NCI distribution (SALS showing type-2 distribution pattern being closely linked to FTLD-U), and that long-term survival supported by a respirator has no apparent influence on the TDP-43 neuronal distribution pattern.

    DOI: 10.1007/s00401-008-0385-z

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  • Glial clusters and perineuronal glial satellitosis in the basal ganglia of neurofibromatosis type 1 査読

    Osamu Yokota, Kuniaki Tsuchiya, Masaharu Hayashi, Akiyoshi Kakita, Kiyoshi Ohwada, Hideki Ishizu, Hitoshi Takahashi, Haruhiko Akiyama

    ACTA NEUROPATHOLOGICA   116 ( 1 )   57 - 66   2008年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Recent biochemical studies demonstrated that astrocytic differentiation and growth regulation are impaired in neurofibromatosis type 1 (NF1). However, non-neoplastic morphological abnormalities of glial cells in the NF1 brain have been hardly explored. We describe here characteristic glial lesions in the basal ganglia in three NF1 cases (age at death in cases 1-3: 77, 6.5, and 11 years). Clusters of 3-10 dysplastic cells similar to reactive astrocytes were observed in the amygdala, caudate nucleus, putamen, thalamus in cases 1 and 2. Gigantic astrocyte-like glial cells were noted in case 2. Perineuronal glial satellitosis was observed in the amygdala in case 1. Many glial clusters were encountered in case 3 as well, but the round nuclei of the glial cells were more hyperchromatic and showed more remarkable variation in size than those in the other cases. Glial clusters in all cases were glial fibrillary acidic protein- and/or vimentin-positive, but synaptophysin-, myelin basic protein-, and olig2-negative. The glial lesions in cases 1 and 3 were excitatory amino acid transporters 1 (EAAT1)- and EAAT2-negative, and those in case 2 EAAT1- and EAAT2-weakly positive. Proliferation markers Ki-67, proliferation cell nuclear antigen, and cyclin D1 were not expressed in any lesion. Glial clusters in case 3 showed weak to intense immunoreactivity to nestin, a stem cell marker protein. The brains of 19 cases including 14 with various degenerative diseases and five normal brains used as controls lacked the glial lesions observed in NF1 cases. Given these findings, glial clusters and perineuronal glial satellitosis may be histopathological features of the NF1 brain and are probably associated with altered regulation of astrocyte growth in NF1.

    DOI: 10.1007/s00401-008-0390-2

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  • Venous congestive myelopathy: Three autopsy cases showing a variety of clinicopathologic features 査読

    Koushun Matsuo, Akiyoshi Kakita, Nobutaka Ishizu, Kohtaro Endo, Yumiko Watanabe, Takashi Morita, Hitoshi Takahashi

    NEUROPATHOLOGY   28 ( 3 )   303 - 308   2008年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    We describe three patients with progressive myelopathy, in whom autopsy revealed spinal cord pathology compatible with that of venous congestive myelopathy (VCM) associated with dural arteriovenous fistula (AVF), formerly known as angiodysgenetic necrotizing myelopathy (Foix-Alajournine syndrome). In these three patients, common symptoms were gait disturbance and sensory disturbance of the extremities, and these symptoms slowly worsened. The clinical diagnoses varied and included spinal cord intramedullary tumor, cervical spondylosis and multiple sclerosis. At autopsy, all the patients showed enlarged, tortuous venous vessels on the dorsal surfaces of the spinal cord at the affected levels. In the affected spinal cord parenchyma, necrotic lesions manifested by various degrees of neuronal loss and gliosis, with increased numbers of hyalinized vessels, were evident. The presence or absence of associated spinal dural AVF could not be identified histopathologically. Even with the help of modern neurological examination methods, early and accurate clinical diagnosis of VCM is sometimes difficult. When encountering patients with progressive myelopathy, VCM, although recognized as rare, should