2021/06/14 更新

写真a

イケウチ タケシ
池内 健
IKEUCHI Takeshi
所属
脳研究所 生命科学リソース研究センター 教授
医歯学総合研究科 分子細胞医学専攻 教授
職名
教授
外部リンク

学位

  • 医学博士 ( 2000年3月   新潟大学 )

研究分野

  • ライフサイエンス / 遺伝学  / 臨床遺伝学

  • ライフサイエンス / 神経内科学  / 認知症学

経歴(researchmap)

  • 新潟大学 医歯学総合病院 ゲノム診療部 遺伝医療センター長(併任)   Medical and Dental Hospital

    2020年 - 現在

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  • 新潟大学   脳研究所 生命科学リソース研究センター   教授

    2013年 - 現在

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  • 新潟大学 研究推進機構 学術超域院   Institute for Research Promotion

    2011年 - 2013年

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  • 文部科学省 研究振興局 学術調査官(併任)

    2007年 - 2008年

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  • 新潟大学 脳研究所 生命科学リソース研究センター   Brain Research Institute

    2004年 - 2010年

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  • 新潟大学 医歯学総合病院 神経内科   Neurology, Medical and Dental Hospital

    2003年 - 2004年

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  • シカゴ大学 神経生物センター

    2000年 - 2003年

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  • 日本学術振興会 海外特別研究員

    2000年 - 2002年

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経歴

  • 新潟大学   医歯学総合病院 遺伝医療支援センター   教授

    2020年4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   教授

    2013年4月 - 現在

  • 新潟大学   医歯学総合研究科 分子細胞医学専攻   教授

    2013年4月 - 現在

  • 新潟大学   医歯学総合研究科 医科学専攻   教授

    2013年4月 - 現在

  • 新潟大学   研究推進機構 超域学術院   准教授

    2011年4月 - 2013年3月

  • 新潟大学   脳研究所 生命科学リソース研究センター   助教

    2007年4月 - 2011年3月

  • 新潟大学   脳研究所 生命科学リソース研究センター   助手

    2004年5月 - 2007年3月

  • 新潟大学   医歯学総合病院   助手

    2003年10月 - 2004年4月

  • 新潟大学   医学部附属病院   医員

    2003年4月 - 2003年9月

▶ 全件表示

学歴

  • 新潟大学 大学院 医学研究科

    1996年4月 - 2000年3月

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  • 新潟大学 医学部 医学科

    1984年4月 - 1991年3月

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論文

  • Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer's disease risk. 国際誌

    Daichi Shigemizu, Risa Mitsumori, Shintaro Akiyama, Akinori Miyashita, Takashi Morizono, Sayuri Higaki, Yuya Asanomi, Norikazu Hara, Gen Tamiya, Kengo Kinoshita, Takeshi Ikeuchi, Shumpei Niida, Kouichi Ozaki

    Translational psychiatry11 ( 1 ) 151 - 151   2021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)  

    Alzheimer's disease (AD) has no cure, but early detection and risk prediction could allow earlier intervention. Genetic risk factors may differ between ethnic populations. To discover novel susceptibility loci of AD in the Japanese population, we conducted a genome-wide association study (GWAS) with 3962 AD cases and 4074 controls. Out of 4,852,957 genetic markers that passed stringent quality control filters, 134 in nine loci, including APOE and SORL1, were convincingly associated with AD. Lead SNPs located in seven novel loci were genotyped in an independent Japanese AD case-control cohort. The novel locus FAM47E reached genome-wide significance in a meta-analysis of association results. This is the first report associating the FAM47E locus with AD in the Japanese population. A trans-ethnic meta-analysis combining the results of the Japanese data sets with summary statistics from stage 1 data of the International Genomics of Alzheimer's Project identified an additional novel susceptibility locus in OR2B2. Our data highlight the importance of performing GWAS in non-European populations.

    DOI: 10.1038/s41398-021-01272-3

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  • Cingulate Island Sign in Single Photon Emission Computed Tomography: Clinical Biomarker Correlations in Lewy Body Disease and Alzheimer's Disease. 国際誌

    Akinori Futamura, Sotaro Hieda, Yukiko Mori, Azusa Sugimoto, Hideyo Kasai, Takeshi Kuroda, Satoshi Yano, Kensaku Kasuga, Hidetomo Murakami, Takeshi Ikeuchi, Kenjiro Ono

    Journal of Alzheimer's disease : JAD79 ( 3 ) 1003 - 1008   2021年

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    記述言語:英語  

    We compared 'CIScore' determined by quantitative single photon emission computed tomography studies of the cingulate island sign to cerebrospinal fluid (CSF) biomarkers in Lewy body disease (LBD) and Alzheimer's disease (AD) to assess its usefulness and pathological background. Among the 16 each age-matched LBD and AD patients, the CIScore differed significantly but was not correlated with CSF biomarkers. In LBD, hippocampal atrophy significantly correlated with Clinical Dementia Rating and CSF p-tau and t-tau levels. Our results showed CIS was not related to CSF biomarkers in LBD and high CSF tau levels were related to clinical disease severity and hippocampal atrophy.

    DOI: 10.3233/JAD-201145

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  • Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations. 国際誌

    Masaki Nakano, Yachiyo Mitsuishi, Lei Liu, Naoki Watanabe, Emi Hibino, Saori Hata, Takashi Saito, Takaomi C Saido, Shigeo Murayama, Kensaku Kasuga, Takeshi Ikeuchi, Toshiharu Suzuki, Masaki Nishimura

    Journal of Alzheimer's disease : JAD80 ( 1 ) 159 - 174   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer's disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. OBJECTIVE: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. METHODS: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. RESULTS: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. CONCLUSION: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.

    DOI: 10.3233/JAD-201174

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  • Prevalence and subtype distribution of early-onset dementia in Japan. 国際誌

    Shuichi Awata, Ayako Edahiro, Tetsuaki Arai, Manabu Ikeda, Takeshi Ikeuchi, Shinobu Kawakatsu, Yoko Konagaya, Kazuo Miyanaga, Hidetaka Ota, Kyoko Suzuki, Satoshi Tanimukai, Kumiko Utsumi, Tatsuyuki Kakuma

    Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society20 ( 6 ) 817 - 823   2020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)  

    AIM: People living with early-onset dementia (EOD) have specific social needs. Epidemiological studies are needed to obtain current information and provide appropriate service planning. This study aimed to clarify the current prevalence and subtype distribution of EOD, as well as the services frequently used by individuals with EOD. METHODS: A multisite, population-based, two-step study was conducted. Questionnaires were sent to 26 416 candidate facilities in 12 areas with a target population of 11 630 322 to inquire whether any individuals with EOD had sought services or stayed during the last 12 months (step 1). When "yes" responses were received, additional questionnaires were sent to the facilities both to complete and to distribute to the target individuals with EOD to obtain more detailed information, including the dementia subtype (step 2). RESULTS: In step 1, valid responses were obtained from 16 848 facilities (63.8%), and 4077 cases were identified. In step 2, detailed information was obtained for 1614 cases (39.6%) from the facilities and 530 cases (13.0%) from the individuals. The national EOD prevalence rate was estimated to be 50.9/100 000 population at risk (95% confidence interval: 43.9-57.9; age range, 18-64 years). The number of individuals with EOD was estimated to be 35 700 as of 2018. Alzheimer-type dementia (52.6%) was the most frequent subtype, followed by vascular dementia (17.1%), frontotemporal dementia (9.4%), dementia due to traumatic brain injury (4.2%), dementia with Lewy bodies/Parkinson's disease dementia (4.1%), and dementia due to alcohol-related disorders (2.8%). Individuals with EOD were most frequently identified at medical centers for dementia. CONCLUSION: The prevalence rate estimated in this study was comparable to those in previous studies in Japan. However, the subtype distribution differed, with Alzheimer-type dementia being the most prominent. Based on the case identification frequencies, medical centers for dementia are expected to continue to function as the primary special health service by providing quality diagnosis and post-diagnostic support for individuals with EOD.

    DOI: 10.1111/psyg.12596

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  • Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3. 国際誌

    Mercedes Prudencio, Hector Garcia-Moreno, Karen R Jansen-West, Rana Hanna Al-Shaikh, Tania F Gendron, Michael G Heckman, Matthew R Spiegel, Yari Carlomagno, Lillian M Daughrity, Yuping Song, Judith A Dunmore, Natalie Byron, Björn Oskarsson, Katharine A Nicholson, Nathan P Staff, Sorina Gorcenco, Andreas Puschmann, João Lemos, Cristina Januário, Mark S LeDoux, Joseph H Friedman, James Polke, Robin Labrum, Vikram Shakkottai, Hayley S McLoughlin, Henry L Paulson, Takuya Konno, Osamu Onodera, Takeshi Ikeuchi, Mari Tada, Akiyoshi Kakita, John D Fryer, Christin Karremo, Inês Gomes, John N Caviness, Mark R Pittelkow, Jan Aasly, Ronald F Pfeiffer, Venka Veerappan, Eric R Eggenberger, William D Freeman, Josephine F Huang, Ryan J Uitti, Klaas J Wierenga, Iris V Marin Collazo, Philip W Tipton, Jay A van Gerpen, Marka van Blitterswijk, Guojun Bu, Zbigniew K Wszolek, Paola Giunti, Leonard Petrucelli

    Science translational medicine12 ( 566 )   2020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)  

    Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

    DOI: 10.1126/scitranslmed.abb7086

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  • Globular glial tauopathy Type I presenting with behavioral variant frontotemporal dementia. 国際誌

    Mitsuaki Hirano, Shuji Iritani, Hiroshige Fujishiro, Youta Torii, Kunihiro Kawashima, Hirotaka Sekiguchi, Chikako Habuchi, Kentaro Yamada, Toshimasa Ikeda, Masato Hasegawa, Takeshi Ikeuchi, Mari Yoshida, Norio Ozaki

    Neuropathology : official journal of the Japanese Society of Neuropathology40 ( 5 ) 515 - 525   2020年10月

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    記述言語:英語  

    Globular glial tauopathy (GGT) is a recently proposed tauopathy characterized by the globular accumulation of four-repeat (4R) tau in the oligodendroglia (globular oligodendroglial inclusion (GOI)) and astrocytes (globular astrocytic inclusion (GAI)), in addition to deposition in neurons. Although it is proposed that GGT should be classified into three different neuropathological subtypes, previous reports have indicated that subclassification might be difficult in some cases. We report an autopy case of a 79-year-old man with behavioral variant frontotemporal dementia (bvFTD). He developed behavioral changes at 67 years of age and had auditory hallucinations and persecutory delusions at admission to a psychiatric hospital at 69 years of age. Neuropathologically, marked atrophy of the frontotemporal lobes and severe degeneration of the white matter and frontopontine tract were observed. The present case corresponded to GGT Type I, as numerous GOIs were observed, predominantly in the frontotemporal region. However, concurrent degeneration of the motor cortex and corticospinal tract suggest characteristics of Type II. Although the relationship between psychotic symptoms and GGT remains unclear, the present case demonstrates heterogeneity of GGT subtypes.

    DOI: 10.1111/neup.12668

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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 medicine26 ( 1 ) 131 - 142   2020年9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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  • 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 communications8 ( 1 ) 134 - 134   2020年8月

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  • A Novel Hypomorphic CSF1R Gene Mutation in the Biallelic State Leading to Fatal Childhood Neurodegeneration. 国際誌

    Parag Mohan Tamhankar, Bin Zhu, Vasundhara Parag Tamhankar, Shilpa Mithbawkar, Luis Seabra, John H Livingston, Takeshi Ikeuchi, Yanick J Crow

    Neuropediatrics51 ( 4 ) 302 - 306   2020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 report the clinical and molecular characterization of a novel biallelic mutation in the CSF1R gene leading to an autosomal recessive form of childhood onset leukoencephalopathy in a consanguineous family. The female child experienced acute encephalopathy at the age of 2 years, followed by spasticity and loss of all achieved milestones over 6 months. Her elder brother presented with encephalopathy at 4 years of age, with a subsequent loss of all achieved milestones over 8 months. Brain imaging in both children revealed multiple well-defined areas of calcification in the parietal and frontal regions and the occipital horns of both lateral ventricles. Clinical exome trio analysis showed homozygosity for a p.T833M mutation in CSF1R in the girl. Heterozygous family members, including both parents, were asymptomatic, with the eldest being 68 years of age. Total CSF1R protein expression levels were normal as compared with wild-type allele, but CSF1 ligand dependent autophosphorylation was consistent with a hypomorphic allele.

    DOI: 10.1055/s-0040-1702161

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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 communications8 ( 1 ) 75 - 75   2020年6月

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  • Author Correction: Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. 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 medicine26 ( 6 ) 981 - 981   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)  

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    DOI: 10.1038/s41591-020-0922-4

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  • Identification of calcium and integrin-binding protein 1 as a novel regulator of production of amyloid β peptide using CRISPR/Cas9-based screening system. 査読 国際誌

    Yung Wen Chiu, Yukiko Hori, Ihori Ebinuma, Haruaki Sato, Norikazu Hara, Takeshi Ikeuchi, Taisuke Tomita

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology34 ( 6 ) 7661 - 7674   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)  

    The aberrant metabolism of amyloid β peptide (Aβ) has been implicated in the etiology of Alzheimer disease (AD). Aβ is produced via the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases. However, the precise regulatory mechanism of Aβ generation still remains unclear. To gain a better understanding of the molecular mechanism of Aβ production, we established a genetic screening method based on the CRISPR/Cas9 system to identify novel regulators of Aβ production. We successfully identified calcium and integrin-binding protein 1 (CIB1) as a potential negative regulator of Aβ production. The disruption of Cib1 significantly upregulated Aβ levels. In addition, immunoprecipitation experiments demonstrated that CIB1 interacts with the γ-secretase complex. Moreover, the disruption of Cib1 specifically reduced the cell-surface localization of mature Nicastrin (Nct), which is a component of the γ-secretase complex, without changing the intrinsic activity of γ-secretase. Finally, we confirmed using the single-cell RNA-seq data in human that CIB1 mRNA level in neuron was decreased in the early stage of AD. Taken together, our results indicate that CIB1 regulates Aβ production via controlling the subcellular localization of γ-secretase, suggesting CIB1 is involved in the development of AD.

    DOI: 10.1096/fj.201902966RR

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  • Novel tau filament fold in corticobasal degeneration. 査読 国際誌

    Wenjuan Zhang, Airi Tarutani, Kathy L Newell, Alexey G Murzin, Tomoyasu Matsubara, Benjamin Falcon, Ruben Vidal, Holly J Garringer, Yang Shi, Takeshi Ikeuchi, Shigeo Murayama, Bernardino Ghetti, Masato Hasegawa, Michel Goedert, Sjors H W Scheres

    Nature580 ( 7802 ) 283 - 287   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)  

    Corticobasal degeneration (CBD) is a neurodegenerative tauopathy-a class of disorders in which the tau protein forms insoluble inclusions in the brain-that is characterized by motor and cognitive disturbances1-3. The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls4,5, and genome-wide association studies have identified additional risk factors6. By histology, astrocytic plaques are diagnostic of CBD7,8; by SDS-PAGE, so too are detergent-insoluble, 37 kDa fragments of tau9. Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease10, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats11-15. This distinguishes such '4R' tauopathies from Pick's disease (the filaments of which are made of three-repeat (3R) tau isoforms) and from Alzheimer's disease and chronic traumatic encephalopathy (CTE) (in which both 3R and 4R isoforms are found in the filaments)16. Here we use cryo-electron microscopy to analyse the structures of tau filaments extracted from the brains of three individuals with CBD. These filaments were identical between cases, but distinct from those seen in Alzheimer's disease, Pick's disease and CTE17-19. The core of a CBD filament comprises residues lysine 274 to glutamate 380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3 and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4.

    DOI: 10.1038/s41586-020-2043-0

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  • Disruption of a RAC1-centred network is associated with Alzheimer's disease pathology and causes age-dependent neurodegeneration. 査読 国際誌

    Masataka Kikuchi, Michiko Sekiya, Norikazu Hara, Akinori Miyashita, Ryozo Kuwano, Takeshi Ikeuchi, Koichi M Iijima, Akihiro Nakaya

    Human molecular genetics29 ( 5 ) 817 - 833   2020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)  

    The molecular biological mechanisms of Alzheimer's disease (AD) involve disease-associated crosstalk through many genes and include a loss of normal as well as a gain of abnormal interactions among genes. A protein domain network (PDN) is a collection of physical bindings that occur between protein domains, and the states of the PDNs in patients with AD are likely to be perturbed compared to those in normal healthy individuals. To identify PDN changes that cause neurodegeneration, we analysed the PDNs that occur among genes co-expressed in each of three brain regions at each stage of AD. Our analysis revealed that the PDNs collapsed with the progression of AD stage and identified five hub genes, including Rac1, as key players in PDN collapse. Using publicly available as well as our own gene expression data, we confirmed that the mRNA expression level of the RAC1 gene was downregulated in the entorhinal cortex (EC) of AD brains. To test the causality of these changes in neurodegeneration, we utilized Drosophila as a genetic model and found that modest knockdown of Rac1 in neurons was sufficient to cause age-dependent behavioural deficits and neurodegeneration. Finally, we identified a microRNA, hsa-miR-101-3p, as a potential regulator of RAC1 in AD brains. As the Braak neurofibrillary tangle (NFT) stage progressed, the expression levels of hsa-miR-101-3p were increased specifically in the EC. Furthermore, overexpression of hsa-miR-101-3p in the human neuronal cell line SH-SY5Y caused RAC1 downregulation. These results highlight the utility of our integrated network approach for identifying causal changes leading to neurodegeneration in AD.

    DOI: 10.1093/hmg/ddz320

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  • A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease. 査読 国際誌

    Nicolas R Barthélemy, Yan Li, Nelly Joseph-Mathurin, Brian A Gordon, Jason Hassenstab, Tammie L S Benzinger, Virginia Buckles, Anne M Fagan, Richard J Perrin, Alison M Goate, John C Morris, Celeste M Karch, Chengjie Xiong, Ricardo Allegri, Patricio Chrem Mendez, Sarah B Berman, Takeshi Ikeuchi, Hiroshi Mori, Hiroyuki Shimada, Mikio Shoji, Kazushi Suzuki, James Noble, Martin Farlow, Jasmeer Chhatwal, Neill R Graff-Radford, Stephen Salloway, Peter R Schofield, Colin L Masters, Ralph N Martins, Antoinette O'Connor, Nick C Fox, Johannes Levin, Mathias Jucker, Audrey Gabelle, Sylvain Lehmann, Chihiro Sato, Randall J Bateman, Eric McDade

    Nature medicine26 ( 3 ) 398 - 407   2020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)  

    Development of tau-based therapies for Alzheimer's disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer's disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.

    DOI: 10.1038/s41591-020-0781-z

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  • Structurally distinct α-synuclein fibrils induce robust parkinsonian pathology. 査読 国際誌

    Hideki Hayakawa, Rie Nakatani, Kensuke Ikenaka, Cesar Aguirre, Chi-Jing Choong, Hiroshi Tsuda, Seiichi Nagano, Masato Koike, Takeshi Ikeuchi, Masato Hasegawa, Stella M Papa, Yoshitaka Nagai, Hideki Mochizuki, Kousuke Baba

    Movement disorders : official journal of the Movement Disorder Society35 ( 2 ) 256 - 267   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: Alpha-synuclein (α-syn) is a major component of Lewy bodies, which are the pathological hallmark in Parkinson's disease, and its genetic mutations cause familial forms of Parkinson's disease. Patients with α-syn G51D mutation exhibit severe clinical symptoms. However, in vitro studies showed low propensity for α-syn with the G51D mutation. We studied the mechanisms associated with severe neurotoxicity of α-syn G51D mutation using a murine model generated by G51D α-syn fibril injection into the brain. METHODS: Structural analysis of wild-type and G51D α-syn-fibrils were performed using Fourier transform infrared spectroscopy. The ability of α-syn fibrils forming aggregates was first assessed in in vitro mammalian cells. An in vivo mouse model with an intranigral injection of α-syn fibrils was then used to evaluate the propagation pattern of α-syn and related cellular changes. RESULTS: We found that G51D α-syn fibrils have higher β-sheet contents than wild-type α-syn fibrils. The addition of G51D α-syn fibrils to mammalian cells overexpressing α-syn resulted in the formation of phosphorylated α-syn inclusions at a higher rate. Similarly, an injection of G51D α-syn fibrils into the substantia nigra of a mouse brain induced more widespread phosphorylated α-syn pathology. Notably, the mice injected with G51D α-syn fibrils exhibited progressive nigral neuronal loss accompanied with mitochondrial abnormalities and motor impairment. CONCLUSION: Our findings indicate that the structural difference of G51D α-syn fibrils plays an important role in the rapidly developed and more severe neurotoxicity of G51D mutation-linked Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

    DOI: 10.1002/mds.27887

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  • Different clinical and neuroimaging features of Japanese dementia siblings with a new N-terminal mutation (Val225Ala) of APP gene. 査読 国際誌

    Yasuyuki Ohta, Nozomi Hishikawa, Ken Ikegami, Kota Sato, Yosuke Osakada, Mami Takemoto, Toru Yamashita, Yoshio Omote, Takeshi Ikeuchi, Koji Abe

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia72   482 - 484   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)  

    Autosomal dominant amyloid precursor protein (APP) mutations in familial Alzheimer's disease accelerate the amyloid beta (Aβ) pathology. Here we describe Japanese siblings with a new N-terminal mutation (a heterogeneous c.674T>C, p.Val225Ala) of the APP gene, developing a progressive dementia at 57 years and Aβ and tau pathologies in cerebrospinal fluid studies. However, the brother and sister showed different clinical and neuroimaging features, suggesting different Aβ pathologies for each sibling.

    DOI: 10.1016/j.jocn.2019.11.009

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  • Effect of apolipoprotein E ε4 allele on the progression of cognitive decline in the early stage of Alzheimer's disease. 査読 国際誌

    Kazushi Suzuki, Akihiro Hirakawa, Ryoko Ihara, Atsushi Iwata, Kenji Ishii, Takeshi Ikeuchi, Chung-Kai Sun, Michael Donohue, Takeshi Iwatsubo

    Alzheimer's & dementia (New York, N. Y.)6 ( 1 ) e12007   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Introduction: Possession of the apolipoprotein E (APOE) ε4 allele advances amyloid β (Aβ) deposition and symptomatic onset of Alzheimer's disease (AD), whereas its effect on the rate of cognitive decline remained controversial. We examined the effects of APOE ε4 allele on cognition in biomarker-confirmed late mild cognitive impairment (LMCI) and mild AD subjects in the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) and North American ADNI (NA-ADNI). Methods: The "early AD" (ie, combined LMCI and mild AD) cohort of 649 subjects from J-ADNI and NA-ADNI were selected based on positivity of Aβ confirmed by amyloid positron emission tomography (PET) or cerebrospinal fluid testing. The rates of cognitive decline in the Mini Mental State Examination (MMSE), the Clinical Dementia Rating Sum of Boxes (CDR-SB), and the Alzheimer's Disease Assessment Scale-cognitive subscale 13 (ADAS-Cog) from baseline were examined using mixed-effects model. The effect of ε4 on time to conversion to dementia was also analyzed in LMCI using the Kaplan-Meier estimator and log-rank test. Results: The rates of cognitive decline were not significantly different between ε4 carriers and ε4 non-carriers in the total early AD cohort, which were affected neither by region nor by the number of ε4 alleles. In LMCI, ε4 carriers showed almost the same progression rates as ε4 non-carriers, except for a significantly faster decline in MMSE (P = .0282). Time to conversion to demenita was not significantly different between ε4 carriers and ε4 non-carriers. In ε4-positive mild AD, the rates of decline in MMSE (P = .003) and CDR-SB (P = .0071) were slower than those in ε4 non-carriers. DISCUSSION: The APOE ε4 allele had little effect on the rates of cognitive decline in the overall biomarker-confirmed early AD, regardless of region and number of ε4 alleles, with a slight variability in different clinical stages, the ε4 allele being slightly accelerative in LMCI, while decelerative in mild AD.

    DOI: 10.1002/trc2.12007

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  • HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature. 国際誌

    Masahiro Uemura, Hiroaki Nozaki, Taisuke Kato, Akihide Koyama, Naoko Sakai, Shoichiro Ando, Masato Kanazawa, Nozomi Hishikawa, Yoshinori Nishimoto, Kiran Polavarapu, Atchayaram Nalini, Akira Hanazono, Daisuke Kuzume, Akihiro Shindo, Mohammad El-Ghanem, Arata Abe, Aki Sato, Mari Yoshida, Takeshi Ikeuchi, Ikuko Mizuta, Toshiki Mizuno, Osamu Onodera

    Frontiers in neurology11   545 - 545   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is clinically characterized by early-onset dementia, stroke, spondylosis deformans, and alopecia. In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds. CARASIL is caused by a homozygous mutation in high-temperature requirement A serine peptidase 1 (HTRA1). Recently, it was reported that several heterozygous mutations in HTRA1 also cause cerebral small vessel disease (CSVD). Although patients with heterozygous HTRA1-related CSVD (symptomatic carriers) are reported to have a milder form of CARASIL, little is known about the clinical and genetic differences between the two diseases. Given this gap in the literature, we collected clinical information on HTRA1-related CSVD from a review of the literature to help clarify the differences between symptomatic carriers and CARASIL and the features of both diseases. Forty-six symptomatic carriers and 28 patients with CARASIL were investigated. Twenty-eight mutations in symptomatic carriers and 22 mutations in CARASIL were identified. Missense mutations in symptomatic carriers are more frequently identified in the linker or loop 3 (L3)/loop D (LD) domains, which are critical sites in activating protease activity. The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL, and the frequency of characteristic extraneurological findings and confluent WMHs were significantly higher in CARASIL than in symptomatic carriers. As previously reported, heterozygous HTRA1-related CSVD has a milder clinical presentation of CARASIL. It seems that haploinsufficiency can cause CSVD among symptomatic carriers according to the several patients with heterozygous nonsense/frameshift mutations. However, the differing locations of mutations found in the two diseases indicate that distinct molecular mechanisms influence the development of CSVD in patients with HTRA1-related CSVD. These findings further support continued careful examination of the pathogenicity of mutations located outside the linker or LD/L3 domain in symptomatic carriers.

    DOI: 10.3389/fneur.2020.00545

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  • Morphological characterisation of glial and neuronal tau pathology in globular glial tauopathy (Types II and III). 査読 国際誌

    H Tanaka, Y Toyoshima, S Kawakatsu, R Kobayashi, O Yokota, S Terada, S Kuroda, T Miura, Y Higuchi, H Otsu, K Sanpei, K Otani, T Ikeuchi, O Onodera, A Kakita, H Takahashi

    Neuropathology and applied neurobiology   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)  

    AIMS: Globular glial tauopathy (GGT) is a new category within the 4-repeat tauopathies that is characterised neuropathologically by tau-positive globular glial inclusions (GGIs), namely, globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). Occurrence of tau-positive neuronal cytoplasmic inclusions (NCIs) is also a feature. GGT is classified into three pathological subtypes (Types I, II and III). We studied the tau pathology in 6 cases of GGT (Type II, n = 3; Type III, n = 3), with special reference to GAIs and NCIs. METHODS: Neuropathological examinations were conducted, along with immunohistochemistry, morphometry and three-dimensional imaging, and biochemical and genetic analysis of tau. RESULTS: The cortical GAIs in Type II and those in Type III were distinguishable from each other. In the motor cortex, GAIs were much more numerous in Type III than in Type II. Prominent occurrence of perikaryal globular structures was a feature of GAIs in Type III. By contrast, prominent occurrence of radiating process-like structures was a feature of GAIs in Type II. Overall, the GAIs were significantly smaller in Type III than in Type II. NCIs were divisible into three subgroups in terms of shape: diffuse granular, thick cord-like, and round/horseshoe-shaped structures. In all cases, NCIs were a feature of the upper and lower motor neurons. Interestingly, the round/horseshoe-shaped NCIs were observed only in Type III cases. CONCLUSIONS: These findings, which characterised GAIs and NCIs, indicated that Type II and Type III constitute two distinct pathological subtypes, and also further strengthen the concept of GGT as a distinct entity.

    DOI: 10.1111/nan.12581

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  • Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs. 査読 国際誌

    Nakamura M, Shiozawa S, Tsuboi D, Amano M, Watanabe H, Maeda S, Kimura T, Yoshimatsu S, Kisa F, Karch CM, Miyasaka T, Takashima A, Sahara N, Hisanaga SI, Ikeuchi T, Kaibuchi K, Okano H

    Stem cell reports13 ( 4 ) 684 - 699   2019年10月

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  • [Exploring Therapeutic Targets for Alzheimer's Disease by Comprehensive Genetic Analysis]. 査読

    Ikeuchi T

    Brain and nerve = Shinkei kenkyu no shinpo71 ( 10 ) 1081 - 1088   2019年10月

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    記述言語:日本語  

    DOI: 10.11477/mf.1416201407

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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 Japan33 ( 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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  • Enhancer variants associated with Alzheimer's disease affect gene expression via chromatin looping. 査読 国際誌

    Kikuchi M, Hara N, Hasegawa M, Miyashita A, Kuwano R, Ikeuchi T, Nakaya A

    BMC medical genomics12 ( 1 ) 128 - 128   2019年9月

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  • <i>APOE</i> Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of <i>APOE</i> ε4 on Alzheimer's Disease Risk in a Multiracial Sample. 査読 国際誌

    Choi KY, Lee JJ, Gunasekaran TI, Kang S, Lee W, Jeong J, Lim HJ, Zhang X, Zhu C, Won SY, Choi YY, Seo EH, Lee SC, Gim J, Chung JY, Chong A, Byun MS, Seo S, Ko PW, Han JW, McLean C, Farrell J, Lunetta KL, Miyashita A, Hara N, Won S, Choi SM, Ha JM, Jeong JH, Kuwano R, Song MK, An SSA, Lee YM, Park KW, Lee HW, Choi SH, Rhee S, Song WK, Lee JS, Mayeux R, Haines JL, Pericak-Vance MA, Choo ILH, Nho K, Kim KW, Lee DY, Kim S, Kim BC, Kim H, Jun GR, Schellenberg GD, Ikeuchi T, Farrer LA, Lee KH, Neuroimaging Initative AD

    Journal of clinical medicine8 ( 8 )   2019年8月

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    記述言語:英語  

    DOI: 10.3390/jcm8081236

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

    Piatnitskaia S, Takahashi M, Kitaura H, Katsuragi Y, Kakihana T, Zhang L, Kakita A, Iwakura Y, Nawa H, Miura T, Ikeuchi T, Hara T, Fujii M

    Scientific reports9 ( 1 ) 10591 - 10591   2019年7月

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  • A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer's disease. 査読 国際誌

    Asanomi Y, Shigemizu D, Miyashita A, Mitsumori R, Mori T, Hara N, Ito K, Niida S, Ikeuchi T, Ozaki K

    Molecular medicine (Cambridge, Mass.)25 ( 1 ) 20 - 20   2019年6月

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  • Correlated levels of cerebrospinal fluid pathogenic proteins in drug-naïve Parkinson's disease. 査読 国際誌

    Murakami H, Tokuda T, El-Agnaf OMA, Ohmichi T, Miki A, Ohashi H, Owan Y, Saito Y, Yano S, Tsukie T, Ikeuchi T, Ono K

    BMC neurology19 ( 1 ) 113 - 113   2019年6月

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  • Cerebral hemorrhagic stroke associated with cerebral amyloid angiopathy in young adults about 3 decades after neurosurgeries in their infancy. 査読 国際誌

    Hamaguchi T, Komatsu J, Sakai K, Noguchi-Shinohara M, Aoki S, Ikeuchi T, Yamada M

    Journal of the neurological sciences399   3 - 5   2019年4月

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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 Neuropathology39 ( 2 ) 111 - 119   2019年4月

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    記述言語:英語  

    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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  • Low serum 25-hydroxyvitamin D increases cognitive impairment in elderly people. 査読

    Mayumi Sakuma, Kaori Kitamura, Naoto Endo, Takeshi Ikeuchi, Akio Yokoseki, Osamu Onodera, Takeo Oinuma, Takeshi Momotsu, Kenji Sato, Kazutoshi Nakamura, Ichiei Narita

    Journal of bone and mineral metabolism37 ( 2 ) 368 - 375   2019年3月

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    記述言語:英語  

    It has been reported that many elderly people have low serum levels of 25-hydroxyvitamin D [25(OH)D] and that serum 25(OH)D levels may have a relationship with cognitive function. The aim of this study was to examine the relationship between serum 25(OH)D levels and cognitive function in a Japanese population. This cross-sectional study was performed as a part of the Project in Sado for Total Health (PROST). The PROST study evaluated cognitive state and serum vitamin D level from June 2011 to November 2013 for 740 patients (431 men and 309 women). The Mini-Mental State Examination-Japanese version (MMSE-J) and serum 25(OH)D level measurements were used as assessment tools. Cognitive impairment was defined using MMSE-J ≤ 23 as a cutoff. Multiple logistic regression analyses were performed to calculate the odds ratios (ORs) for low MMSE-J scores. The average subject age was 68.1 years, the average MMSE- J score was 25.9, and the average 25(OH)D level was 24.6 ng/mL. Significant ORs for cognitive impairment were observed for both high age and low serum 25(OH)D. The adjusted OR for the lowest versus highest serum 25(OH)D quartiles was 2.70 (95% confidence interval 1.38-5.28, P = 0.0110). Low serum 25(OH)D levels were independently associated with a higher prevalence of cognitive impairment.

    DOI: 10.1007/s00774-018-0934-z

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  • Young adult-onset, very slowly progressive cognitive decline with spastic paraparesis in Alzheimer's disease with cotton wool plaques due to a novel presenilin1 G417S mutation. 査読 国際誌

    Miki T, Yokota O, Haraguchi T, Ikeuchi T, Zhu B, Takenoshita S, Terada S, Yamada N

    Acta neuropathologica communications7 ( 1 ) 19 - 19   2019年2月

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  • Soluble LR11 competes with amyloid β in binding to cerebrospinal fluid-high-density lipoprotein. 査読

    Yano K, Hirayama S, Misawa N, Furuta A, Ueno T, Motoi Y, Seino U, Ebinuma H, Ikeuchi T, Schneider WJ, Bujo H, Miida T

    Clinica chimica acta; international journal of clinical chemistry489   29 - 34   2019年2月

  • Molecular Network Analysis of the Urinary Proteome of Alzheimer's Disease Patients. 査読

    Watanabe Y, Hirao Y, Kasuga K, Tokutake T, Semizu Y, Kitamura K, Ikeuchi T, Nakamura K, Yamamoto T

    Dementia and geriatric cognitive disorders extra9 ( 1 ) 53 - 65   2019年1月

  • Visualizing modules of coordinated structural brain atrophy during the course of conversion to Alzheimer's disease by applying methodology from gene co-expression analysis. 査読 国際誌

    Kenichiro Sato, Tatsuo Mano, Hiroshi Matsuda, Michio Senda, Ryoko Ihara, Kazushi Suzuki, Hiroyuki Arai, Kenji Ishii, Kengo Ito, Takeshi Ikeuchi, Ryozo Kuwano, Tatsushi Toda, Takeshi Iwatsubo, Atsushi Iwata

    NeuroImage. Clinical24   101957 - 101957   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: We aimed to identify modularized structural atrophy of brain regions with a high degree of connectivity and its longitudinal changes associated with the progression of Alzheimer's disease (AD) using weighted gene co-expression network analysis (WGCNA), which is an unsupervised hierarchical clustering method originally used in genetic analysis. METHODS: We included participants with late mild cognitive impairment (MCI) at baseline from the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) study. We imputed normalized and Z-transformed structural volume or cortical thickness data of 164 parcellated brain regions/structures based on the calculations of the FreeSurfer software. We applied the WGCNA to extract modules with highly interconnected structural atrophic patterns and examined the correlation between the identified modules and clinical AD progression. RESULTS: We included 204 participants from the baseline dataset, and performed a follow-up with 100 in the 36-month dataset of MCI cohort participants from the J-ADNI. In the univariate correlation or variable importance analysis, baseline atrophy in temporal lobe regions/structures significantly predicted clinical AD progression. In the WGCNA consensus analysis, co-atrophy modules associated with MCI conversion were first distributed in the temporal lobe and subsequently extended to adjacent parietal cortical regions in the following 36 months. CONCLUSIONS: We identified coordinated modules of brain atrophy and demonstrated their longitudinal extension along with the clinical course of AD progression using WGCNA, which showed a good correspondence with previous pathological studies of the tau propagation theory. Our results suggest the potential applicability of this methodology, originating from genetic analyses, for the surrogate visualization of the underlying pathological progression in neurodegenerative diseases not limited to AD.

    DOI: 10.1016/j.nicl.2019.101957

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  • Decrease in p3-Alcβ37 and p3-Alcβ40, products of Alcadein β generated by γ-secretase cleavages, in aged monkeys and patients with Alzheimer's disease. 査読 国際誌

    Saori Hata, Chiori Omori, Ayano Kimura, Haruka Saito, Nobuyuki Kimura, Veer Gupta, Steve Pedrini, Eugene Hone, Pratishtha Chatterjee, Kevin Taddei, Kensaku Kasuga, Takeshi Ikeuchi, Masaaki Waragai, Masaki Nishimura, Anqi Hu, Tadashi Nakaya, Laurent Meijer, Masahiro Maeda, Tohru Yamamoto, Colin L Masters, Chris C Rowe, David Ames, Kazuo Yamamoto, Ralph N Martins, Sam Gandy, Toshiharu Suzuki

    Alzheimer's & dementia (New York, N. Y.)5   740 - 750   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Introduction: Neuronal p3-Alcβ peptides are generated from the precursor protein Alcadein β (Alcβ) through cleavage by α- and γ-secretases of the amyloid β (Aβ) protein precursor (APP). To reveal whether p3-Alcβ is involved in Alzheimer's disease (AD) contributes for the development of novel therapy and/or drug targets. Methods: We developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF). Results: In monkeys, CSF p3-Alcβ decreases with age, and the aging is also accompanied by decreased brain expression of Alcβ. In humans, CSF p3-Alcβ levels decrease to a greater extent in those with AD than in age-matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3-Alcβ level. A cell study with an inverse modulator of γ-secretase remarkably reduces the generation of p3-Alcβ37 while increasing the production of Aβ42. Discussion: Aging decreases the generation of p3-Alcβ, and further significant decrease of p3-Alcβ caused by aberrant γ-secretase activity may accelerate pathogenesis in AD.

    DOI: 10.1016/j.trci.2019.09.015

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  • Lower Serum Calcium as a Potentially Associated Factor for Conversion of Mild Cognitive Impairment to Early Alzheimer's Disease in the Japanese Alzheimer's Disease Neuroimaging Initiative. 査読 国際誌

    Kenichiro Sato, Tatsuo Mano, Ryoko Ihara, Kazushi Suzuki, Naoki Tomita, Hiroyuki Arai, Kenji Ishii, Michio Senda, Kengo Ito, Takeshi Ikeuchi, Ryozo Kuwano, Hiroshi Matsuda, Takeshi Iwatsubo, Tatsushi Toda, Atsushi Iwata

    Journal of Alzheimer's disease : JAD68 ( 2 ) 777 - 788   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Effect of serum calcium level to the incidence of mild cognitive impairment (MCI) conversion to early Alzheimer's disease (AD) remains uncertain. OBJECTIVE: To investigate association between baseline serum calcium and the MCI conversion in the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) study cohort. METHODS: In this sub-analysis of J-ADNI study, we reviewed data from MCI participants at baseline regarding their conversion to early AD during the 3 years of observation period and assessed the associated factors including serum calcium level. In addition, we compared our results from the J-ADNI study with the corresponding results from the North American (NA)-ADNI. RESULTS: Of 234 eligible MCI participants from the J-ADNI cohort, 121 (51.7%) converted to AD during the first 36 months of observation. Using univariate analysis, being female, having shorter years of education, and lower serum calcium level were correlated with increased risk of MCI-to-AD conversion exclusively in J-ADNI cohort. The lower corrected serum calcium level remained as one of conversion-associated factors in the J-ADNI cohort even after adjustment for multiple confounding variables, although this was not observed in the NA-ADNI cohort. CONCLUSION: Our findings suggest that lower serum calcium may be associated with an increased risk of MCI conversion to AD in Japanese cohorts. The reason for this correlation remains unclear and further external validation using other Asian cohorts is needed. It would be interesting for future AD studies to obtain serum calcium levels and other related factors, such as vitamin D levels, culture-specific dietary or medication information.

    DOI: 10.3233/JAD-181115

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  • CSF1R-related leukoencephalopathy: A major player in primary microgliopathies. 査読 国際誌

    Takuya Konno, Koji Kasanuki, Takeshi Ikeuchi, Dennis W Dickson, Zbigniew K Wszolek

    Neurology91 ( 24 ) 1092 - 1104   2018年12月

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    記述言語:英語  

    Since the discovery of CSF1R gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, CSF1R-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s-50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of Csf1r haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic phenotypes consistent with those of human patients with CSF1R mutations. In vitro, perturbation of CSF1R signaling is shown in cultured cells expressing mutant CSF1R. However, the underlying mechanisms by which CSF1R mutations selectively lead to white matter degeneration remains to be elucidated. Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies, of which microglia have a pivotal and primary role in pathogenesis. In this review, we address the current knowledge of CSF1R-related leukoencephalopathy and discuss the putative pathophysiology, with a focus on microglia, as well as future research directions.

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  • 前頭側頭型認知症の前方向的コホート研究FTLD-Jの現状

    新井, 哲明, 桝田 道人, 渡辺 宏久, 小倉 礼, 加藤 隼康, 森 康治, 繁信 和恵, 三木 知子, 品川 俊一郎, 東 晋二, 渡辺 保裕, 横田 修, 池内 健, 和泉 唯信, 森 悦朗, 中島 健二, 勝野 雅央, 池田 学, 祖父江 元

    臨床神経学58   2018年12月

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    記述言語:日本語   掲載種別:研究論文(その他学術会議資料等)  

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  • Duplication and deletion upstream of <i>LMNB1</i> in autosomal dominant adult-onset leukodystrophy. 査読 国際誌

    Mezaki N, Miura T, Ogaki K, Eriguchi M, Mizuno Y, Komatsu K, Yamazaki H, Suetsugi N, Kawajiri S, Yamasaki R, Ishiguro T, Konno T, Nozaki H, Kasuga K, Okuma Y, Kira JI, Hara H, Onodera O, Ikeuchi T

    Neurology. Genetics4 ( 6 ) e292   2018年12月

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  • Remarkable behavioural signs and progressive non-fluent aphasia in a patient with adult-onset leucoencephalopathy with axonal spheroids and pigmented glia. 査読

    Funayama M, Sugihara M, Takata T, Mimura M, Ikeuchi T

    Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society   2018年11月

  • Identification and functional characterization of novel mutations including frameshift mutation in exon 4 of CSF1R in patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. 査読 国際誌

    Takeshi Miura, Naomi Mezaki, Takuya Konno, Akio Iwasaki, Naoyuki Hara, Masatomo Miura, Michitaka Funayama, Yuki Unai, Yuichi Tashiro, Kenji Okita, Takeshi Kihara, Nobuo Ito, Yoichi Kanatsuka, David T Jones, Norikazu Hara, Takanobu Ishiguro, Takayoshi Tokutake, Kensaku Kasuga, Hiroaki Nozaki, Dennis W Dickson, Osamu Onodera, Zbigniew K Wszolek, Takeshi Ikeuchi

    Journal of neurology265 ( 10 ) 2415 - 2424   2018年10月

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    記述言語:英語  

    OBJECTIVE: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutations in CSF1R. Pathogenic mutations in exons 12-22 including coding sequence of the tyrosine kinase domain (TKD) of CSF1R were previously identified. We aimed to identify CSF1R mutations in patients who were clinically suspected of having ALSP and to determine the pathogenicity of novel CSF1R variants. METHODS: Sixty-one patients who fulfilled the diagnostic criteria of ALSP were included in this study. Genetic analysis of CSF1R was performed for all the coding exons. The haploinsufficiency of CSF1R was examined for frameshift mutations by RT-PCR. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing CSF1R mutants. RESULTS: We identified ten variants in CSF1R including two novel frameshift, five novel missense, and two known missense mutations as well as one known missense variant. Eight mutations were located in TKD. One frameshift mutation (p.Pro104LeufsTer8) and one missense variant (p.His362Arg) were located in the extracellular domain. RT-PCR analysis revealed that the frameshift mutation of p.Pro104LeufsTer8 caused nonsense-mediated mRNA decay. Functional assay revealed that none of the mutations within TKD showed autophosphorylation of CSF1R. The p.His362Arg variant located in the extracellular domain showed comparable autophosphorylation of CSF1R to the wild type, suggesting that this variant is not likely pathogenic. CONCLUSIONS: The detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of ALSP with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP.

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  • Japanese and North American Alzheimer's Disease Neuroimaging Initiative studies: Harmonization for international trials. 査読 国際誌

    Takeshi Iwatsubo, Atsushi Iwata, Kazushi Suzuki, Ryoko Ihara, Hiroyuki Arai, Kenji Ishii, Michio Senda, Kengo Ito, Takeshi Ikeuchi, Ryozo Kuwano, Hiroshi Matsuda, Chung-Kai Sun, Laurel A Beckett, Ronald C Petersen, Michael W Weiner, Paul S Aisen, Michael C Donohue

    Alzheimer's & dementia : the journal of the Alzheimer's Association14 ( 8 ) 1077 - 1087   2018年8月

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    記述言語:英語  

    INTRODUCTION: We conducted Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) and compared the basic characteristics and progression profiles with those of ADNI in North America. METHODS: A total of 537 Japanese subjects with normal cognition, late amnestic mild cognitive impairment (LMCI), or mild Alzheimer's disease (AD) were enrolled using the same criteria as ADNI. Rates of changes in representative cognitive or functional measures were compared for amyloid positron emission tomography- or cerebrospinal fluid amyloid β(1-42)-positive LMCI and mild AD between J-ADNI and ADNI. RESULTS: Amyloid positivity rates were significantly higher in normal cognition of ADNI but at similar levels in LMCI and mild AD between J-ADNI and ADNI. Profiles of decline in cognitive or functional measures in amyloid-positive LMCI in J-ADNI (n = 75) and ADNI (n = 269) were remarkably similar, whereas those in mild AD were milder in J-ADNI (n = 73) compared with ADNI (n = 230). DISCUSSION: These results support the feasibility of bridging of clinical trials in the prodromal stage of AD between Asia and western countries.

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  • Partial loss of function of colony-stimulating factor 1 receptor in a patient with white matter abnormalities 査読

    T. Konno, T. Miura, A. M. Harriott, N. Mezaki, E. S. Edwards, R. Rademakers, O. A. Ross, J. F. Meschia, T. Ikeuchi, Z. K. Wszolek

    European Journal of Neurology25 ( 6 ) 875 - 881   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:Blackwell Publishing Ltd  

    Background and purpose: Mutations in colony-stimulating factor 1 receptor (CSF1R) cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Patients with ALSP can be misdiagnosed as having acute ischemic stroke due to hyperintensity lesions on diffusion-weighted magnetic resonance imaging. Mutant CSF1R proteins identified in ALSP show a complete loss of autophosphorylation of CSF1R. Methods: We conducted mutation screening of CSF1R in 123 patients with definite acute ischemic cerebrovascular syndrome and positive family history of stroke. The pathogenicity of identified variants was evaluated using functional analyses. The levels of autophosphorylation of CSF1R in response to treatment with ligands of CSF1R were examined in cells transfected with wild-type and mutant CSF1R. Results: We identified eight CSF1R variants, six were known non-pathogenic polymorphisms, whereas the other two were missense variants inducing substitution of amino acid residues (p.Glu573Lys and p.Gly747Arg). Functional assay showed that the levels of autophosphorylation of p.Gly747Arg were similar to those of wild-type when treated with ligands. The autophosphorylation of p.Glu573Lys was detectable, but significantly decreased compared with those of wild-type CSF1R (P &lt
    0.001, two-way anova with Bonferroni). The clinical presentation of the patient with p.Glu573Lys was consistent with cerebral embolism. The patient did not have typical clinical findings of ALSP. However, periventricular white matter abnormalities, unrelated to the recent infarct, were evident on brain magnetic resonance imaging. Conclusions: In contrast to ALSP-associated missense mutations, CSF1R p.Glu573Lys variant in a patient with acute ischemic cerebrovascular syndrome showed a partial loss of autophosphorylation of CSF1R
    its clinical significance warrants further investigation.

    DOI: 10.1111/ene.13611

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  • A novel presenilin 1 mutation (Leu418Trp) associated with spasticity, parkinsonism, and white matter lesion in a dominant Alzheimer's family. 査読 国際誌

    Yoshiaki Takahashi, Yasuyuki Ohta, Ryo Sasaki, Kou Tadokoro, Kota Sato, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Takashi Haraguchi, Takeshi Ikeuchi, Koji Abe

    Journal of the neurological sciences387   166 - 169   2018年4月

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  • Familial and sporadic chronic progressive degenerative parietal ataxia. 査読 国際誌

    Ryuta Morihara, Toru Yamashita, Kentaro Deguchi, Tomoko Kurata, Emi Nomura, Kota Sato, Yumiko Nakano, Yasuyuki Ohta, Nozomi Hishikawa, Takeshi Ikeuchi, Masataka Kitaguchi, Koji Abe

    Journal of the neurological sciences387   70 - 74   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)  

    BACKGROUND & OBJECTIVE: Parietal ataxia has been mainly reported as a consequence of acute ischemic stroke, while degenerative parietal ataxia has not been reported. METHODS: We investigated clinical characteristics, neuroimaging data, and genetic analysis of patients with cerebellar ataxia plus parietal atrophy. RESULTS: We identified seven patients, including five patients from two families, with chronic progressive cerebellar ataxia due to degenerative parietal atrophy but not stroke. Age at onset of ataxia was 57.6 ± 6.9 years. All patients showed chronic progressive cerebellar ataxia with severity of ataxic gait > limb ataxia > dysarthria. Patients showed no cognitive dysfunction, muscle weakness, or parkinsonism, and only two patients showed mild sensory disturbances. The seven patients showed lateralized limb ataxia with greater contralateral parietal lobe atrophy by magnetic resonance imaging, and hypoperfusion by single photon emission computed tomography, without any abnormal cerebellar pathology (i.e., crossed cerebellar diaschisis). Pathogenic mutations in the microtubule-associated protein tau gene were not found using two single nucleotide polymorphisms. CONCLUSIONS: This is the first description showing unique clinical features of familial and sporadic chronic progressive degenerative parietal ataxia.

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  • Background pathology of 'corticobasal degeneration (CBD) mimics' -Japanese validation study of CBD (J-VAC study)-

    Shimohata, Takayoshi, Aiba, Ikuko, Yoshida, Mari, Toyoshima, Yasuko, Murayama, Shigeo, Uchihara, Toshiki, Arai, Tetsuaki, Yabe, Ichiro, Hasegawa, Takafumi, Hasegawa, Kazuko, Ikeuchi, Takeshi, Hasegawa, Masato, Komori, Takashi, Wakabayashi, Koichi, Tokumaru, Aya, Sakurai, Keita, Nakashima, Kenji

    NEUROLOGY90 ( 15 )   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:LIPPINCOTT WILLIAMS & WILKINS  

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  • An autopsy case of globular glial tauopathy presenting with clinical features of motor neuron disease with dementia and iron deposition in the motor cortex. 査読

    Hasegawa I, Takeda A, Hatsuta H, Kubo Y, Ohsawa M, Nakano Y, Ikeuchi T, Hasegawa M, Murayama S, Itoh Y

    Neuropathology : official journal of the Japanese Society of Neuropathology38 ( 4 ) 372 - 379   2018年3月

  • 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 medicine10 ( 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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  • Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation 査読

    T. Konno, K. Yoshida, I. Mizuta, T. Mizuno, T. Kawarai, M. Tada, H. Nozaki, S. I. Ikeda, O. Onodera, Z. K. Wszolek, T. Ikeuchi

    European Journal of Neurology25 ( 1 ) 142 - 147   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)   出版者・発行元:Blackwell Publishing Ltd  

    Background and purpose: To establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. Methods: We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide ‘probable’ and ‘possible’ designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. Results: Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as ‘probable’ and 32 (39%) were diagnosed as ‘possible,’ leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled ‘probable’ or ‘possible’ to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. Conclusions: These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

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  • Cognitive dysfunction and symptoms of movement disorders in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia 査読

    Takeshi Ikeuchi, Naomi Mezaki, Takeshi Miura

    Parkinsonism and Related Disorders46   S39 - S41   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)   出版者・発行元:Elsevier Ltd  

    Adult-onset leukoencephalopathies are clinically and genetically heterogeneous disorders that affect predominantly the cerebral white matter of the central nervous system. Clinical and neuroimaging-based approaches have been developed to improve diagnostic processes for adult-onset leukoencephalopathies. However, the differential diagnosis is often challenging. Recently, knowledge of the genetic basis of leukoencephalopathies has been accumulated rapidly, which provides powerful diagnostic approaches. The article provides an overview of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), focusing on the clinical presentations of cognitive impairment and symptoms of movement disorders. ALSP is a subtype of dominantly inherited leukoencephalopathy caused by CSF1R mutations. ALSP typically develop in adulthood, with cognitive decline, psychiatric symptoms, and motor symptoms of movement disorders. Cognitive symptoms in ALSP are characterized by frontal lobe dysfunctions such as executive dysfunction, attention deficits and indifference. The cardinal motor symptoms of movement disorders ALSP were gait disturbance and bradykinesia, which may appear as the initial symptoms. Thus, ALSP should be recognized as both a cognitive disorder and a movement disorder.

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  • Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation 査読

    T. Konno, K. Yoshida, I. Mizuta, T. Mizuno, T. Kawarai, M. Tada, H. Nozaki, S. I. Ikeda, O. Onodera, Z. K. Wszolek, T. Ikeuchi

    European Journal of Neurology25 ( 1 ) 142 - 147   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)   出版者・発行元:Blackwell Publishing Ltd  

    Background and purpose: To establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. Methods: We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide ‘probable’ and ‘possible’ designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. Results: Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as ‘probable’ and 32 (39%) were diagnosed as ‘possible,’ leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled ‘probable’ or ‘possible’ to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. Conclusions: These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

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  • Clinical and cognitive characteristics of preclinical Alzheimer's disease in the Japanese Alzheimer's Disease Neuroimaging Initiative cohort. 査読

    Ihara R, Iwata A, Suzuki K, Ikeuchi T, Kuwano R, Iwatsubo T, Japanese Alzheimer's, Disease Neuroimaging Initiative

    Alzheimer's & dementia (New York, N. Y.)4   645 - 651   2018年

  • Preoperative Phosphorylated Tau Concentration in the Cerebrospinal Fluid Can Predict Cognitive Function Three Years after Shunt Surgery in Patients with Idiopathic Normal Pressure Hydrocephalus. 査読 国際誌

    Madoka Nakajima, Masakazu Miyajima, Ikuko Ogino, Chihiro Akiba, Kaito Kawamura, Chihiro Kamohara, Keiko Fusegi, Yoshinao Harada, Takeshi Hara, Hidenori Sugano, Yuichi Tange, Kostadin Karagiozov, Kensaku Kasuga, Takeshi Ikeuchi, Takahiko Tokuda, Hajime Arai

    Journal of Alzheimer's disease : JAD66 ( 1 ) 319 - 331   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer's disease (AD) pathology is debated. OBJECTIVE: To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH. METHODS: Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (≥30 pg/mL) p-Tau groups and followed up for three years after lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low (n = 24; mean age 75.7 years [SD 5.3]) and high (n = 11; mean age 76.0 years [SD 5.6]) p-Tau groups. RESULTS: Cognitive function improved early in the low p-Tau group and was maintained thereafter (p = 0.005). In contrast, the high p-Tau group showed a gradual decline to baseline levels by the third postoperative year (p = 0.040). Although the p-Tau concentration did not correlate with the preoperative MMSE score, a negative correlation appeared and strengthened during follow-up (R2 = 0.352, p < 0.001). Furthermore, the low p-Tau group showed rapid and sustained mRS grade improvement, whereas mRS performance gradually declined in the high p-Tau group. CONCLUSIONS: Preoperative CSF p-Tau concentration predicted some aspects of cognitive function after shunt intervention in patients with iNPH. The therapeutic effects of shunt treatment were shorter-lasting in patients with coexisting AD pathology.

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  • Effects of sex, educational background, and chronic kidney disease grading on longitudinal cognitive and functional decline in patients in the Japanese Alzheimer's Disease Neuroimaging Initiative study. 査読 国際誌

    Iwata A, Iwatsubo T, Ihara R, Suzuki K, Matsuyama Y, Tomita N, Arai H, Ishii K, Senda M, Ito K, Ikeuchi T, Kuwano R, Matsuda H, Alzheimer's Disease Neuroimaging Initiative, Japanese Alzheimer’s, Disease Neuroimaging Initiative

    Alzheimer's & dementia (New York, N. Y.)4   765 - 774   2018年

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  • Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease 査読

    Tatsuo Mano, Kenichi Nagata, Takashi Nonaka, Airi Tarutani, Tomohiro Imamura, Tadafumi Hashimoto, Taro Bannai, Kagari Koshi-Mano, Takeyuki Tsuchida, Ryo Ohtomo, Junko Takahashi-Fujigasaki, Satoshi Yamashita, Yasumasa Ohyagi, Ryo Yamasaki, Shoji Tsuji, Akira Tamaoka, Takeshi Ikeuchi, Takaomi C. Saido, Takeshi Iwatsubo, Toshikazu Ushijima, Shigeo Murayama, Masato Hasegawa, Atsushi Iwata

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA114 ( 45 ) E9645 - E9654   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:NATL ACAD SCIENCES  

    Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid beta (A beta) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by A beta. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under A beta burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

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  • Partial Loss of Autophosphorylation of CSF1R in a Patient with Familial Ischemic Cerebrovascular Syndrome 査読

    Takuya Konno, Andrea M. Harriott, Takeshi Miura, Naomi Mezaki, Emily S. Edwards, Owen A. Ross, James F. Meschia, Takeshi Ikeuchi, Zbigniew K. Wszolek

    ANNALS OF NEUROLOGY82   S42 - S42   2017年10月

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    記述言語:英語   出版者・発行元:WILEY  

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  • Semagacestat Is a Pseudo-Inhibitor of γ-Secretase. 査読

    Tagami S, Yanagida K, Kodama TS, Takami M, Mizuta N, Oyama H, Nishitomi K, Chiu YW, Okamoto T, Ikeuchi T, Sakaguchi G, Kudo T, Matsuura Y, Fukumori A, Takeda M, Ihara Y, Okochi M

    Cell reports21 ( 1 ) 259 - 273   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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  • Association between dialysis treatment and cognitive decline: A study from the Project in Sado for Total Health (PROST), Japan 査読

    Yumi Watanabe, Kaori Kitamura, Kazutoshi Nakamura, Kazuhiro Sanpei, Minako Wakasugi, Akio Yokoseki, Keiko Kabasawa, Osamu Onodera, Takeshi Ikeuchi, Ryozo Kuwano, Takeshi Momotsu, Ichici Narita, Naoto Endo

    GERIATRICS & GERONTOLOGY INTERNATIONAL17 ( 10 ) 1584 - 1587   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:WILEY  

    Aim: Evidence for the association between dialysis treatment and cognitive decline is limited. The present study aimed to determine whether dialysis treatment is associated with cognitive decline in adult outpatients of a general hospital in Japan.
    Methods: This was a cross-sectional substudy of the Project in Sado for Total Etealth (PROST). Total Etealth PROST targeted adult outpatients of a general hospital in Sado City, Niigata, Japan. Among 753 patients (mean age 68.1 11.6 years) analyzed, 66 received dialysis. Cognitive state was evaluated using the Mini-Mental State Examination, and those with a Mini-Mental State Examination score &lt;24 were considered "cognitively declined." The prevalence of cognitive decline was compared by odds ratios calculated with multiple logistic regression analysis. Variables included in the analyses were dialysis, age, sex and self-reported histories of hypertension, diabetes, stroke and ischemic heart disease.
    Results: Of the 66 dialysis patients, 24 (36.4%) showed cognitive decline, whereas 172 (25.0%) of 687 non-dialysis patients showed cognitive decline. The age and sex-adjusted odds ratio for cognitive decline in dialysis patients was 2.57 (95% confidence interval 1.43-4.61), relative to non-dialysis patients. The odds ratio remained significant (odds ratio 2.69, 95% confidence interval 1.49-4.88) even after adjusting for all covariates.
    Conclusion: The prevalence of cognitive decline was high in dialysis patients relative to non-dialysis patients among outpatients of a general hospital in Japan..

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  • Longitudinal clinical and neuro-radiological findings in a patient with leukoencephalopathy with brain calcifications and cysts (Labrune syndrome) 査読

    Yasushi Iwasaki, Ken-ichiro Hoshino, Keiko Mori, Masumi Ito, Yoshinari Kawai, Maya Mimuro, Tamao Tsukie, Takeshi Ikeuchi, Mari Yoshida

    eNeurologicalSci8   28 - 30   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 B.V.  

    Since she was 4 years old, the patient had exhibited frequent convulsive seizures, and she experienced severe headaches and depression in adulthood. At the age of 37 years, cerebral calcifications were detected, but she exhibited no cognitive or motor problems. She suffered a cerebral haemorrhage at 49 years old and experienced cognitive dysfunction, dysarthria, dysphagia, and left-hemiparesis as sequelae. After undergoing gastrostomy, she exhibited very slow cognitive deterioration associated with speech disturbance over more than 10 years. She also gradually developed limb spasticity with Babinski signs. Repeated computerised tomography scans revealed unexpected changes including 2 cysts that appeared separately after small haemorrhages, an intracerebral haemorrhage, and intra-cyst bleeding. These longitudinal scans also showed progressive ventricular dilatation and expansion of the leukoencephalopathy, but there were no apparent changes in the intracranial calcifications. Magnetic resonance imaging revealed numerous microbleeds, and magnetic resonance angiography revealed irregularity of the cerebral artery walls with stoppage. Her SNORD118 gene exhibited compound heteromutation of c.38C &gt
    G and c.116G &gt
    C on different alleles. She was finally diagnosed with leukoencephalopathy with brain calcifications and cysts (Labrune syndrome) at the age of 61 years. Past reports have suggested that diffuse cerebral microangiopathy underlies Labrune syndrome's pathogenesis, but we speculate that cerebral macroangiopathy may also underlie it.

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  • A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review 査読

    Takashi Hosaka, Kazuhiro Ishii, Takeshi Miura, Naomi Mezaki, Kensaku Kasuga, Takeshi Ikeuchi, Akira Tamaoka

    BMC NEUROLOGY17   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:BIOMED CENTRAL LTD  

    Background: Progranulin gene (GRN) mutations are major causes of frontotemporal lobar degeneration. To date, 68 pathogenic GRN mutations have been identified. However, very few of these mutations have been reported in Asians. Moreover, some GRN mutations manifest with familial phenotypic heterogeneity. Here, we present a novel GRN mutation resulting in frontotemporal lobar degeneration with a distinct clinical phenotype, and we review reports of GRN mutations associated with familial phenotypic heterogeneity.
    Case presentation: We describe the case of a 74-year-old woman with left frontotemporal lobe atrophy who presented with progressive anarthria and non-fluent aphasia. Her brother had been diagnosed with corticobasal syndrome (CBS) with right-hand limb-kinetic apraxia, aphasia, and a similar pattern of brain atrophy. Laboratory blood examinations did not reveal abnormalities that could have caused cognitive dysfunction. In the cerebrospinal fluid, cell counts and protein concentrations were within normal ranges, and concentrations of tau protein and phosphorylated tau protein were also normal. Since similar familial cases due to mutation of GRN and microtubule-associated protein tau gene (MAPT) were reported, we performed genetic analysis. No pathological mutations of MAPT were identified, but we identified a novel GRN frameshift mutation (c. 1118_1119delCCinsG:p.Pro373ArgX37) that resulted in progranulin haploinsufficiency.
    Conclusion: This is the first report of a GRN mutation associated with familial phenotypic heterogeneity in Japan. Literature review of GRN mutations associated with familial phenotypic heterogeneity revealed no tendency of mutation sites. The role of progranulin has been reported in this and other neurodegenerative diseases, and the analysis of GRN mutations may lead to the discovery of a new therapeutic target.

    DOI: 10.1186/s12883-017-0959-2

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  • Emerging therapeutic targets revealed by genome analysis in Alzheimer's disease 査読

    Takeshi Ikeuchi

    Brain and Nerve69 ( 7 ) 789 - 798   2017年7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:Igaku-Shoin Ltd  

    Cutting-edge genomics technologies have substantially improved our understanding of the pathogenesis of Alzheimer's disease (AD). The identification of mutations in APP, PSEN1, and PSEN2 causative for autosomal dominant AD (ADAD) has provided the basis of the "amyloid cascade" hypothesis of the pathogenetic mechanism of AD. While a number of therapeutic candidates targeting amyloid-β were developed using genetically engineered mouse models of ADAD, none have proven successful in mitigating the symptoms of AD in phase III clinical trials Thus, we must reconsider the modification of AD pathogenesis by targets within the amyloid cascade, and explore new targets for AD therapy. This review provides a comprehensive summary of the recent genetic studies of AD from this perspective, and discusses prospective and emerging therapeutic interventions for patients with AD.

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  • An Autopsy Case of Early Onset Alzheimer's Disease with G378E Mutation in PSEN1 Showing Widespread Tau and A beta Pathologies 査読

    Hajime Miyata, Taizen Nakase, Takeshi Ikeuchi, Yasuji Yoshida

    JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY76 ( 6 ) 503 - 503   2017年6月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS INC  

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  • Effects of super-hard rice bread blended with black rice bran on amyloid peptide production and abrupt increase in postprandial blood glucose levels in mice 査読

    Sumiko Nakamura, Takashi Hara, Toshio Joh, Atsushi Kobayashi, Akira Yamazaki, Kensaku Kasuga, Takeshi Ikeuchi, Ken'ichi Ohtsubo

    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY81 ( 2 ) 323 - 334   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:TAYLOR & FRANCIS LTD  

    Alzheimer's disease and type 2 diabetes are very serious diseases with the latter having been suggested to cause the former. We prepared super-hard rice bread blended with black rice bran (SRBBB), which contained a high amount of resistant starch that showed strong inhibitory activities against beta-secretase and acetylcholinesterase even after heating. Black rice bran showed greater beta-secretase inhibitory activity (3.6-fold) than Koshihikari rice. The bran contained more oleic acid and anthocyanin, meaning that it is potentially a biofunctional food with a high antioxidant capacity. Furthermore, aged mice, which were fed a SRBBB diet for four weeks, showed lower amyloid beta 40 peptide in the blood than mice fed a commercial diet (p &lt; 0.01). Additionally, their initial blood glucose levels (BGLs) after 12 weeks of being fed SRBBB were significantly lower than those in the control group. Taken together, our results indicate SRBBB shows promise for inhibiting not only amyloid beta production, but also abrupt increases in postprandial BGLs.

    DOI: 10.1080/09168451.2016.1240605

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  • Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation 査読

    T. Konno, K. Yoshida, T. Mizuno, T. Kawarai, M. Tada, H. Nozaki, S. I. Ikeda, M. Nishizawa, O. Onodera, Z. K. Wszolek, T. Ikeuchi

    European Journal of Neurology24 ( 1 ) 37 - 45   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:Blackwell Publishing Ltd  

    Background and purpose: The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated. Methods: Clinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data. Results: In all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18–78 years), the mean age at death was 53 years (range 23–84 years) and the mean disease duration was 6.8 years (range 1–29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158–11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype−genotype correlations. Conclusions: The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

    DOI: 10.1111/ene.13125

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  • Co-existence of spastic paraplegia-30 with novel KIFIA mutation and spinocerebellar ataxia 31 with intronic expansion of BEAN and TK2 in a family 査読

    Arika Hasegawa, Ryoko Koike, Kishin Koh, Akio Kawakami, Norikazu Hara, Yoshihisa Takiyama, Takeshi Ikeuchi

    JOURNAL OF THE NEUROLOGICAL SCIENCES372   128 - 130   2017年1月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    DOI: 10.1016/j.jns.2016.11.032

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  • Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation 査読

    T. Konno, K. Yoshida, T. Mizuno, T. Kawarai, M. Tada, H. Nozaki, S. -I. Ikeda, M. Nishizawa, O. Onodera, Z. K. Wszolek, T. Ikeuchi

    EUROPEAN JOURNAL OF NEUROLOGY24 ( 1 ) 37 - 45   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:WILEY  

    Background and purpose: The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated.
    Methods: Clinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data.
    Results: In all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18-78 years), the mean age at death was 53 years (range 23-84 years) and the mean disease duration was 6.8 years (range 1-29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158-11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype similar to genotype correlations.
    Conclusions: The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

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  • Diagnostic Value of Brain Calcifications in Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia 査読

    T. Konno, D. F. Broderick, N. Mezaki, A. Isami, D. Kaneda, Y. Tashiro, T. Tokutake, B. M. Keegan, B. K. Woodruff, T. Miura, H. Nozaki, M. Nishizawa, O. Onodera, Z. K. Wszolek, T. Ikeuchi

    AMERICAN JOURNAL OF NEURORADIOLOGY38 ( 1 ) 77 - 83   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:AMER SOC NEURORADIOLOGY  

    Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is a rare neurodegenerative disease resulting from mutations in the colony stimulating factor 1 receptor gene. Accurate diagnosis can be difficult because the associated clinical and MR imaging findings are nonspecific. We present 9 cases with intracranial calcifications distributed in 2 brain regions: the frontal white matter adjacent to the anterior horns of the lateral ventricles and the parietal subcortical white matter. Thin-section (1-mm) CT scans are particularly helpful in detection due to the small size of the calcifications. These calcifications had a symmetric "stepping stone appearance" in the frontal pericallosal regions, which was clearly visible on reconstructed sagittal CT images. Intrafamilial variability was seen in 2 of the families, and calcifications were seen at birth in a single individual. These characteristic calcification patterns may assist in making a correct diagnosis and may contribute to understanding of the pathogenesis of leukoencephalopathy.

    DOI: 10.3174/ajnr.A4938

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  • Serum microRNA miR-501-3p as a potential biomarker related to the progression of Alzheimer's disease 査読

    Norikazu Hara, Masataka Kikuchi, Akinori Miyashita, Hiroyuki Hatsuta, Yuko Saito, Kensaku Kasuga, Shigeo Murayama, Takeshi Ikeuchi, Ryozo Kuwano

    ACTA NEUROPATHOLOGICA COMMUNICATIONS5   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:BIOMED CENTRAL LTD  

    MicroRNAs (miRNAs) are attractive molecules to utilize as one of the blood-based biomarkers for neurodegenerative disorders such as Alzheimer's disease (AD) because miRNAs are relatively stable in biofluid, including serum or plasma. To determine blood miRNA biomarkers for AD with next-generation sequencing genome-wide, we first surveyed 45 serum samples. These came from 27 AD patients and 18 controls (discovery set) that underwent autopsy within two weeks after their serum sampling and were neuropathologically diagnosed. We found that three miRNAs, hsa-miR-501-3p, hsa-let-7f-5p, and hsa-miR-26b-5p, were significantly deregulated between the AD samples and the controls. The deregulation for hsa-miR-501-3p was further confirmed by quantitative reverse transcription polymerase chain reaction (PCR) in a validation set composed of 36 clinically diagnosed AD patients and 22 age-matched cognitively normal controls with a sensitivity and specificity of 53% and 100%, respectively (area under the curve = 0.82). Serum hsa-miR-501-3p levels were downregulated in AD patients, and its lower levels significantly correlated with lower Mini-Mental State Examination scores. Contrary to its serum levels, we found that hsa-miR-501-3p was remarkably upregulated in the same donors' AD brains obtained at autopsy from the discovery set. The hsa-miR-501-3p overexpression in cultured cells, which mimicked the hsa-miR-501-3p upregulation in the AD brains, induced significant downregulation of 128 genes that overrepresented the Gene Ontology terms, DNA replication, and the mitotic cell cycle. Our results suggest that hsa-miR-501-3p is a novel serum biomarker that presumably corresponds to pathological events occurring in AD brains.

    DOI: 10.1186/s40478-017-0414-z

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  • A novel frameshift GRN mutation results in frontotemporal lober degeneration presenting a distinct clinical phenotype in a family 査読

    Hosaka T, Ishii K, Miura T, Mezaki N, Kasuga K, Ikeuchi T, Tamaoka A

    a literature review. BMC Neurology   2017年

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    掲載種別:研究論文(学術雑誌)  

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  • DIAN-J登録事業 査読

    森啓, 嶋田裕之, 東海林幹夫, 池内健, 鈴木一詩, 千田道雄, 石井賢二, 松田博史, 岩田 淳。井原涼子, 岩坪威, 武藤香織, 中澤栄輔, 関島良樹, 森悦朗, 池田学, 池田将樹, 川勝忍, 中西亜紀, 橋本衛, 布村明彦, 松原悦朗, 福井充, 白戸朋代, 平井香織, 坂本昌子, 藤井比佐子, 石井一成, 西郷和真

    実地診療のための最新認知症学/検査・治療・予防・支援76   258 - 265   2017年

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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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  • 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 NEUROLOGY80 ( 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.

    DOI: 10.1002/ana.24754

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  • Clinical Characterization of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia 査読

    Takuya Konno, Kunihiro Yoshida, Toshiki Mizuno, Toshitaka Kawarai, Masayoshi Tada, Hiroaki Nozaki, Shu-ichi Ikeda, Masatoyo Nishizawa, Osamu Onodera, Zbigniew K. Wszolek, Takeshi Ikeuchi

    ANNALS OF NEUROLOGY80   S194 - S194   2016年10月

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

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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

    NEUROPATHOLOGY36 ( 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.

    DOI: 10.1111/neup.12280

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  • [Multifunctional Roles of APOE in Alzheimer's Disease Pathogenesis]. 査読

    Tokutake T, Kasuga K, Hara N, Ikeuchi T

    Brain and nerve = Shinkei kenkyu no shinpo68 ( 7 ) 703 - 12   2016年7月

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    記述言語:日本語  

    DOI: 10.11477/mf.1416200498

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  • Classification method of severe accident condition for the development of severe accident instrumentation and monitoring system in nuclear power plant 査読

    Akira Murata, Koichiro Isoda, Takeshi Ikeuchi, Tetsuya Matsui, Fujio Shiraishi, Masato Oba

    Journal of Nuclear Science and Technology53 ( 6 ) 870 - 877   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)   出版者・発行元:Taylor and Francis Ltd.  

    Instrumentation and monitoring systems in a nuclear power plant are very important to monitor plant conditions for safe operations and a plant shutdown. The severe accident at Tokyo ELECTRIC POWER COMPANY's Fukushima Daiichi Nuclear Power Station (hereinafter called as TF1) in March 2011 caused several severe situations such as core damage, hydrogen explosion, etc. Lessons learned from the severe accident at TF1 show that an appropriate operable instrumentation and monitoring system for a severe accident should be developed so that the system will deliver an appropriate performance for mitigation of severe accident condition in a nuclear power plant.This paper proposes the classification method of severe accident condition for the development of an appropriate operable instrumentation and monitoring system for a severe accident based on the problem analysis of monitoring variables during the severe accident at TF1. The classification is formed on the basis of the integrity of boundary for plant safety and the successful (or unsuccessful) condition of the cooling water injection, and is used for an establishment of defining severe accident environmental conditions for the instrumentation and monitoring system. Examples of the establishment method are also shown in this paper.

    DOI: 10.1080/00223131.2015.1076746

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  • Co-Existence of Novel KIF1A Mutation (SPG30) and Intronic Expansion of (SCA31) in a Family: Clinical and Genetic Characterization 査読

    Arika Hasegawa, Ryoko Koike, Akio Kawakami, Kishin Koh, Yoshihisa Takiyama, Takeshi Ikeuchi

    NEUROLOGY86   2016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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  • Proposed Diagnostic Criteria for Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia 査読

    Takuya Konno, Kunihiro Yoshida, Toshiki Mizuno, Toshitaka Kawarai, Masayoshi Tada, Hiroaki Nozaki, Shu-Ichi Ikeda, Masatoyo Nishizawa, Osamu Onodera, Zbigniew Wszolek, Takeshi Ikeuchi

    NEUROLOGY86   2016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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  • 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 PATHOLOGY26 ( 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.

    DOI: 10.1111/bpa.12265

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  • Assessment of motor imaginary of gait by timed up and go test and cognitive impairment in Parkinson's disease 査読

    Yasuko Kuroha, Arika Hasegawa, Takashi Tani, Nae Matsubara, Takeshi Ikeuchi, Ryoko Koike

    MOVEMENT DISORDERS31   S40 - S40   2016年3月

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

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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.

    DOI: 10.1111/bpa.12262

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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 PATHOLOGY26 ( 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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  • Elevated C-Reactive Protein is Associated with Cognitive Decline in Outpatients of a General Hospital: The Project in Sado for Total Health (PROST) 査読

    Yumi Watanabe, Kaori Kitamura, Kazutoshi Nakamura, Kazuhiro Sanpei, Minako Wakasugi, Akio Yokoseki, Osamu Onodera, Takeshi Ikeuchi, Ryozo Kuwano, Takeshi Momotsu, Ichiei Narita, Naoto Endo

    Dementia and Geriatric Cognitive Disorders Extra6 ( 1 ) 10 - 19   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:S. Karger AG  

    Background/Aims: We aimed to determine whether the concentration of serum C-reactive protein (CRP) is associated with cognitive function in an adult Japanese population. Methods: Participants of this cross-sectional study were from a subgroup of the Project in Sado for Total Health (PROST
    n = 454
    mean age, 70.5 years). The cognitive state was evaluated using the Mini-Mental State Examination (MMSE), and those with an MMSE score &lt
    24 were considered 'cognitively declined'. Concentrations of serum high-sensitivity CRP were measured. Multiple logistic regression analysis was used to calculate odds ratios (ORs) for cognitive decline, adjusting for the covariates of age, sex, BMI, disease history, and APOE allele. Results: Of the 454 participants, 94 (20.7%) were cognitively declined. Relative to the lowest (first) quartile of CRP concentration, adjusted ORs were 1.29 (95% CI 0.61-2.75) for the second, 1.78 (95% CI 0.82-3.86) for the third, and 3.05 (95% CI 1.45-6.42) for the highest (fourth) quartiles (p for trend = 0.018). When data were stratified by sex, the association between CRP concentration and cognitive decline was observed only in women. Conclusion: Our findings suggest an association between higher CRP concentration and lower cognitive function. Chronic inflammation may affect cognitive function in adults, in particular women.

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  • Modifiable Factors Associated with Cognitive Impairment in 1,143 Japanese Outpatients: The Project in Sado for Total Health (PROST) 査読

    Kaori Kitamura, Yumi Watanabe, Kazutoshi Nakamura, Kazuhiro Sanpei, Minako Wakasugi, Akio Yokoseki, Osamu Onodera, Takeshi Ikeuchi, Ryozo Kuwano, Takeshi Momotsu, Ichiei Narita, Naoto Endo

    Dementia and Geriatric Cognitive Disorders Extra6 ( 2 ) 341 - 349   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:S. Karger AG  

    Background/Aims: Evidence on modifiable factors associated with cognitive impairment in Japanese patients is scarce. This study aimed to determine modifiable factors for cognitive impairment in a Japanese hospital-based population. Methods: Subjects of this cross-sectional study were 1,143 patients of Sado General Hospital (Niigata, Japan) registered in the Project in Sado for Total Health (PROST) between June 2008 and September 2014. We assessed disease history, body mass index (BMI), leisure time physical activity, walking time, smoking and drinking habits, and consumption of vegetables, fruits, and green tea as predictors, with cognitive impairment defined by the Mini-Mental State Examination (score &lt
    24) as an outcome. Multiple logistic regression analysis was performed to calculate odds ratios (ORs) for cognitive impairment. Results: The mean subject age was 68.9 years, and the prevalence of cognitive impairment was 21.5%. Multivariate analysis revealed that age (p &lt
    0.001), low BMI (&lt
    21.1
    OR 1.39, 95% CI 1.12-1.72), a history of stroke (p = 0.003), a history of myocardial infarction (p = 0.038), low fruit consumption (p for trend = 0.012), and low green tea consumption (p for trend = 0.032) were independently associated with a higher prevalence of cognitive impairment. Conclusions: Modifiable factors, such as low BMI, low fruit consumption, and low green tea consumption, are associated with cognitive impairment. Longitudinal studies will be needed to confirm these findings.

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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

    NEUROGENETICS16 ( 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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  • Reduced CSF Water Influx in Alzheimer's Disease Supporting the beta-Amyloid Clearance Hypothesis 査読

    Yuji Suzuki, Yukihiro Nakamura, Kenichi Yamada, Hironaka Igarashi, Kensaku Kasuga, Yuichi Yokoyama, Takeshi Ikeuchi, Masatoyo Nishizawa, Ingrid L. Kwee, Tsutomu Nakada

    PLOS ONE10 ( 5 )   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)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Objective
    To investigate whether water influx into cerebrospinal fluid (CSF) space is reduced in Alzheimer's patients as previously shown in the transgenic mouse model for Alzheimer's disease.
    Methods
    Ten normal young volunteers (young control, 21-30 years old), ten normal senior volunteers (senior control, 60-78 years old, MMSE &gt;= 29), and ten Alzheimer's disease (AD) patients (study group, 59-84 years old, MMSE: 13-19) participated in this study. All AD patients were diagnosed by neurologists specializing in dementia based on DSM-IV criteria. CSF dynamics were analyzed using positron emission tomography (PET) following an intravenous injection of 1,000 MBq [O-15]H2O synthesized on-line.
    Results
    Water influx into CSF space in AD patients, expressed as influx ratio, (0.755 +/- 0.089) was significantly reduced compared to young controls (1.357 +/- 0.185; p &lt; 0.001) and also compared to normal senior controls (0.981 +/- 0.253, p &lt; 0.05). Influx ratio in normal senior controls was significantly reduced compared to young controls (p &lt; 0.01).
    Conclusion
    Water influx into the CSF is significantly reduced in AD patients. beta-amyloid clearance has been shown to be dependent on interstitial flow and CSF production. The current study indicates that reduction in water influx into the CSF may disturb the clearance rate of beta-amyloid, and therefore be linked to the pathogenesis of AD.

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  • Systematic review and meta-analysis of Japanese familial Alzheimer's disease and FTDP-17 査読

    Kensaku Kasuga, Masataka Kikuchi, Takayoshi Tokutake, Akihiro Nakaya, Toshiyuki Tezuka, Tamao Tsukie, Norikazu Hara, Akinori Miyashita, Ryozo Kuwano, Takeshi Ikeuchi

    JOURNAL OF HUMAN GENETICS60 ( 5 ) 281 - 283   2015年5月

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

    Mutations in APP, PSEN1 and PSEN2 as the genetic causes of familial Alzheimer's disease (FAD) have been found in various ethnic populations. A substantial number of FAD pedigrees with mutations have been reported in the Japanese population; however, it remains unclear whether the genetic and clinical features of FAD in the Japanese population differ from those in other populations. To address this issue, we conducted a systematic review and meta-analysis of Japanese FAD and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) by literature search. Using this analysis, we identified 39 different PSEN1 mutations in 140 patients, 5 APP mutations in 35 patients and 16 MAPT mutations in 84 patients. There was no PSEN2 mutation among Japanese patients. The age at onset in Japanese FAD patients with PSEN1 mutations was significantly younger than that in patients with APP mutations. Kaplan-Meier analysis revealed that patients with MAPT mutations showed a shorter survival than patients with PSEN1 or APP mutations. Patients with mutations in different genes exhibit characteristic clinical presentations, suggesting that mutations in causative genes may modify the clinical presentations. By collecting and cataloging genetic and clinical information on Japanese FAD and FTDP-17, we developed an original database designated as Japanese Familial Alzheimer's Disease Database, which is accessible at http://alzdb.bri. niigata-u.ac.jp/.

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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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  • ApoE-isoform-dependent cellular uptake of amyloid-beta is mediated by lipoprotein receptor LR11/SorLA 査読

    Ryuji Yajima, Takayoshi Tokutake, Akihide Koyama, Kensaku Kasuga, Toshiyuki Tezuka, Masatoyo Nishizawa, Takeshi Ikeuchi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS456 ( 1 ) 482 - 488   2015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 formation of senile plaques composed of beta-amyloid (A beta) in the brain is likely the initial event in Alzheimer's disease (AD). Possession of the APOE epsilon 4 allele, the strong genetic factor for AD, facilitates the A beta deposition from the presymptomatic stage of AD in a gene-dosage-dependent manner. However, the precise mechanism by which apoE isoforms differentially induce the AD pathology is largely unknown. LR11/SorLA is a type I membrane protein that functions as the neuronal lipoprotein endocytic receptor of apoE and the sorting receptor of the amyloid precursor protein (APP) to regulate amyloidogenesis. Recently, LR11/SorLA has been reported to be involved in the lysosomal targeting of extracellular amyloid-beta (A beta) through the binding of A beta to the vacuolar protein sorting 10 (VPS10) protein domain of LR11/SorLA. Here, we attempted to examine the human-apoE-isoform-dependent effect on the cellular uptake of A beta through the formation of a complex between an apoE isoform and LR11/SorLA. Cell culture experiments using Neuro2a cells revealed that the cellular uptake of secreted apoE3 and apoE4 was enhanced by the overexpression of LR11/SorLA. In contrast, the cellular uptake of apoE2 was not affected by the expression of LR11/SorLA. Co-immunoprecipitation assay revealed that apoE-isoform-dependent differences were observed in the formation of an apoE-LR11 complex (apoE4 &gt; apoE3 &gt; apoE2). ApoE-isoform-dependent differences in cellular uptake of FAM-labeled A beta were further investigated by coculture assay in which donor cells secrete one of the apoE isoforms and recipient cells express FL-LR11. The cellular uptake of extracellular A beta into the recipient cells was most prominently accentuated when co-cultured with the donor cells secreting apoE4 in the medium, followed by apoE3 and apoE2. Taken together, our results provide evidence for the mechanism whereby human-apoE-isoform-dependent differences modulate the cellular uptake of A beta mediated by LR11/SorLA. (C) 2014 Elsevier Inc. All rights reserved.

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  • A Second Pedigree with Amyloid-less Familial Alzheimer's Disease Harboring an Identical Mutation in the Amyloid Precursor Protein Gene (E693delta) 査読

    Yumiko Kutoku, Yutaka Ohsawa, Ryozo Kuwano, Takeshi Ikeuchi, Haruhisa Inoue, Suzuka Ataka, Hiroyuki Shimada, Hiroshi Mori, Yoshihide Sunada

    INTERNAL MEDICINE54 ( 2 ) 205 - 208   2015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 59-year-old woman developed early-onset, slowly progressive dementia and spastic paraplegia. positron emission tomography (PET) imaging revealed a large reduction in the level of glucose uptake without amyloid deposition in the cerebral cortex. We identified a homozygous microdeletion within the amyloid beta (A beta) coding sequence in the amyloid precursor protein (APP) gene (c.2080_ 2082delGAA, p.E693del) in three affected siblings and a heterozygous microdeletion in an unaffected sibling. The identical mutation was previously reported in the first Alzheimer's pedigree without amyloid deposits. Furthermore, an increase in high-molecular-weight A beta-reactive bands was detected in the patient's CSF. Our findings suggest that soluble A beta-oligomers induce neuronal toxicity, independent of insoluble A beta fibrils.

    DOI: 10.2169/internalmedicine.54.3021

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  • Reduced plasma desmosterol-to-cholesterol ratio and longitudinal cognitive decline in Alzheimer's disease 査読

    Yoshiaki Sato, Francois Bernier, Yasukazu Yamanaka, Ken Aoshima, Yoshiya Oda, Martin Ingelsson, Lars Lannfelt, Akinori Miyashita, Ryozo Kuwano, Takeshi Ikeuchi

    Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring1 ( 1 ) 67 - 74   2015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:Elsevier Inc.  

    Background: We here examined whether plasma desmosterol-to-cholesterol ratio (DES/CHO) is decreased in patients with Alzheimer's disease (AD) and investigated the association between plasma DES/CHO and longitudinal cognitive decline. Methods: Plasma DES/CHO of AD patients and age-matched controls in a Japanese cross-sectional cohort was determined. Plasma DES/CHO at baseline and follow-up visits was assessed in relation to cognitive decline in Japanese and Swedish longitudinal cohorts. Results: Plasma DES/CHO was significantly reduced in Japanese AD patients and significantly correlated with Mini-Mental State Examination (MMSE) score. The longitudinal analysis revealed that plasma DES/CHO in AD patients shows a significant decrease at follow-up intervals. The decline in plasma DES/CHO is larger in the AD group with rapid progression than in that with slow progression. The changes in plasma DES/CHO significantly correlated with changes in the MMSE score. Conclusion: Plasma DES/CHO is decreased in AD patients and may serve as a longitudinal surrogate marker associated with cognitive decline.

    DOI: 10.1016/j.dadm.2014.11.009

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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 PSYCHIATRY4   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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  • Clinical and neuroimaging features of patient with early-onset Parkinson's disease with dementia carrying SNCA p.G51D mutation 査読

    Takayoshi Tokutake, Atsuhi Ishikawa, Nahoko Yoshimura, Akinori Miyashita, Ryozo Kuwano, Masatoyo Nishizawa, Takeshi Ikeuchi

    PARKINSONISM & RELATED DISORDERS20 ( 2 ) 262 - 264   2014年2月

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    記述言語:英語   出版者・発行元:ELSEVIER SCI LTD  

    DOI: 10.1016/j.parkreldis.2013.11.008

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  • 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

    NEUROLOGY82 ( 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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  • A Japanese family with idiopathic basal ganglia calcification with novel SLC20A2 mutation presenting with late-onset hallucination and delusion 査読

    Kensaku Kasuga, Takuya Konno, Kento Saito, Ayako Ishihara, Masatoyo Nishizawa, Takeshi Ikeuchi

    JOURNAL OF NEUROLOGY261 ( 1 ) 242 - 244   2014年1月

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    記述言語:英語   出版者・発行元:SPRINGER HEIDELBERG  

    DOI: 10.1007/s00415-013-7205-7

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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 : JAD41 ( 4 ) 1031 - 8   2014年

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    記述言語:英語  

    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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  • Relative Ratio and Level of Amyloid-beta 42 Surrogate in Cerebrospinal Fluid of Familial Alzheimer Disease Patients with Presenilin 1 Mutations 査読

    Shinji Tagami, Masayasu Okochi, Kanta Yanagida, Takashi Kodama, Tetsuaki Arai, Ryozo Kuwano, Takeshi Ikeuchi, Masatoshi Takeda

    NEURODEGENERATIVE DISEASES13 ( 2-3 ) 166 - 170   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:KARGER  

    Background: Presenilin 1 (PS1) mutations associated with familial Alzheimer disease (FAD) generally increase the amyloid-beta 42 (A beta 42) to A beta 40 ratio secreted in cultured cells. Some of these mutants reduce the secretion of A beta 40 rather than increase that of A beta 42. Since it has been difficult to estimate A beta 42 secretion in brains of P51-FAD patients due to substantial A beta 42 accumulation, it remains unknown whether the enhanced A beta 42 to A beta 40 ratio in brains of FAD patients is caused by elevated 442 secretion or by reduced secretion of A beta 40. Objective/Methods: Cerebrospinal fluids (CSF) of PS1-FAD patients and neurological control patients (controls) were collected. Levels of CSF amyloid precursorlike protein-1-derived A beta-like peptide (APL1 beta), including APL1 beta 28, an A beta 42 surrogate marker, were quantified by liquid chromatography tandem mass spectrometry, and A beta 42 secretion in the brain was estimated. Results: The relative ratio of CSF APL1 beta 28 to total APL1 beta was higher in PS1-FAD patients than in controls. Importantly, CSF APL1 beta 28 was not significantly higher. However, C-terminally shorter CSF APL1 beta 25 and APL1 beta 27 were significantly lower in PS1-FAD patients and, as expected, so were CSF A beta 40 and A beta 42. Conclusion: A higher relative ratio of the CSF A beta 42 surrogate in PS1-FAD patients is not due to its increase in CSF, suggesting that massive A beta 42 accumulation in the PS1-FAD brain occurs without an apparent increase in A beta 42 secretion. (C) 2013 S. Karger AG, Basel

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  • Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS): A review of the literature on its clinical characteristics and mutations in the colony-stimulating factor-1 receptor gene

    Takuya Konno, Masayoshi Tada, Mari Tada, Masatoyo Nishizawa, Takeshi Ikeuchi

    Brain and Nerve66 ( 5 ) 581 - 590   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)   出版者・発行元:Igaku-Shoin Ltd  

    Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an early-onset dementia that predominantly affects the cerebral white matter. After the discovery of a gene encoding the colony stimulating factor 1 receptor (CSF-1R) as a causative gene in patients with HDLS, gene analysis of CSF-1R enabled the diagnosis of HDLS without histopathological evidence. To clarify the genetic and clinical characteristics of HDLS, here, we reviewed the characteristics of patients with HDLS with CSF-1R mutations in the literature. Seventy-three patients from 54 pedigrees with HDLS from various ethnic backgrounds have been reported. Among them, Japanese patients account for 22% (16 patients from 15 pedigrees). Mean age at onset was 45 years (18 to 78 years). A wide range of clinical features including cognitive decline, behavioral changes, seizures, pyramidal signs, and parkinsonism have been described in these patients. Various kinds of mutations were found in the tyrosine kinase domain of CSF-1R. A frameshift mutation causing nonsense-mediated mRNA decay was also described. This suggests that haploinsufficiency of CSF-1R is sufficient to cause HDLS. Neuropathological analysis revealed that microglia in the brains of patients demonstrated distinct morphology and distribution. These results suggest that primary microglial dysfunction due to CSF-1R signaling perturbation may underlie the pathogenesis of HDLS.

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  • Clinical and neuroimaging characteristics of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) 査読

    Takeshi Ikeuchi

    Clinical Neurology54 ( 12 ) 1158 - 1161   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  

    Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant early-onset dementia that affects the cerebral white matter predominantly. Mutations in colony stimulating factor-1 receptor (CSF-1R) were identified as the genetic cause of HDLS, and this enabled the antemorterm diagnosis of HDLS by genetic testing. This review paper describes clinical and neuroimaging findings in genetically-proven HDLS cases. The mean age at onset was 45 years ranging from 18 to 78 years. The most frequent initial symptom was cognitive decline. A wide range of clinical features including intellectual decline, behavioral and character changes, convulsion, pyramidal signs and motor symptoms have been described. Series of brain MRI study exhibit the white matter changes on FLAIR images, which were occasionally asymmetric in the early phase of the disease. Early MRI features are alteration of corpus callosum and dilatation of lateral ventricles showing central atrophy. Hyperintensity lesions detected by diffusion weighted images were detectable in some cases with HDLS. Brain CT study showed spotty calcification in the affected white matter. HDLS is not rare disease and should be considered as differential diagnosis of early-onset dementia exhibiting the white matter disease.

    DOI: 10.5692/clinicalneurol.54.1158

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  • Aβはどこからくるのか? 査読

    春日 健作, 西澤 正豊, 池内 健, Koo Edward

    臨床神経学53 ( 12 ) 1482 - 1482   2013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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  • 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 Neuropathologica126 ( 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.

    DOI: 10.1007/s00401-013-1150-5

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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

    NEUROLOGY80   2013年2月

  • SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians. 査読 国際誌

    Akinori Miyashita, Asako Koike, Gyungah Jun, Li-San Wang, Satoshi Takahashi, Etsuro Matsubara, Takeshi Kawarabayashi, Mikio Shoji, Naoki Tomita, Hiroyuki Arai, Takashi Asada, Yasuo Harigaya, Masaki Ikeda, Masakuni Amari, Haruo Hanyu, Susumu Higuchi, Takeshi Ikeuchi, Masatoyo Nishizawa, Masaichi Suga, Yasuhiro Kawase, Hiroyasu Akatsu, Kenji Kosaka, Takayuki Yamamoto, Masaki Imagawa, Tsuyoshi Hamaguchi, Masahito Yamada, Takashi Morihara, Masatoshi Takeda, Takeo Takao, Kenji Nakata, Yoshikatsu Fujisawa, Ken Sasaki, Ken Watanabe, Kenji Nakashima, Katsuya Urakami, Terumi Ooya, Mitsuo Takahashi, Takefumi Yuzuriha, Kayoko Serikawa, Seishi Yoshimoto, Ryuji Nakagawa, Jong-Won Kim, Chang-Seok Ki, Hong-Hee Won, Duk L Na, Sang Won Seo, Inhee Mook-Jung, Peter St George-Hyslop, Richard Mayeux, Jonathan L Haines, Margaret A Pericak-Vance, Makiko Yoshida, Nao Nishida, Katsushi Tokunaga, Ken Yamamoto, Shoji Tsuji, Ichiro Kanazawa, Yasuo Ihara, Gerard D Schellenberg, Lindsay A Farrer, Ryozo Kuwano

    PloS one8 ( 4 ) e58618   2013年

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    記述言語:英語  

    To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10(-9)) and rs3781834 (P = 1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10(-5)) and rs744373 near BIN1 (P = 1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.

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  • Extensive aggregation of alpha-synuclein and tau in juvenile-onset neuroaxonal dystrophy: an autopsied individual with a novel mutation in the PLA2G6 gene-splicing site 査読

    Yuichi Riku, Takeshi Ikeuchi, Hiroyo Yoshino, Maya Mimuro, Kazuo Mano, Yoji Goto, Nobutaka Hattori, Gen Sobue, Mari Yoshida

    ACTA NEUROPATHOLOGICA COMMUNICATIONS1   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:BIOMED CENTRAL LTD  

    Background: Infantile neuroaxonal dystrophy (INAD) is a rare autosomal-recessive neurodegenerative disorder. Patients with INAD usually show neurological symptoms with infant onset and die in childhood. Recently, it was reported that mutations in the PLA2G6 gene cause INAD, but neuropathological analysis of genetically confirmed individuals with neuroaxonal dystrophy has been limited.
    Results: Here, we report a Japanese individual with neuroaxonal dystrophy associated with compound heterozygous mutations in the PLA2G6 gene. A novel splice-site mutation resulting in skipping and missense mutations (p. R538C) in exon 9 was identified in the patient. This patient initially presented with cerebellar ataxia at the age of 3 years, which was followed by symptoms of mental retardation, extrapyramidal signs, and epileptic seizure. The patient survived until 20 years of age. Neuropathological findings were characterized by numerous axonal spheroids, brain iron deposition, cerebellar neuronal loss, phosphorylated alpha-synuclein-positive Lewy bodies (LBs), and phosphorylated-tau-positive neurofibrillary tangles. In particular, LB pathology exhibited a unique distribution with extremely severe cortical involvement.
    Conclusions: Our results support a genetic clinical view that compound heterozygous mutations with potential residual protein function are associated with a relatively mild phenotype. Moreover, the severe LB pathology suggests that dysfunction of the PLA2G6 gene primarily contributes to LB formation.

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  • Hyperphosphorylation of Tau Induced by Naturally Secreted Amyloid-beta at Nanomolar Concentrations Is Modulated by Insulin-dependent Akt-GSK3 beta Signaling Pathway 査読

    Takayoshi Tokutake, Kensaku Kasuga, Ryuji Yajima, Yumi Sekine, Toshiyuki Tezuka, Masatoyo Nishizawa, Takeshi Ikeuchi

    JOURNAL OF BIOLOGICAL CHEMISTRY287 ( 42 ) 35222 - 35233   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:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Alzheimer disease (AD) is neuropathologically characterized by the formation of senile plaques from amyloid-beta (A beta) and neurofibrillary tangles composed of phosphorylated Tau. Although there is growing evidence for the pathogenic role of soluble A beta species in AD, the major question of how A beta induces hyperphosphorylation of Tau remains unanswered. To address this question, we here developed a novel cell coculture system to assess the effect of extracellular A beta at physiologically relevant levels naturally secreted from donor cells on the phosphorylation of Tau in recipient cells. Using this assay, we demonstrated that physiologically relevant levels of secreted A beta are sufficient to cause hyperphosphorylation of Tau in recipient N2a cells expressing human Tau and in primary culture neurons. This hyperphosphorylation of Tau is inhibited by blocking A beta production in donor cells. The expression of familial AD-linked PSEN1 mutants and APP Delta E693 mutant that induce the production of oligomeric A beta in donor cells results in a similar hyperphosphorylation of Tau in recipient cells. The mechanism underlying the A beta-induced Tau hyperphosphorylation is mediated by the impaired insulin signal transduction because we demonstrated that the phosphorylation of Akt and GSK3 beta upon insulin stimulation is less activated under this condition. Treating cells with the insulin-sensitizing drug rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist, attenuates the A beta-dependent hyperphosphorylation of Tau. These findings suggest that the disturbed insulin signaling cascade may be implicated in the pathways through which soluble A beta induces Tau phosphorylation and further support the notion that correcting insulin signal dysregulation in AD may offer a potential therapeutic approach.

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  • Novel G37V mutation of SOD1 gene in autopsied patient with familial amyotrophic lateral sclerosis 査読

    Junpei Kobayashi, Masatoshi Kuroda, Akihiro Kawata, Yoko Mochizuki, Toshio Mizutani, Takashi Komori, Takeshi Ikeuchi, Reiji Koide

    AMYOTROPHIC LATERAL SCLEROSIS13 ( 6 ) 570 - 572   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:INFORMA HEALTHCARE  

    We report a novel missense mutation (G37V) in exon 2 of the superoxide dismutase-1 gene in a 63-years-old Japanese male with purely lower motor neuron disease. His disease duration was 14 months, and he died of respiratory failure. The disease in this patient with the G37V mutation showed a rapid progression, although patients with G37R mutation are known to have a long survival.

    DOI: 10.3109/17482968.2012.686512

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  • Parkinsonian features in a patient with diffuse neurofibrillary tangles with calcification (DNTC) 査読

    Takeshi Ikeuchi, Takemi Katsui, Kensaku Kasuga, Masaki Hirose, Masatoyo Nishizawa

    PARKINSONISM & RELATED DISORDERS18 ( 5 ) 649 - 650   2012年6月

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    記述言語:英語   出版者・発行元:ELSEVIER SCI LTD  

    DOI: 10.1016/j.parkreldis.2011.08.008

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  • [Cerebrospinal fluid and plasma biomarkers for dementia with lewy bodies]. 査読

    Kasuga K, Ikeuchi T

    Brain and nerve = Shinkei kenkyu no shinpo64 ( 5 ) 505 - 13   2012年5月

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    記述言語:日本語  

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  • Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of gamma-secretase using synthetic antibodies 査読

    Xulun Zhang, Robert J. Hoey, Guoqing Lin, Akiko Koide, Brenda Leung, Kwangwook Ahn, Georgia Dolios, Marcin Paduch, Takeshi Ikeuchi, Rong Wang, Yue-Ming Li, Shohei Koide, Sangram S. Sisodia

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA109 ( 22 ) 8534 - 8539   2012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:NATL ACAD SCIENCES  

    The gamma-secretase complex, composed of presenilin, anterior-pharynx-defective 1, nicastrin, and presenilin enhancer 2, catalyzes the intramembranous processing of a wide variety of type I membrane proteins, including amyloid precursor protein (APP) and Notch. Earlier studies have revealed that nicastrin, a type I membrane-anchored glycoprotein, plays a role in gamma-secretase assembly and trafficking and has been proposed to bind substrates. To gain more insights regarding nicastrin structure and function, we generated a conformation-specific synthetic antibody and used it as a molecular probe to map functional domains within nicastrin ectodomain. The antibody bound to a conformational epitope within a nicastrin segment encompassing residues 245-630 and inhibited the processing of APP and Notch substrates in in vitro gamma-secretase activity assays, suggesting that a functional domain pertinent to gamma-secretase activity resides within this region. Epitope mapping and database searches revealed the presence of a structured segment, located downstream of the previously identified DAP domain (DYIGS and peptidase; residues 261-502), that is homologous to a tetratricopeptide repeat (TPR) domain commonly involved in peptide recognition. Mutagenesis analyses within the predicted TPR-like domain showed that disruption of the signature helical structure resulted in the loss of gamma-secretase activity but not the assembly of the gamma-secretase and that Leu571 within the TPR-like domain plays an important role in mediating substrate binding. Taken together, these studies offer provocative insights pertaining to the structural basis for nicastrin function as a "substrate receptor" within the gamma-secretase complex.

    DOI: 10.1073/pnas.1202691109

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  • Multiple gamma-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer's disease subjects 査読

    Saori Hata, Miyako Taniguchi, Yi Piao, Takeshi Ikeuchi, Anne M. Fagan, David M. Holtzman, Randall Bateman, Hamid R. Sohrabi, Ralph N. Martins, Sam Gandy, Katsuya Urakami, Toshiharu Suzuki

    MOLECULAR NEURODEGENERATION7   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:BIOMED CENTRAL LTD  

    Background: Alcadein(alpha) (Alc(alpha)) is a neuronal membrane protein that colocalizes with the Alzheimer's amyloid-beta precursor protein (APP). Successive cleavage of APP by beta- and gamma-secretases generates the aggregatable amyloid-beta peptide (A beta), while cleavage of APP or Alc(alpha) by alpha- and gamma-secretases generates non-aggregatable p3 or p3-Alc(alpha) peptides. A beta and p3-Alc(alpha) can be recovered from human cerebrospinal fluid (CSF). We have previously reported alternative processing of APP and Alc(alpha) in the CSF of some patients with sporadic mild cognitive impairment (MCI) and AD (SAD).
    Results: Using the sandwich enzyme-linked immunosorbent assay (ELISA) system that detects total p3-Alc(alpha), we determined levels of total p3-Alc(alpha) in CSF from subjects in one of four diagnostic categories (elderly controls, MCI, SAD, or other neurological disease) derived from three independent cohorts. Levels of A beta 40 correlated with levels of total p3-Alc(alpha) in all cohorts.
    Conclusions: We confirm that A beta 40 is the most abundant A beta species, and we propose a model in which CSF p3-Alc(alpha) can serve as a either (1) a nonaggregatable surrogate marker for gamma-secretase activity; (2) as a marker for clearance of transmembrane domain peptides derived from integral protein catabolism; or (3) both. We propose the specification of an MCI/SAD endophenotype characterized by co-elevation of levels of both CSF p3-Alc(alpha) and A beta 40, and we propose that subjects in this category might be especially responsive to therapeutics aimed at modulation of gamma-secretase function and/or transmembrane domain peptide clearance. These peptides may also be used to monitor the efficacy of therapeutics that target these steps in A beta metabolism.

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  • Altered ?-secretase activity in mild cognitive impairment and Alzheimer's disease 査読

    Nobuto Kakuda, Mikio Shoji, Hiroyuki Arai, Katsutoshi Furukawa, Takeshi Ikeuchi, Kohei Akazawa, Mako Takami, Hiroyuki Hatsuta, Shigeo Murayama, Yasuhiro Hashimoto, Masakazu Miyajima, Hajime Arai, Yu Nagashima, Haruyasu Yamaguchi, Ryozo Kuwano, Kazuhiro Nagaike, Yasuo Ihara

    EMBO MOLECULAR MEDICINE4 ( 4 ) 344 - 352   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  

    We investigated why the cerebrospinal fluid (CSF) concentrations of A beta 42 are lower in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. Because A beta 38/42 and A beta 40/43 are distinct product/precursor pairs, these four species in the CSF together should faithfully reflect the status of brain gamma-secretase activity, and were quantified by specific enzyme-linked immunosorbent assays in the CSF from controls and MCI/AD patients. Decreases in the levels of the precursors, A beta 42 and 43, in MCI/AD CSF tended to accompany increases in the levels of the products, A beta 38 and 40, respectively. The ratios A beta 40/43 versus A beta 38/42 in CSF (each representing cleavage efficiency of A beta 43 or A beta 42) were largely proportional to each other but generally higher in MCI/AD patients compared to control subjects. These data suggest that gamma-secretase activity in MCI/AD patients is enhanced at the conversion of A beta 43 and 42 to A beta 40 and 38, respectively. Consequently, we measured the in vitro activity of raft-associated gamma-secretase isolated from control as well as MCI/AD brains and found the same, significant alterations in the gamma-secretase activity in MCI/AD brains.

    DOI: 10.1002/emmm.201200214

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  • Clinical/Scientific notes 査読

    M. Omoto, S. Suzuki, T. Ikeuchi, T. Ishihara, T. Kobayashi, Y. Tsuboi, J. Ogasawara, M. Koga, M. Kawai, T. Iwaki, T. Kanda

    Neurology78 ( 10 ) 762 - 764   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:Lippincott Williams and Wilkins  

    DOI: 10.1212/WNL.0b013e318248e531

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  • α-Synuclein as CSF and Blood Biomarker of Dementia with Lewy Bodies. 査読 国際誌

    Kasuga K, Nishizawa M, Ikeuchi T

    International journal of Alzheimer's disease2012   437025 - 437025   2012年

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    DOI: 10.1155/2012/437025

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  • Adult-onset hereditary leukoencephalopathy: Classification and molecular basis of the disorder 査読

    Takeshi Ikeuchi

    Clinical Neurology52 ( 11 ) 1386 - 1389   2012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)  

    Adult-onset leukoencephalopathy involving the white matter of the brain is a heterogeneous disorder that exhibits a wide range of clinical manifestations. Recent advances in molecular genetics enable gene-based diagnosis of some forms of adult-onset leukoencephalopathy. In this review, the classification of adult-onset leukoencephalopathy based on molecular genetic findings is proposed. The autosomal dominant forms of adult-onset leukoencephalopathy include hereditary diffuse leukoencephalopathy with spheroids (HDLS), autosomal dominant adultonset leukoencephalopathy (ALDL), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and Alexander disease. The autosomal recessive forms of adult-onset leukoencephalopathy include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), vanishing white matter (VWM) with leukoencephalopathy, Nasu-Hakola disease, and metachromatic leukodystrophy (MDL). X-chromosome-linked disorders include fragile X-associated tremor and ataxia syndrome (FXTAS) and adrenoleukodystrophy (ALD). Identification of the genes responsible for adult-onset leukoencephalopathy provides an important clue for elucidation of molecular pathophysiology underlying white matter disorders. One example is the identification of mutations in colony stimulating factor 1 receptor (CSF-1R) in patients with HDLS. Missense and splice site mutations have been found in the tyrosine kinase domain of CSF-1R. CSF-1R is highly expressed in microglia in the brain. It has been demonstrated that mice depleted of CSF-1R exhibit loss of microglia in the brain. In addition, stimulation of IL-34, a ligand of CSF-1R, induces proliferation and activation of microglia. These findings raise an intriguing possibility that dysfunction of microglia may play a role in the pathogenesis of white matter lesions occurring in patients with HDLS.

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  • Coordinated increase of gamma-secretase reaction products in the plasma of some female Japanese sporadic Alzheimer's disease patients: quantitative analysis of p3-Alc alpha with a new ELISA system 査読

    Tomoko Konno, Saori Hata, Yukiko Hamada, Yuko Horikoshi-Sakuraba, Tadashi Nakaya, Yuhki Saito, Tohru Yamamoto, Takayuki Yamamoto, Masahiro Maeda, Takeshi Ikeuchi, Sam Gandy, Hiroyasu Akatsu, Toshiharu Suzuki

    MOLECULAR NEURODEGENERATION6   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:BIOMED CENTRAL LTD  

    Background: Aggregatable amyloid beta-peptide (A beta) and non-aggregatable p3-Alc alpha are metabolic products of the gamma-secretase cleavage of amyloid beta-protein precursor (APP) and Alcadein alpha (Alc alpha), respectively. Familial AD (FAD)-linked mutations in the presenilin 1 or 2 (PS1 or PS2) component of gamma-secretase can cause alternative intramembranous processing of APP and Alc alpha, leading to a coordinated generation of variants of both A beta and p3-Alc alpha. Variant Alc alpha peptides have been observed in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and sporadic Alzheimer's disease (AD). Since, like APP, Alc alpha is largely expressed in brain, one might predict that alternative processing of Alca would be reflected in body fluids of some AD patients. These patients with misprocessing of multiple gamma-secretase substrates might define an endophenotype of p3-Alc alpha, in whom AD is due either to dysfunction of gamma-secretase or to a disorder of the clearance of hydrophobic peptides such as those derived from transmembrane domains.
    Results: We developed a simple procedure for extraction of p3-Alc alpha from plasma and for analyzing this extract in a sensitive, p3-Alc alpha-specific sandwich enzyme-linked immunosorbent assay (ELISA) system. Plasma p3-Alca levels and A beta 40 levels were examined in sporadic AD subjects from two independent Japanese cohorts. In some of these patients, levels of plasma p3-Alc alpha were significantly higher, and were accompanied by parallel changes in A beta 40 levels. This AD-related difference was more marked in female subjects, but this phenomenon was not observed in subjects with frontotemporal lobar degeneration (FTLD).
    Conclusion: Reagents and procedures have been established that enable extraction of p3-Alc alpha from plasma and for quantification of plasma p3-Alc alpha levels by ELISA. Some populations of AD subjects apparently show increased levels of both p3-Alc alpha and A beta 40. Quantification of p3-Alc alpha level may be useful as a readily accessible biomarker for a population of sporadic AD patients in which disease pathogenesis is associated with either dysfunction of gamma-secretase or with a disorder of the clearance of transmembrane domain-derived peptides.

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  • A patient with fragile x-associated tremor/ataxia syndrome presenting with executive cognitive deficits and cerebral white matter lesions. 査読 国際誌

    Kasuga K, Ikeuchi T, Arakawa K, Yajima R, Tokutake T, Nishizawa M

    Case reports in neurology3 ( 2 ) 118 - 23   2011年5月

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    記述言語:英語  

    DOI: 10.1159/000328838

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  • Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-beta 1 via cleavage of proTGF-beta 1 査読

    Atsushi Shiga, Hiroaki Nozaki, Akio Yokoseki, Megumi Nihonmatsu, Hirotoshi Kawata, Taisuke Kato, Akihide Koyama, Kunimasa Arima, Mari Ikeda, Shinichi Katada, Yasuko Toyoshima, Hitoshi Takahashi, Akira Tanaka, Imaharu Nakano, Takeshi Ikeuchi, Masatoyo Nishizawa, Osamu Onodera

    HUMAN MOLECULAR GENETICS20 ( 9 ) 1800 - 1810   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:OXFORD UNIV PRESS  

    Cerebral small-vessel disease is a common disorder in elderly populations; however, its molecular basis is not well understood. We recently demonstrated that mutations in the high-temperature requirement A (HTRA) serine peptidase 1 (HTRA1) gene cause a hereditary cerebral small-vessel disease, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). HTRA1 belongs to the HTRA protein family, whose members have dual activities as chaperones and serine proteases and also repress transforming growth factor-beta (TGF-beta) family signaling. We demonstrated that CARASIL-associated mutant HTRA1s decrease protease activity and fail to decrease TGF-beta family signaling. However, the precise molecular mechanism for decreasing the signaling remains unknown. Here we show that increased expression of ED-A fibronectin is limited to cerebral small arteries and is not observed in coronary, renal arterial or aortic walls in patients with CARASIL. Using a cell-mixing assay, we found that HTRA1 decreases TGF-beta 1 signaling triggered by proTGF-beta 1 in the intracellular space. HTRA1 binds and cleaves the pro-domain of proTGF-beta 1 in the endoplasmic reticulum (ER), and cleaved proTGF-beta 1 is degraded by ER-associated degradation. Consequently, the amount of mature TGF-beta 1 is reduced. These results establish a novel mechanism for regulating the amount of TGF-proTGF-beta 1, specifically, the intracellular cleavage of proTGF-beta 1 in the ER.

    DOI: 10.1093/hmg/ddr063

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  • Genotype-phenotype correlations in early onset ataxia with ocular motor apraxia and hypoalbuminaemia 査読

    Akio Yokoseki, Tomohiko Ishihara, Akihide Koyama, Atsushi Shiga, Mitsunori Yamada, Chieko Suzuki, Yoshiki Sekijima, Kyoko Maruta, Miyuki Tsuchiya, Hidetoshi Date, Tatsuya Sato, Masayoshi Tada, Takeshi Ikeuchi, Shoji Tsuji, Masatoyo Nishizawa, Osamu Onodera

    BRAIN134   1387 - 1399   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:OXFORD UNIV PRESS  

    Early onset ataxia with ocular motor apraxia and hypoalbuminaemia/ataxia-oculomotor apraxia 1 is a recessively inherited ataxia caused by mutations in the aprataxin gene. We previously reported that patients with frameshift mutations exhibit a more severe phenotype than those with missense mutations. However, reports on genotype-phenotype correlation in early onset ataxia with ocular motor apraxia and hypoalbuminaemia are controversial. To clarify this issue, we studied 58 patients from 39 Japanese families, including 40 patients homozygous for c.689_690insT and nine patients homozygous or compound heterozygous for p.Pro206Leu or p.Val263Gly mutations who were compared with regard to clinical phenotype. We performed Kaplan-Meier analysis and log-rank tests for the ages of onset of gait disturbance and the inability to walk without assistance. The cumulative rate of gait disturbance was lower among patients with p.Pro206Leu or p.Val263Gly mutations than among those homozygous for the c.689_690insT mutation (P = 0.001). The cumulative rate of inability to walk without assistance was higher in patients homozygous for the c.689_690insT mutation than in those with p.Pro206Leu or p.Val263Gly mutations (P = 0.004). Using a Cox proportional hazards model, we found that the homozygous c.689_690insT mutation was associated with an increased risk for onset of gait disturbance (adjusted hazard ratio: 6.60) and for the inability to walk without assistance (adjusted hazard ratio: 2.99). All patients homozygous for the c.689_690insT mutation presented ocular motor apraxia at &lt; 15 years of age. Approximately half the patients homozygous for the c.689_690insT mutation developed cognitive impairment. In contrast, in the patients with p.Pro206Leu or p.Val263Gly mutations, only similar to 50% of the patients exhibited ocular motor apraxia and they never developed cognitive impairment. The stepwise multivariate regression analysis using sex, age and the number of c.689_690insT alleles as independent variables revealed that the number of c.689_690insT alleles was independently and negatively correlated with median motor nerve conduction velocities, ulnar motor nerve conduction velocities and values of serum albumin. In the patient with c.[689_690insT]+[840delT], p.[Pro206Leu]+[Pro206Leu] and p.[Pro206Leu]+[Val263Gly] mutations, aprataxin proteins were not detected by an antibody to the N-terminus of aprataxin. Furthermore Pro206Leu and Val263Gly aprataxin proteins are unstable. However, the amount of the 689_690insT aprataxin messenger RNA was also decreased, resulting in more dramatic reduction in the amount of aprataxin protein from the c.689_690insT allele. In conclusion, patients with early onset ataxia with ocular motor apraxia and hypoalbuminaemia homozygous for the c.689_690insT mutation show a more severe phenotype than those with a p.Pro206Leu or p.Val263Gly mutation.

    DOI: 10.1093/brain/awr069

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  • Evidence for a Common Founder and Clinical Characteristics of Japanese Families with the MAPT R406W Mutation. 査読 国際誌

    Takeshi Ikeuchi, Toru Imamura, Yasuhiro Kawase, Yoshimi Kitade, Miyuki Tsuchiya, Takayoshi Tokutake, Kensaku Kasuga, Ryuji Yajima, Tamao Tsukie, Akinori Miyashita, Morihiro Sugishita, Ryozo Kuwano, Masatoyo Nishizawa

    Dementia and geriatric cognitive disorders extra1 ( 1 ) 267 - 75   2011年1月

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    記述言語:英語  

    BACKGROUND/AIM: Mutations in MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Patients with the MAPT R406W mutation were reported to show phenotypic heterogeneity in different ethnic backgrounds. We here report the clinical and genetic characteristics of Japanese families with the R406W mutation. METHODS: We examined the clinical and neuroimaging features of 6 patients from three families with the R406W mutation. We determined the genotypes of intragenic MAPT single-nucleotide polymorphisms (SNPs) and the flanking microsatellite markers to search for a common founder. RESULTS: The initial symptom was memory loss with the average age at onset being 54 years. Anterograde amnesia with episodic memory impairment was the predominant phenotype. Behavioral and personality changes or parkinsonism is not a prominent feature. A brain MRI study revealed marked atrophy of the medial temporal lobe. Genetic analysis of SNPs and microsatellite markers revealed that the affected members of the three families share common genotypes. CONCLUSION: The findings of the affected members in this study, which corroborate previously reported findings of European families, suggest that the R406W mutation may represent a phenotype of predominant anterograde amnesia in FTLD-17. Our genetic data suggest that a founder effect may account for some families with the R406W mutation.

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  • Involvement of Onuf&apos;s nucleus in Machado-Joseph disease: a morphometric and immunohistochemical study 査読

    Hiroshi Shimizu, Mitsunori Yamada, Yasuko Toyoshima, Takeshi Ikeuchi, Osamu Onodera, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA120 ( 4 ) 439 - 448   2010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  

    Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disease caused by an expansion of CAG repeats in the MJD1 gene, in which lower urinary tract dysfunction is known to be the most commonly encountered autonomic failure. However, it remains unclear whether Onuf&apos;s nucleus (ON), which plays major roles in the micturition reflex and voluntary continence, degenerates during the disease process. In the present study, we conducted a morphometric and immunohistochemical study of ON, together with the lateral nuclear group (LNG) of the sacral anterior horns, in seven patients with MJD. When compared with controls, the number of lower motor neurons in both ON and LNG was significantly smaller in the MJD patients, the former being inversely correlated with the size of the expanded CAG repeats. Notably, MJD patients with a large CAG-repeat expansion showed an ON-predominant pattern of neuronal loss, while in the remaining patients, ON and LNG were affected to a similar degree, or rather an LNG-predominant pattern of neuronal loss was evident. Moreover, when adjusted for age, the degree of neuronal loss in both ON and LNG was significantly correlated with the extent of expansion of the CAG repeats. In MJD, the remaining lower motor neurons in ON often exhibited ataxin-3- or 1C2-immunoreactive (ir) neuronal intranuclear inclusions, while no pTDP-43-ir neuronal cytoplasmic inclusions were present in these neurons. In conclusion, the present findings strongly suggest that neuronal loss in ON, the degree of which is highly influenced by the extent of expansion of CAG repeats, is a consistent feature in MJD.

    DOI: 10.1007/s00401-010-0699-5

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  • Long-Term Disability and Prognosis in Dentatorubral-Pallidoluysian Atrophy: a Correlation with CAG Repeat Length 査読

    Arika Hasegawa, Takeshi Ikeuchi, Ryoko Koike, Nae Matsubara, Miyuki Tsuchiya, Hiroaki Nozaki, Atsushi Homma, Jiro Idezuka, Masatoyo Nishizawa, Osamu Onodera

    MOVEMENT DISORDERS25 ( 11 ) 1694 - 1700   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:WILEY-LISS  

    Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder caused by CAG repeat expansion. Previous studies demonstrated that the onset of DRPLA is closely associated with CAG repeat length. However, the natural history of DRPLA has not yet been evaluated. We here retrospectively investigated the factors that determine the disease milestones and prognosis in 183 Japanese patients genetically diagnosed with DRPLA. We determined the age at onset, age at which each of the subsequent clinical manifestations appeared, age at becoming wheelchair-bound, and age at death. Kaplan-Meier analysis revealed that the patients with CAG repeats larger than the median length of 65 repeats developed each of the clinical features of DRPLA at a younger age than those with &lt;65 repeats. The patients became wheelchair-bound at a median age of 33 years (n = 61; range, 3-77 years) and died at a median age of 49 years (n = 23; range, 18-80 years). The ages at becoming wheelchair-bound and at death strongly correlated with the expanded CAG repeat length. Moreover, the patients with &gt;= 65 CAG repeats showed a more severe long-term disability and a poorer prognosis. In contrast, the rate of progression after the onset did not correlate with CAG repeat length. The CAG repeat length may have a considerable effect on not only the disease onset but also the disease milestones and prognosis in DRPLA patients. These effects of CAG repeat length may be relevant in designing future clinical therapeutic trials. (C) 2010 Movement Disorder Society

    DOI: 10.1002/mds.23167

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  • 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 NEUROPATHOLOGICA120 ( 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.

    DOI: 10.1007/s00401-010-0649-2

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  • Differential levels of alpha-synuclein, beta-amyloid42 and tau in CSF between patients with dementia with Lewy bodies and Alzheimer&apos;s disease 査読

    Kensaku Kasuga, Takayoshi Tokutake, Atsushi Ishikawa, Tsuyoshi Uchiyama, Takahiko Tokuda, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY81 ( 6 ) 608 - 610   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:B M J PUBLISHING GROUP  

    Background The clinical diagnosis of dementia with Lewy bodies (DLB) is made on the basis of consensus criteria; however, the sensitivity of the criteria is relatively low. There are no generally accepted biomarkers to distinguish DLB from other dementias. Here the utility of quantification of a-synuclein, beta-amyloid42 (A beta 42) and tau in the CSF of patients with DLB, Alzheimer&apos;s disease (AD) and other dementias was examined.
    Methods 86 patients were divided into three age and sex matched groups: DLB (n=34), AD (n=31) and other dementias (n=21). Two patients with alpha-synuclein gene (SNCA) duplication were also examined. A beta and tau were quantified using an ELISA kit. A modified sandwich ELISA was developed which enables the sensitive quantification of CSF alpha-synuclein.
    Results Total and phosphorylated tau levels as well as A beta 40/42 and tau/A beta 42 ratios were significantly higher in AD patients than in patients with DLB (p&lt;0.01) and other dementias (p&lt;0.01). CSF alpha-synuclein levels in DLB patients were significantly lower than those in patients with AD (p&lt;0.05) and other dementias (p&lt;0.01). CSF alpha-synuclein level correlated with the A beta 42 level in DLB patients (p=0.01, r=0.43). Two patients with SNCA duplication exhibited relatively low levels of CSF alpha-synuclein.
    Conclusions The study suggests that reduced levels of CSF alpha-synuclein in DLB may reflect the accumulation of alpha-synuclein with Lewy pathology in the brain and that quantification of CSF alpha-synuclein helps in the differentiation of DLB from AD and other dementias in combination with A beta 42 and tau analysis.

    DOI: 10.1136/jnnp.2009.197483

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  • Alzheimer&apos;s disease: Report of two autopsy cases with a clinical diagnosis of corticobasal degeneration 査読

    Kenichi Okazaki, Yong-Juan Fu, Yasushi Nishihira, Minoru Endo, Takao Fukushima, Takeshi Ikeuchi, Kouichirou Okamoto, Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi

    NEUROPATHOLOGY30 ( 2 ) 140 - 148   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:WILEY-BLACKWELL PUBLISHING, INC  

    Alzheimer&apos;s disease (AD) is the most common cause of dementia in the elderly. Corticobasal degeneration (CBD) is a rare neurodegenerative disease affecting adults, being characterized clinically by a combination of extrapyramidal signs and focal cortical syndromes. In both diseases, tau deposits are a characteristic neuropathological feature. We report two new patients with autopsy-proven AD, in whom clinical diagnoses of CBD were made during life. The ages of the patients at onset were 52 and 67 years, and the disease durations were 9 and 15 years, respectively. At autopsy, both cases exhibited marked cortical atrophy with evident neuronal loss in the convex areas of the frontal and parietal lobes. Immunohistochemically, AT8-positive neurofibrillary tangles (NFTs) and A beta-positive senile plaques (SPs) were widespread and abundant in the cerebral cortex (Alzheimer pathology stage VI/C of Braak and Braak), leading us to the final pathological diagnosis of AD. No tau lesions suggestive of CBD were observed, and the deep gray matter areas, including the substantia nigra, were unremarkable (exceptionally, only mild neuronal loss was noted in the putamen in case 2). These findings further strengthen the idea that in AD, neurodegeneration with tau and A beta deposits may begin in the fronto-parietal neocortical areas, which are often preferentially affected in CBD, earlier than, or as early as the medial temporal lobe, and that extrapyramidal signs, such as rigidity and tremor, can occur in the absence of neuronal loss in the basal ganglia and substantia nigra.

    DOI: 10.1111/j.1440-1789.2009.01062.x

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  • Increased TGF-beta Signaling Underlies the Pathogenesis of Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) 査読

    Hiroaki Nozaki, Atushi Shiga, Hirotoshi Kawata, Kunimasa Arima, Kenju Hara, Toshio Fukutake, Akio Yokoseki, Akihide Koyama, Toshiaki Takahashi, Mari Ikeda, Akira Tanaka, Imaharu Nakano, Shu-ichi Ikeda, Tadashi Yamamoto, Takeshi Ikeuchi, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

    NEUROLOGY74 ( 9 ) A445 - A445   2010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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  • Tauopathy with intronic 10+14 splice site tau gene mutation mimicking Perry syndrome 査読

    Omoto Masatoshi, Suzuki Satoshi, Ikeuchi Takeshi, Kobayashi Tomonori, Tsuboi Yoshio, Ogasawara Jun-ichi, Koga Michiaki, Kawai Motoharu, Iwaki Toru, Kanda Takashi

    XVII INTERNATIONAL CONGRESS OF NEUROPATHOLOGY (ICN)   65 - 70   2010年

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    記述言語:英語   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:MEDIMOND S R L  

    We report peculiar clinical, biochemical and neuropathological manifestations of Japanese sisters with the mutation of intron 10+14 in the MAPT gene. The 44-years-old woman presented as parkinsonism, weight loss and central hypoventilation without dementia and showed a reduced serotonin concentration in CSF. She died due to apnea 22 months after the onset. Although the clinical and biochemical features of the proband mimicked those in Perry syndrome, neuropathological characteristics of our patient showed PSP-like changes with 4-repeat tau deposition. Severe gliosis and rarefaction which were observed in the widespread lesion of brainstem, as well as a reduced serotonin concentration in CSF, suggest that central hypoventilation of the present patient might be caused by the similar mechanism of Perry syndrome. We conclude that clinical and biochemical features of Perry syndrome can also be caused by the mutation of MAPT, especially the intron 10+14, with tauopathy composed predominantly of 4-repeat tau isoforms.

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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 DISORDERS30 ( 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

    DOI: 10.1159/000315539

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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 NEUROPATHOLOGICA118 ( 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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  • Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease 査読

    K. Kasuga, T. Shimohata, A. Nishimura, A. Shiga, T. Mizuguchi, J. Tokunaga, T. Ohno, A. Miyashita, R. Kuwano, N. Matsumoto, O. Onodera, M. Nishizawa, T. Ikeuchi

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY80 ( 9 ) 1050 - 1052   2009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:B M J PUBLISHING GROUP  

    Background: The occurrence of duplications of the amyloid precursor protein gene (APP) has been described in European families with early-onset familial Alzheimer disease (EO-FAD) and cerebral amyloid angiopathy. However, the contribution of APP duplication to the development of AD in other ethnic populations remains undetermined.
    Methods: The occurrence of APP duplication in probands from 25 families with FAD and 11 sporadic EO-AD cases in the Japanese population was examined by quantitative PCR and microarray-based comparative genomic hybridisation analyses. APP expression level was determined by real-time quantitative reverse-transcription (RT) PCR analysis using mRNA extracted from the peripheral blood of the patients.
    Results: We identified APP locus duplications in two unrelated EO-FAD families. The duplicated genomic regions in two patients of these families differed from each other. No APP duplication was found in the late-onset FAD families or sporadic EO-AD patients. The patients with APP duplication developed insidious memory disturbance in their fifties without intracerebral haemorrhage and epilepsy. Quantitative RT-PCR analysis showed the increased APP mRNA expression levels in these patients compared with those in age- and sex-matched controls.
    Conclusions: Our results suggest that APP duplication should be considered in patients with EO-FAD in various ethnic groups, and that increased APP mRNA expression level owing to APP duplication contributes to AD development.

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  • Depression and psychiatric symptoms preceding onset of dementia in a family with early-onset Alzheimer disease with a novel PSEN1 mutation 査読

    Kensaku Kasuga, Tsukasa Ohno, Tomohiko Ishihara, Akinori Miyashita, Ryozo Kuwano, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

    JOURNAL OF NEUROLOGY256 ( 8 ) 1351 - 1353   2009年8月

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    記述言語:英語   出版者・発行元:DR DIETRICH STEINKOPFF VERLAG  

    DOI: 10.1007/s00415-009-5096-4

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  • Novel GFAP Mutation in Patient with Adult-Onset Alexander Disease Presenting with Spastic Ataxia 査読

    Hiroyuki Kaneko, Masaki Hirose, Shinichi Katada, Toshiaki Takahashi, Satoshi Naruse, Miyuki Tsuchiya, Tomokatsu Yoshida, Masanori Nakagawa, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

    MOVEMENT DISORDERS24 ( 9 ) 1393 - 1395   2009年7月

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    記述言語:英語   出版者・発行元:WILEY-LISS  

    DOI: 10.1002/mds.22556

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  • The 28-amino acid form of an APLP1-derived A beta-like peptide is a surrogate marker for A beta 42 production in the central nervous system 査読

    Kanta Yanagida, Masayasu Okochi, Shinji Tagami, Taisuke Nakayama, Takashi S. Kodama, Kouhei Nishitomi, Jingwei Jiang, Kohji Mori, Shin-ichi Tatsumi, Tetsuaki Arai, Takeshi Ikeuchi, Kensaku Kasuga, Takahiko Tokuda, Masaki Kondo, Masaki Ikeda, Kentaro Deguchi, Hiroaki Kazui, Toshihisa Tanaka, Takashi Morihara, Ryota Hashimoto, Takashi Kudo, Harald Steiner, Christian Haass, Kuniaki Tsuchiya, Haruhiko Akiyama, Ryozo Kuwano, Masatoshi Takeda

    EMBO MOLECULAR MEDICINE1 ( 4 ) 223 - 235   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-BLACKWELL PUBLISHING, INC  

    Surrogate markers for the Alzheimer disease (AD)-associated 42-amino acid form of amyloid-beta (A beta 42) have been sought because they may aid in the diagnosis of AD and for clarification of disease pathogenesis. Here, we demonstrate that human cerebrospinal fluid (CSF) contains three APLP1-derived A beta-like peptides (APL1 beta) that are generated by beta- and gamma-cleavages at a concentration of similar to 4.5 nM. These novel peptides, APL1 beta 25, APL1 beta 27 and APL1 beta 28, were not deposited in AD brains. Interestingly, most g-secretase modulators (GSMs) and familial AD-associated presenilin1 mutants that up-regulate the relative production of A beta 42 cause a parallel increase in the production of APL1 beta 28 in cultured cells. Moreover, in CSF from patients with pathological mutations in presenilin1 gene, the relative APL1 beta 28 levels are higher than in non-AD controls, while the relative A beta 42 levels are unchanged or lower. Most strikingly, the relative APL1 beta 28 levels are higher in CSF from sporadic AD patients (regardless of whether they are at mild cognitive impairment or AD stage), than those of non-AD controls. Based on these results, we propose the relative level of APL1 beta 28 in the CSF as a candidate surrogate marker for the relative level of A beta 42 production in the brain.

    DOI: 10.1002/emmm.200900026

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  • Association of HTRA1 Mutations and Familial Ischemic Cerebral Small-Vessel Disease 査読

    Kenju Hara, Atsushi Shiga, Toshio Fukutake, Hiroaki Nozaki, Akinori Miyashita, Akio Yokoseki, Hirotoshi Kawata, Akihide Koyama, Kunimasa Arima, Toshiaki Takahashi, Mari Ikeda, Hiroshi Shiota, Masato Tamura, Yutaka Shimoe, Mikio Hirayama, Takayo Arisato, Sohei Yanagawa, Akira Tanaka, Imaharu Nakano, Shu-ichi Ikeda, Yutaka Yoshida, Tadashi Yamamoto, Takeshi Ikeuchi, Ryozo Kuwano, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

    NEW ENGLAND JOURNAL OF MEDICINE360 ( 17 ) 1729 - 1739   2009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:MASSACHUSETTS MEDICAL SOC  

    BACKGROUND
    The genetic cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is characterized by ischemic, non-hypertensive, cerebral small-vessel disease with associated alopecia and spondylosis, is unclear.
    METHODS
    In five families with CARASIL, we carried out linkage analysis, fine mapping of the region implicated in the disease, and sequence analysis of a candidate gene. We also conducted functional analysis of wild-type and mutant gene products and measured the signaling by members of the transforming growth factor beta (TGF-beta) family and gene and protein expression in the small arteries in the cerebrum of two patients with CARASIL.
    RESULTS
    We found linkage of the disease to the 2.4-Mb region on chromosome 10q, which contains the HtrA serine protease 1 (HTRA1) gene. HTRA1 is a serine protease that represses signaling by TGF-beta family members. Sequence analysis revealed two nonsense mutations and two missense mutations in HTRA1. The missense mutations and one of the nonsense mutations resulted in protein products that had comparatively low levels of protease activity and did not repress signaling by the TGF-beta family. The other nonsense mutation resulted in the loss of HTRA1 protein by nonsense-mediated decay of messenger RNA. Immunohistochemical analysis of the cerebral small arteries in affected persons showed increased expression of the extra domain-A region of fibronectin and versican in the thickened tunica intima and of TGF-beta 1 in the tunica media.
    CONCLUSIONS
    CARASIL is associated with mutations in the HTRA1 gene. Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.

    DOI: 10.1056/NEJMoa0801560

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  • Functional regulation of Presenilin1 via insulin signaling 査読

    Masato Maesako, Kengo Uemura, Masakazu Kubota, Akira Kuzuya, Koichi Ando, Takeshi Ikeuchi, Megumi Asada, Ayae Kinoshita

    NEUROSCIENCE RESEARCH65   S115 - S115   2009年

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    DOI: 10.1016/j.neures.2009.09.536

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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 NEUROPATHOLOGICA116 ( 5 ) 575 - 577   2008年11月

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    記述言語:英語   出版者・発行元:SPRINGER  

    DOI: 10.1007/s00401-008-0428-5

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  • Prominent psychiatric symptoms and glucose hypometabolism in a family with a SNCA duplication 査読

    T. Uchiyama, T. Ikeuchi, Y. Ouchi, M. Sakamoto, K. Kasuga, A. Shiga, M. Suzuki, M. Ito, T. Atsumi, T. Shimizu, T. Ohashi

    NEUROLOGY71 ( 16 ) 1289 - 1291   2008年10月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    DOI: 10.1212/01.wnl.0000327607.28928.e6

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  • Determination of 24S-hydroxycholesterol in human cerebrospinal fluid by gas chromatography/mass spectrometry 査読

    Reiko Yamazaki, Saori Nakagawa, Akiko Tanabe, Takeshi Ikeuchi, Takashi Miida, Susumu Yamato

    BUNSEKI KAGAKU57 ( 9 ) 707 - 713   2008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)   出版者・発行元:JAPAN SOC ANALYTICAL CHEMISTRY  

    A simple pretreatment method for the determination of 24S-hydroxycholesterol in human cerebrospinal fluid by gas chromatography/mass spectrometry (GC/MS) has been developed. Esterified cholesterol was saponified by a high concentration of potassium hydroxide (25 M, 1 mL) in a small volume (10 mL) of a conical test tube with a stopper made of glass. Next, free cholesterol was extracted with a small volume of n-hexane. The combined extracts obtained by the twice extraction were then applied on a silica cartridge for solid-phase extraction. A slight amount of 24S-hydroxycholestertol was separated from a large amount of cholesterol using n-hexane and ethylacetate as an elution solvent. 24S-hydroxycholestertol and 27-hydroxycholesterol-26,26,26,27,27-D-5 as an internal standard were converted to trimethylsilyl ethers by the trimethylsilyl (TMS) reagent, and then the TMS derivatives were determined by GC/MS. The method was successfully applied to the determination of 24S-hydroxycholestertol in human cerebrospinal fluid from patients of non-neurodegenerative disorders. The pretreatment method reported here was simple and useful for one multi-specimen material pretreatment.

    DOI: 10.2116/bunsekikagaku.57.707

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  • Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families 査読

    K. Hara, A. Shiga, H. Nozaki, J. Mitsui, Y. Takahashi, H. Ishiguro, H. Yomono, H. Kurisaki, J. Goto, T. Ikeuchi, S. Tsuji, M. Nishizawa, O. Onodera

    NEUROLOGY71 ( 8 ) 547 - 551   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:LIPPINCOTT WILLIAMS & WILKINS  

    Background: Spinocerebellar ataxia type 15 (SCA15) is a progressive neurodegenerative disorder characterized by pure cerebellar ataxia, very slow progression, and distinct cerebellar atrophy. The locus for SCA15 was first mapped to 3p24.2-3pter in an Australian family. We have subsequently mapped two Japanese families presenting with ataxia and postural tremor of the head, arm, or trunk to the SCA15 locus. Recently, partial deletions involving both the type 1 inositol 1,4,5-triphosphate receptor (ITPR1) and sulfatase modifying factor 1 (SUMF1) genes have been identified in Australian and British families with SCA15.
    Methods: We conducted fine haplotype analysis on the region including ITPR1. To identify the deletion, we conducted gene dosage analysis and array-based comparative genomic hybridization (aCGH) analysis. Gene expression analysis was performed using quantitative real-time reverse transcription PCR. Mutational analyses of ITPR1 and SUMF1 were also performed.
    Results: We have identified a 414-kb deletion including the entire ITPR1 and exon 1 of SUMF1 in patients in family A. The expression levels of ITPR1 and SUMF1 mRNAs of the patient were half those of the normal control. Furthermore, in family B, we have identified a C-to-T substitution at position 8581 of ITPR1, resulting in the amino acid substitution of leucine for proline at codon 1059, which is highly conserved among species.
    Conclusions: Our results strongly confirm that ITPR1 is the causative gene for SCA15 and suggest that we need to investigate the point mutation in ITPR1 in the patients with autosomal dominant cerebellar ataxia and tremor.

    DOI: 10.1212/01.wnl.0000311277.71046.a0

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  • TDP-43 mutation in familial amyotrophic lateral sclerosis 査読

    Akio Yokoseki, Atsushi Shiga, Chun-Feng Tan, Asako Tagawa, Hiroyuki Kaneko, Akihide Koyama, Hiroto Eguchi, Akira Tsujino, Takeshi Ikeuchi, Akiyoshi Kakita, Koichi Okamoto, Masatoyo Nishizava, Hitoshi Takahashi, Osamu Onodera

    ANNALS OF NEUROLOGY63 ( 4 ) 538 - 542   2008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-LISS  

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Accumulating evidence has shown that 43kDa TAR-DNA-binding protein (TDP-43) is the disease protein in ALS and frontotemporal lobar degeneration. We previously reported a familial ALS with Bumina bodies and TDP-43-positive skein-like inclusions in the lower motor neurons; these findings are indistinguishable from those of sporadic ALS. In three affected individuals in two generations of one family, we found a single base-pair change from A to G at position 1028 in TDP-43, which resulted in a Gln-to-Arg substitution at position 343. Our findings provide a new insight into the molecular pathogenesis of ALS.

    DOI: 10.1002/ana.21392

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  • Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia 査読

    Takeshi Ikeuchi, Akiyoshi Kakita, Atsushi Shiga, Kensaku Kasuga, Hiryoyuki Kaneko, Chun-Feng Tan, Jiro Idezuka, Koichi Wakabayashi, Osamu Onodera, Takeshi Iwatsubo, Masatoyo Nishizawa, Hitoshi Takahashi, Atsushi Ishikawa

    ARCHIVES OF NEUROLOGY65 ( 4 ) 514 - 519   2008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:AMER MEDICAL ASSOC  

    Background: Multiplication of the alpha-synuclein gene (SNCA) (OMIM 163890) has been identified as a causative mutation in hereditary Parkinson disease or dementia with Lewy bodies.
    Objective: To determine the genetic, biochemical, and neuropathologic characteristics of patients with autopsy-confirmed autosomal dominant Lewy body disease, with particular reference to the dosage effects of SNCA.
    Design: Four-generation family study.
    Setting: Academic research.
    Patients: We fractionated samples extracted from frozen brain tissues of 4 patients for biochemical characterization, followed by immunoblot analysis.
    Main Outcome Measures: We determined the dosages of SNCA and its surrounding genes by quantitative polymerase chain reaction analysis.
    Results: Quantitative polymerase chain reaction analysis revealed that 3 patients were heterozygous for SNCA duplication and 1 patient was homozygous for SNCA duplication. The homozygous patient showed earlier age at onset and earlier death, with more severe cognitive impairment than the heterozygous patients. Biochemical analysis revealed that phosphorylated alpha-synuclein accumulated in the sarkosyl-insoluble urea-extracted fraction of the brains of the patients.
    Conclusions: Pathologically confirmed Lewy body disease clinically characterized by progressive parkinsonism and cognitive dysfunction is caused by SNCA duplication. The homozygous patient demonstrated the most severe phenotype, suggesting that SNCA dosage has a considerable effect on disease phenotype even within a family. SNCA duplication results in the hyperaccumulation of phosphorylated alpha-synuclein in the brains of patients.

    DOI: 10.1001/archneur.65.4.514

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  • The clinical-genealogic and molecular-genetic characteristics of oculopharyngeal muscular dystrophy in the Republic of Sakha (Yakutia) 査読

    N. R. Maksimova, I. A. Nikolaeva, M. N. Korotov, T. Ikeuchi, O. Onodera, M. Nishizawa, S. K. Stepanova, Kh. A. Kurtanov, A. L. Sukhomyasova, A. N. Nogovitcina, E. E. Gurinova, V. A. Stepanov, V. P. Puzyrev

    ZHURNAL NEVROLOGII I PSIKHIATRII IMENI S S KORSAKOVA108 ( 6 ) 52 - 60   2008年

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    記述言語:ロシア語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IZDATELSTVO MEDITSINA  

    The clinical-genealogic and molecular-genetic investigation of oculopharyngeal muscular dystrophy (OPMD) in the Republic of Sakha (Yakutia) was performed. it was investigated 33 unrelated yakut families with 38 patients and 2 russian families with 2 patients and 59 their healthy relatives as well. The high clinical polymorphism of disease was found in patients with OPMD. The mutation in exon 1 of the PABPN1 gene resulting in the expansion of GCG-repeats up to 10 is revealed. Using direct sequencing of the PABPN1 gene in 17 families (16 yakut, 1 russian), we identified a type of this mutation as an insertion of 4 GCG-repeats. Frequency of OPMD in the yakut population is 1:11 680 that is 10-20 times higher comparing to european populations. This is a first report on the patients with OPMD from the Republic of Sakha with diagnosis confirmed by molecular-genetic analysis.

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  • Mutational analysis in early-onset familial dementia in the Japanese population 査読

    Takeshi Ikeuchi, Hiroyuki Kaneko, Akinori Miyashita, Hiroaki Nozaki, Kensaku Kasuga, Tamao Tsukie, Miyuki Tsuchiya, Toru Imamura, Hideki Ishizu, Kenju Aoki, Atsushi Ishikawa, Osamu Onodera, Ryozo Kuwano, Masatoyo Nishizawa

    DEMENTIA AND GERIATRIC COGNITIVE DISORDERS26 ( 1 ) 43 - 49   2008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: Three major causative genes have been implicated as the cause of early-onset familial Alzheimer's disease (AD): the amyloid precursor protein gene (APP), presenilin-1 (PSEN1) and PSEN2. Although rare, a tau-related dementia with mutations in the microtubule-associated protein tau gene (MAPT) has been identified in patients showing clinical presentations similar to those of AD. Methods: We performed mutational analysis of APP, PSEN1, PSEN2, and MAPT in 10 Japanese families with early-onset dementia clinically diagnosed as probable Alzheimer's disease. Results: In 4 index patients, we identified 4 missense PSEN1 mutations, namely, L286V, G378E, L381V, and L392V. The mean age at onset in the patients with PSEN1 mutations was 39 years. In 2 families, we found the R406W mutation in MAPT. The mean age at onset of the patients carrying the R406W mutation was 52 years, and they presented with the peculiar AD-like phenotype without apparent behavioral or language problems. Conclusion: These observations suggest that although PSEN1 mutations are the most frequent cause, the MAPT R406W mutation is an important cause of early-onset familial dementia clinically diagnosed as AD. Differentiation of patients with the MAPT mutation from AD patients by genetic testing would be meaningful, considering that a different therapeutic approach should be applied. Copyright (c) 2008 S. Karger AG, Basel.

    DOI: 10.1159/000141483

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  • Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families 査読

    Hiroaki Nozaki, Kenju Hara, Atsushi Shiga, Jun Mitsui, Yuuji Takahashi, Hideaki Ishiguro, Harumi Shimono, Hiroshi Kurisaki, Jun Goto, Takeshi Ikeuchi, Shouji Tsuji, Masatoyo Nishizawa, Osamu Onodera

    NEUROSCIENCE RESEARCH61   S206 - S206   2008年

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

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  • TDP-43 mutation in familial amyotrophic lateral sclerosis 査読

    Akio Yokoseki, Atsushi Shiga, Chun Feng Tan, Asako Tagawa, Hiroyuki Kaneko, Akihide Koyama, Hiroto Eguchi, Akira Tsujino, Takeshi Ikeuchi, Akiyoshi Kakita, Koichi Okamoto, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

    NEUROSCIENCE RESEARCH61   S267 - S267   2008年

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

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  • Contribution of APP duplication as a cause in a cohort of Japanese Alzheimer disease patients 査読

    Kensaku Kasuga, Atsushi Shiga, Takayoshi Shimohata, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

    NEUROSCIENCE RESEARCH61   S264 - S264   2008年

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

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  • Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia 査読

    N. Maksimova, K. Hara, A. Miyashia, I. Nikolaeva, A. Shiga, A. Nogovicina, A. Sukhomyasova, V. Argunov, A. Shvedova, T. Ikeuchi, M. Nishizawa, R. Kuwano, O. Onodera

    JOURNAL OF MEDICAL GENETICS44 ( 12 ) 772 - 778   2007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:BMJ PUBLISHING GROUP  

    Background: In total, 43 patients having short stature syndrome in 37 Yakut families with autosomal recessive prenatal and postnatal nonprogressive growth failure and facial dysmorphism but with normal intelligence have been identified.
    Methods: Because Yakuts are considered as a population isolate and the disease is rare in other populations, genomewide homozygosity mapping was performed using 763 microsatellite markers and candidate gene approach in the critical region to identify the causative gene for the short stature syndrome in Yakut.
    Results: All families shared an identical haplotype in the same region as the identical loci responsible for 3-M and gloomy face syndromes and a novel homozygous 4582insT mutation in Cullin 7 (CUL7) was found, which resulted in a frameshift mutation and the formation of a subsequent premature stop codon at 1553 ( Q1553X). Yakut patients with short stature syndrome have unique features such as a high frequency of neonatal respiratory distress and few bone abnormalities, whereas the clinical features of the other Yakut patients were similar to those of 3-M syndrome. Furthermore, abnormal vascularisation was present in the fetal placenta and an abnormal development of cartilage tissue in the bronchus of a fetus with CUL7 mutation.
    Conclusion: These findings may provide a new understanding of the clinical diversity and pathogenesis of short stature syndrome with CUL7 mutation.

    DOI: 10.1136/jmg.2007.051979

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  • Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 Delta T440 mutant associated with familial Lewy body disease and variant Alzheimer's disease 査読

    Hiroyuki Kaneko, Akiyoshi Kakita, Kensaku Kasuga, Hiroaki Nozaki, Atsushi Ishikawa, Akinori Miyashita, Ryozo Kuwano, Genta Ito, Takeshi Iwatsubo, Hitoshi Takahashi, Masatoyo Nishizawa, Osamu Onodera, Sangram S. Sisodia, Takeshi Ikeuchi

    JOURNAL OF NEUROSCIENCE27 ( 48 ) 13092 - 13097   2007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:SOC NEUROSCIENCE  

    Mutations in the PSEN1 gene encoding presenilin 1 ( PS1) are linked to a vast majority of pedigrees with early- onset, autosomal dominant forms of familial Alzheimer's disease ( FAD). Lewy body ( LB) pathology is frequently found in the brains of FAD patients harboring PSEN1 mutations. We recently reported on a novel PS1 mutation with the deletion of threonine at codon 440 (Delta T440) in a familial case diagnosed as having the neocortical type of dementia with LBs ( DLB) and variant AD. In this report, we investigated the possible involvement of PS1 Delta T440 mutation in aberrant alpha-synuclein accumulation. We established cell lines that stably express either wild- type ( WT) PS1 or the FAD- linked PS1 H163R, E280A, Delta E9, and PS1 Delta T440 mutants and now demonstrate that the expression of the PS1 Delta T440 mutant led to a marked elevation in the ratio of beta-amyloid (A beta) 42/40 peptides in a conditioned medium. More importantly, we report here that the levels of phosphorylated alpha-synuclein increase in neuronal and non- neuronal cells expressing the PS1 Delta T440 mutant compared with cells that express WT PS1 or the PS1 H163R and E280A variants that are not associated with LB pathology. This finding is consistent with our demonstration of elevated levels of phosphorylated alpha-synuclein in the detergent-resistant fraction prepared from a patient's brain with PS1 Delta T440 mutation. These observations raise the intriguing suggestion that the mechanism( s) by which the PS1 Delta T440 mutant causes DLB and variant AD are by enhancing the phosphorylation of alpha-synuclein and the ratio of A beta(42/40) peptides, respectively, in the brain.

    DOI: 10.1523/JNEUROSCI.4244-07.2007

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  • Generation of intracellular domain of insulin receptor tyrosine kinase by gamma-secretase 査読

    K. Kasuga, H. Kaneko, M. Nishizawa, O. Onodera, T. Ikeuchi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS360 ( 1 ) 90 - 96   2007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 proteolytic cleavage of a precursor protein into alpha- and beta-subunits by furin is required to form functional insulin receptor (IR). In this study, we examined if IR undergoes the additional presenilin (PS)/gamma- secretase-dependent processing. In cells treated with gamma-secretase inhibitors or expressing the dominant-negative PS1 variant led to the accumulation of an endogenous IR C-terminal fragment. In the presence of proteasome inhibitors, we detected a PS/gamma-secretase cleavage product of the IR, termed the IR intracellular domain (ICD). Cellular fractionation and confocal microscopy analyses showed that the IR-ICD is predominantly detected in the nucleus. These data indicate that IR is a tyrosine kinase receptor, which undergoes PS/gamma-secretase-dependent processing. We also show that the auto-phosphorylation levels of the IR P-subunit upon insulin stimulation were decreased by the inactivation of PS/gamma-secretase, raising the possibility that the PS/gamma-secretase proteolysis of IR may play a modulatory role in insulin signaling. (c) 2007 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2007.06.022

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  • Clinical and genetic characterizations of 16q-linked autosomal dominant spinocerebellar ataxia (AD-SCA) and frequency analysis of AD-SCA in the Japanese population 査読

    Hiroaki Nozaki, Takeshi Ikeuchi, Akio Kawakami, Akio Kimura, Reiji Koide, Miyuki Tsuchiya, Yuusaku Nakmura, Tatsuro Mutoh, Hiroko Yamamoto, Naoki Nakao, Ko Sahashi, Masatoyo Nishizawa, Osamu Onodera

    MOVEMENT DISORDERS22 ( 6 ) 857 - 862   2007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-LISS  

    Autosomal dominant spinocerebellar ataxias (AD-SCAs) form a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, a single nucleotide substitution in the 5'-untranstated region of the puratrophin-1 gene was found to be associated with one type of AD-SCA linked to chromosome 16q (16q-SCA). To obtain further insight into the contribution of the C-to-T substitution in the puratrophin-1 gene to the clinical and genetic characteristics of patients with 16q-SCA, we analyzed 686 families with 719 individuals diagnosed with progressive ataxia. We found C-to-T substitution in the puratrophin-1 gene in 57 unrelated families with 65 affected individuals. The mean age at onset in the patients with 16q-SCA was 59.1 (range, 46-77). Ataxia is the most common initial symptom. The elderly patients over 65 occasionally showed other accompanying clinical features including abnormalities in tendon reflexes, involuntary movements, and reduced vibration sense. We also examined the frequency of the AD-SCA subtype, considering the effects of age at onset. In the 686 AD-SCA families, SCA6 and Machado-Joseph disease/ SCA3 are frequent subtypes, followed by dentatorubral-pallidoluysian atrophy and 16q-SCA. 16q-SCA is not a rare subtype of Japanese AD-SCA, particularly in patients with ages at onset over 60. (c) 2007 Movement Disorder Society.

    DOI: 10.1002/mds.21443

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  • Prevention of stroke and dementia by statin therapy: Experimental and clinical evidence of their pleiotropic effects 査読

    Takashi Miida, Akihiro Takahashi, Takeshi Ikeuchi

    PHARMACOLOGY & THERAPEUTICS113 ( 2 ) 378 - 393   2007年2月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Stroke and dementia are major causes of disability in most countries. Epidemiological studies have demonstrated that statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are likely to reduce the risk for developing these formidable disorders. The favorable outcomes in statin users may be attributable to not only cholesterol-dependent actions, but also various cholesterol-independent actions called "pleiotropic effects." Several clinical trials have suggested that statins decrease the incidence of stroke, especially ischemic stroke. Statins improve endothelial function, inhibit platelet activation, reduce blood coagulability, and suppress inflammatory reactions, all of which may contribute to the beneficial effects of the therapy. Statins also reduce the risk of vasospasm caused by subarachnoid hemorrhage (SAH). In addition, statins might inhibit the development and progression of Alzheimer's disease (AD), the dominant type of dementia in most industrialized countries, upstream of the amyloid cascade. In vitro studies have shown that statins modulate the metabolism of the p-amyloid precursor protein (APP) and reduce the extracellular level of its proteolytic product, amyloid-beta (A beta). The aggregated A beta is cytotoxic, leading to formation of neurofibrillary tangles and neuronal loss in the brain. Inflammatory processes are active in AD and may contribute significantly to AD pathology. We review the experimental background regarding the pleiotropic effects of statins and summarize clinical trials that examined the preventative effects of statin therapy on stroke and dementia. We include current trials in which statin therapy is initiated within 24 hr of onset of acute ischernic stroke. (c) 2006 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.pharmthera.2006.09.003

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  • A possible variant of neuro-Behcet disease presenting chronic progressive ataxia without mucocutaneo-ocular symptoms 査読

    Masaki Hirose, Takeshi Ikeuchi, Shintaro Hayashi, Kenshi Terajima, Kotaro Endo, Tsunemi Hayashi, Akiyoshi Kakita, Teruo Kimura, Hitoshi Takahashi, Masatoyo Nishizawa

    RHEUMATOLOGY INTERNATIONAL27 ( 1 ) 61 - 65   2006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  

    Behcet disease (BD) is a chronic relapsing multisystem disorder of unknown etiology, which preferentially affects the oral and genital mucous membranes, skin, and eyes. Neurological involvement is one of the most serious manifestations of BD, known as neuro-Behcet disease (NBD). We here describe clinical, radiological, and neuropathological findings for two patients with a possible variant of NBD, who manifested progressive ataxia in the absence of mucocutaneo-ocular signs characteristic for BD. Both patients presented a slowly progressive cerebellar phenotype, accompanied by behavioral changes and sphincter disturbance. Brain MRI scan revealed mild atrophy in pons and cerebellum. Both patients showed a mild CSF pleocytosis, and were positive for HLA-B51. The post-mortem examination performed in one patient, showed widespread foci of chronic encephalitis, consistent with the diagnosis of NBD. Steroid pulse therapy was effective in one patient. Identifying the progressive ataxia phenotype of NBD without mucocutaneo-ocular symptoms is important, because these patients may benefit from early steroid therapy.

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  • Can statin therapy really reduce the risk of Alzheimer's disease and slow its progression? 査読

    T Miida, A Takahashi, N Tanabe, T Ikeuchi

    CURRENT OPINION IN LIPIDOLOGY16 ( 6 ) 619 - 623   2005年12月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Purpose of Review Statins are the most used cholesterol-lowering agents worldwide. Earlier studies suggested that they may have preventative effects in Alzheimer's disease. However, prospective studies have questioned this hypothesis.
    Recent findings Statins regulate beta-amyloid metabolism and microglial activation. Pathologically, patients with Alzheimer's disease have more severe atherosclerosis in cerebral arteries than do controls. Such lesions may cause cerebral hypofusion, a risk factor for dementia and cognitive decline. Although most population-based studies have failed to show a beneficial effect of statins in Alzheimer's disease, two randomized controlled trials have suggested that statins slow cognitive decline in mild to moderate Alzheimer's disease.
    Summary There is still some hope that statins reduce the incidence of Alzheimer's disease and slow its progression. Large-scale randomized controlled trials of simvastatin and atorvastatin for mild to moderate Alzheimer's disease are underway, which might provide more conclusive results than earlier studies.

    DOI: 10.1097/01.hjh.0000191246.68443.ff

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  • A late-onset case of oculopharyngeal muscular dystrophy carrying a (GCG) 8 repeat expansion in the PAPBN1 gene 査読

    Takayoshi Tokutake, Takeshi Ikeuchi, Keiko Tanaka, Osamu Onodera, Masatoyo Nishizawa

    Clinical Neurology45 ( 6 ) 437 - 440   2005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)  

    We report a sporadic case of a female patient with oculopharyngeal muscular dystrophy (OPMD). Her father died at age 86 and mother at age 74. There was no familial occurrence of the disease. The patient initially developed a nasal voice at age 66. Neurological examinations on admission at age 72 revealed bilateral ptosis, a limitation of ocular movement without diplopia, dysphagia, and proximal muscle weakness. Serum creatine kinase level was slightly increased. Biopsied muscle specimens showed variation in fiber size as well as the occasional presence of rimmed vacuoles. On the basis of these clinical and laboratory findings, we suspected a diagnosis of OPMD, although a family history was absent. To confirm the diagnosis of OPMD, we performed a gene analysis for poly A binding protein, nuclear 1 (PABPN1
    PABP2), which revealed a mild expansion of GCG repeat (8 repeats) as a heterozygous state. Clinical features of the patient were consistent with those in a previous literature reporting that patients carrying (GCG) 8 repeat as a heterozygous state show a relatively late onset and a mild phenotype. The case of this patient emphasizes the importance of the PABPN1 gene analysis for patients showing muscular weakness involving oculopharyngeal and proximal limb muscles even when a familial occurrence of the disease is not apparent.

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  • Progression of cluster headache to Raeder's syndrome with marked response to corticosteroid therapy: A case report 査読

    Takeshi Ikeuchi, Takayoshi Tokutake, Yuuichi Sakamaki, Mineo Takagi, Masatoyo Nishizawa

    Clinical Neurology45 ( 4 ) 321 - 323   2005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)   出版者・発行元:4  

    A 42-year-old man complained of severe left orbital pain for 7 months. The diagnosis of cluster headache was made on the basis of diagnostic criteria formed by the International Headache Society. Sumatriptan was effective in relieving pain to a certain degree, but the frequency of the occurrence of pain gradually increased. Subsequently, he presented sensory disturbances in the left trigeminal nerve, and was admitted to our hospital. On admission, his neurological examination revealed left miosis and paresthesia in the first branch of the left trigeminal nerve. Neither anhidrosis nor ptosis was noted. His autonomic failure was consistent with post-synaptic disturbance as determined by pharmacological analysis for pupil's function. On the basis of the unique combination of neurological sings and symptoms including the unilateral headache, partial Horner's syndrome, and V1 sensory disturbance, we diagnosed him as having Raeder's syndrome. To exclude the possibility of a lesion in the Gasser ganglion of the middle fossa of the cranium or carotid artery causing symptomatic Raeder's syndrome, imaging studies including brain MRI, cervical MRA, and Doppler ultrasonography were performed, which revealed normal findings. We started him on oral prednisolone at 1 mg/kg once a day, which resulted in a rapid and dramatic suppression of pain. Thus, this case showed a progression from cluster headache to idiopathic Raeder's syndrome, which suggests that these two disorders might share common pathological and anatomical lesions.

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  • DIRECT technologies for molecular cloning of genes containing expanded CAG repeats. 査読

    Sanpei K, Ikeuchi T, Tsuji S

    Methods in molecular biology (Clifton, N.J.)217   73 - 81   2003年

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  • Dementia and delirium in 4 patients with Machado-Joseph disease 査読

    A Ishikawa, M Yamada, K Makino, Aida, I, J Idezuka, T Ikeuchi, Y Soma, H Takahashi, S Tsuji

    ARCHIVES OF NEUROLOGY59 ( 11 ) 1804 - 1808   2002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 MEDICAL ASSOC  

    Background: Machado-Joseph disease (MJD; spinocerebellar ataxia type 3) is a hereditary neurodegenerative disease caused by mutation of the MJD1 gene. Patients with MJD usually present with cerebellar ataxia, external ophthalmoplegia, pyramidal and extrapyramidal signs, and muscle wasting. However, it has been reported that these patients do not demonstrate dementia.
    Case Description: We noticed symptoms of dementia and delirium in 4 patients with MJD. The symptoms included abnormal behavior, excitation, an uncooperative attitude, crying, disorientation, slow thought processes, hallucinations, and delusions. These symptoms were observed in patients with a relatively young onset age, and after a long clinical course. In these patients, the CAG repeat length in the MJD1 gene was much longer compared with the mean repeat length found in patients with MJD. On electroencephalographical examination, they showed slow background activity, but computed tomography and magnetic resonance imaging scans showed no cerebrocortical atrophy. Neuropathological findings in. 2 patients revealed a normal cortical structure on conventional morphological examination, but at immunohistochemical examination, we found abnormal staining by an antipolyglutamine antibody in the cerebrocortical neuronal nuclei.
    Conclusions: Symptoms of dementia and delirium in patients with MJD could occur in the late stages, and they might be caused not by loss of cerebrocortical neurons, but by their dysfunction.

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  • Multiple founder effects in Japanese families with primary torsion dystonia harboring the GAG deletion in the TOR1A (DYT1) gene 査読

    T Ikeuchi, Y Nomura, M Segawa, LJ Ozelius, T Shimohata, S Tsuji

    NEUROGENETICS4 ( 2 ) 105 - 106   2002年10月

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    記述言語:英語   出版者・発行元:SPRINGER-VERLAG  

    DOI: 10.1007/s10048-002-0135-7

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  • A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees 査読

    A Arai, K Tanaka, T Ikeuchi, S Igarashi, H Kobayashi, T Asaka, H Date, M Saito, H Tanaka, S Kawasaki, E Uyama, H Mizusawa, N Fukuhara, S Tsuji

    ANNALS OF NEUROLOGY52 ( 4 ) 516 - 519   2002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-LISS  

    Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive muscular disorder characterized by weakness of the anterior compartment of the lower limbs with onset in early adulthood and sparing of the quadricep muscles. The UDP-N-acetylglucosamine-2-epimerase/N-acetyl-mannosamine kinase (GNE) gene was recently identified as the causative gene for hereditary inclusion body myopathy (HIBM). To investigate whether DMRV and HIBM are allelic diseases, we conducted mutational analysis of the GNE gene of six Japanese DMRV pedigrees and found that all the pedigrees share a homozygous mutation (V572L) associated with a strong linkage disequilibrium, suggesting a strong founder effect in Japanese DMRV pedigrees.

    DOI: 10.1002/ana.10341

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  • Analysis of the expression level of α-synuclein mRNA using postmortem brain samples from pathologically confirmed cases of multiple system atrophy 査読

    Tetsutaro Ozawa, Kaoru Okuizumi, Takeshi Ikeuchi, Koichi Wakabayashi, Hitoshi Takahashi, Shoji Tsuji

    Acta Neuropathologica102 ( 2 ) 188 - 190   2001年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To determine whether multiple system atrophy (MSA) is associated with altered expression levels of the α-synuclein messenger RNA (mRNA), we performed quantitative reverse transcription polymerase chain reaction for α-synuclein mRNA using postmortem brain samples from 11 cases of MSA and 14 age-matched control subjects. The brain specimens used in this study contained both the gray matter and white matter, which were dissected from the frontal, temporal or occipital lobe. The expression levels of α-synuclein mRNA in the brain specimens of MSA cases were not different from those of the control subjects. These results suggest that the transcriptional regulation of the α-synuclein gene is unlikely to be affected in MSA brains.

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  • Dentatorubral-pallidoluysian atrophy (DRPLA) presenting with psychosis 査読

    N. Adachi, K. Arima, T. Asada, M. Kato, N. Minami, Y. I. Goto, T. Onuma, T. Ikeuchi, S. Tsuji, M. Hayashi, Y. Fukutani

    Journal of Neuropsychiatry and Clinical Neurosciences13 ( 2 ) 258 - 260   2001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:American Psychiatric Publishing Inc.  

    The authors report on four DRPLA patients who manifested delusions. All patients demonstrated autosomal dominant DRPLA confirmed by standard gene analysis. Patients with DRPLA can exhibit a variety of psychiatric symptoms in addition to extrapyramidal and cerebellar symptoms.

    DOI: 10.1176/jnp.13.2.258

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  • Expanded polyglutamine stretches interact with TAF(II)130, interfering with CREB-dependent transcription 査読

    T Shimohata, T Nakajima, M Yamada, C Uchida, O Onodera, S Naruse, T Kimura, R Koide, K Nozaki, Y Sano, H Ishiguro, K Sakoe, T Ooshima, A Sato, T Ikeuchi, M Oyake, T Sato, Y Aoyagi, Hozumi, I, T Nagatsu, Y Takiyama, M Nishizawa, J Goto, Kanazawa, I, Davidson, I, N Tanese, H Takahashi, S Tsuji

    NATURE GENETICS26 ( 1 ) 29 - 36   2000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:NATURE PUBLISHING GROUP  

    At least eight inherited neurodegenerative diseases are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches are implicated, the molecular mechanisms of neurodegeneration remain unclear. We found that expanded! polyQ stretches preferentially bind to TAF(II)130, a coactivator involved in cAMP-responsive element binding protein (CREB)-dependent transcriptional activation, and strongly suppress CREB-dependent transcriptional activation. The suppression of CREB-dependent transcription and the cell death induced by polyQ stretches were restored by the co-expression of TAF(II)130. Our results indicate that interference of transcription by the binding of TAF(II)130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.

    DOI: 10.1038/79139

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  • Two phenotypes and anticipation observed in Japanese cases with early onset torsion dystonia (DYT1) - pathophysiological consideration 査読

    Y Nomura, T Ikeuchi, S Tsuji, M Segawa

    BRAIN & DEVELOPMENT22   S92 - S101   2000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  

    Early onset torsion dystonia (DYT1) is a dominantly inherited dystonia caused by a deletion of three bases, GAG, coding glutamic acid, in chromosome 9q34. The protein coded by this gene was named as torsin A. DYT1 is common among the Ashkenazi Jewish population, but has been thought to be rare among Japanese. Among the idiopathic torsion dystonias being followed in this clinic, we found five families with DYT1 by gene analysis. This is the first report of genetically proven Japanese DYT1. The clinical features of five proband cases were divided into two types. One type is postural dystonia with marked trunkal torsion, and the other is action dystonia associated with violent dyskinetic movements. The affected family members in the upper generations presented with focal or segmental dystonia; it was postural dystonia of the legs in the former, and writer's cramp or tremor of the arms in the latter families. There was an asymptomatic carrier in the upper generation. Anticipation in the age of onset and severity of the disease was observed in all families. Medical treatment, including anticholinergics and levodopa, did not show apparent effects, while stereotactic thalamotomy to the nucleus ventralis lateralis (VL) or ventralis intermedius (Vim), with or without posterior ventral pallidotomy, were effective with action dystonia, but not postural dystonia. This study suggests the existence of at least two phenotypes in DYT1, in which different pathways of the basal ganglia an involved. (C) 2000 Elsevier Science B.V. All rights reserved.

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  • Novel mutations, pseudo-dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism 査読

    M Maruyama, T Ikeuchi, M Saito, A Ishikawa, T Yuasa, H Tanaka, S Hayashi, K Wakabayashi, H Takahashi, S Tsuji

    ANNALS OF NEUROLOGY48 ( 2 ) 245 - 250   2000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  

    Autosomal recessive juvenile parkinsonism is a hereditary neurodegenerative disorder, usually beginning before the age of 40. We found three exonic deletions and two novel point mutations (Arg33Stop and Cys431Phe) in six families with autosomal recessive juvenile parkinsonism. In 1 family, in which an autosomal dominant mode of inheritance was suspected, multiple mutant alleles were identified. Although a wide range of ages at onset was observed, there was no correlation between age at onset and genotype.

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  • A CAG trinucleotide repeat expansion and familial schizophrenia 査読

    Koichi Ohara, Takeshi Ikeuchi, Yasuo Suzuki, Mikihisa Ohtani, Kenshiro Ohara, Shoji Tsuji

    Psychiatry Research94 ( 3 ) 257 - 262   2000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)  

    Studies which showed anticipation in families with schizophrenia suggested that a trinucleotide repeat expansion mechanism may be involved in the pathogenesis of familial schizophrenia. Furthermore, some studies involving the repeat expansion detection (RED) method showed the median length of CAG repeats to be longer in probands with schizophrenia than that in control subjects. We screened for a possible expanded CAG repeat by means of the direct identification of repeat expansion and cloning technique in 23 subjects (affected, 14
    unaffected, 9) from six families with schizophrenia which showed anticipation. The polymorphism of a long and unstable CAG/CTG trinucleotide repeat, Dir1, was studied by PCR. No unusual expanded CAG/CTG trinucleotide repeat was detected in the subjects with familial schizophrenia. There was no significant difference between the affected and unaffected subjects in the allele frequency of Dir1. Our results suggest that a CAG expansion is not the mechanism underlying familial schizophrenia. Copyright (C) 2000 Elsevier Science Ireland Ltd.

    DOI: 10.1016/S0165-1781(00)00156-6

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  • Studies of the candidate genes in X-linked congenital cerebellar hypoplasia 査読

    SN Illarioshkin, KM Allen, JG Gleeson, S Tsuji, T Ikeuchi, ED Markova, CA Walsh, IA Ivanova-Smolenskaya

    JOURNAL OF NEUROLOGY246 ( 12 ) 1177 - 1180   1999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:DR DIETRICH STEINKOPFF VERLAG  

    A gene for X-linked congenital cerebellar hypoplasia was recently localized to chromosome Xp11.21-q24. This region comprises several brain-specific genes responsible for various neurological disorders, including the proteolipid protein (PLP), doublecortin, and PAK3 genes. We screened these genes for mutations in patients with X-linked congenital cerebellar hypoplasia and found no pathogenic nucleotide changes or gene dose alterations. These findings allow the ruling out of PLP, doublecortin, and PAK3 as the disease-causing genes in this hereditary neurological syndrome.

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  • Novel chloride channel gene mutations in two unrelated Japanese families with Becker's autosomal recessive generalized myotonia 査読

    R Sasaki, H Ichiyasu, N Ito, T Ikeda, H Takano, T Ikeuchi, S Kuzuhara, M Uchino, S Tsuji, E Uyama

    NEUROMUSCULAR DISORDERS9 ( 8 ) 587 - 592   1999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:PERGAMON-ELSEVIER SCIENCE LTD  

    We investigated the skeletal muscle voltage-gated chloride channel gene (CLCN1) in two unrelated Japanese patients with Becker's myotonia congenita. The non-myotonic parents of each patient were consanguineous. The proband of each family shares generalized myotonia, transient weakness after rest, and leg muscle hypertrophy. However, the disease severity related to the degree of myotonia differed, even in view of the response to long train nerve stimulation tests. CLCN1 gene analysis revealed a novel Ala659Val missense mutation identified to be homozygous in the more severe patient, while a novel Gln445Stop nonsense mutation was present in the other patient. Both mutations were absent in 90 Japanese normal controls. This is the first report of Japanese cases of Becker's myotonia congenita with CLCN1 gene mutations. (C) 1999 Elsevier Science B.V. All rights reserved.

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  • A case of primary torsion dystonia in Japan with the 3-bp (GAG) deletion in the DYT1 gene with a unique clinical presentation 査読

    T Ikeuchi, T Shimohata, R Nakano, R Koide, H Takano, S Tsuji

    NEUROGENETICS2 ( 3 ) 189 - 190   1999年9月

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    記述言語:英語   出版者・発行元:SPRINGER VERLAG  

    DOI: 10.1007/s100480050082

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  • No mutation in the entire coding region of the alpha-synuclein gene in pathologically confirmed cases of multiple system atrophy 査読

    T Ozawa, H Takano, O Onodera, H Kobayashi, T Ikeuchi, R Koide, K Okuizumi, T Shimohata, K Wakabayashi, H Takahashi, S Tsuji

    NEUROSCIENCE LETTERS270 ( 2 ) 110 - 112   1999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 SCI IRELAND LTD  

    To determine whether mutations in the coding region of the alpha-synuclein gene are relevant in cases of multiple system atrophy (MSA), detailed nucleotide sequence analysis of the alpha-synuclein gene was performed using total RNA obtained from autopsied brain specimens of 11 pathologically confirmed cases of MSA. The brain specimens used in this study contained both gray and white matter, which were dissected from the frontal, temporal or occipital lobe. No nucleotide alterations were found in the entire coding region of the alpha-synuclein gene in any of the cases. While mutations In the regulatory or intronic regions of the gene were not ruled out, our results suggest that mutations in the coding region of the alpha-synuclein gene are unlikely to contribute to the pathogenesis of MSA. (C) 1999 Elsevier Science ireland ltd. All rights reserved.

    DOI: 10.1016/S0304-3940(99)00475-9

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  • Hereditary dentatorubral-pallidoluysian atrophy: detection of widespread ubiquitinated neuronal and glial intranuclear inclusions in the brain 査読

    Y Hayashi, A Kakita, M Yamada, R Koide, S Igarashi, H Takano, T Ikeuchi, K Wakabayashi, S Egawa, S Tsuji, H Takahashi

    ACTA NEUROPATHOLOGICA96 ( 6 ) 547 - 552   1998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 VERLAG  

    `We examined the brains and spinal cords of seven patients with clinicopathologically and genetically confirmed hereditary dentatorubral-pallidoluysian atrophy (DRPLA) using an antibody against ubiquitin, and found small, round immunoreactive intranuclear inclusions in both neurons and glial cells in various brain regions. Ubiquitinated neuronal intranuclear inclusions (uNIIs) were consistently found in the striatum, the pontine nuclei, the inferior olivary complex, the cerebellar cortex and the dentate nucleus. Ubiquitinated glial intranuclear inclusions (uGIIs) were found less frequently than uNIIs. Most of the inclusion-bearing nuclei were of an astrocytic nature. Immunostaining with an antibody against DRPLA protein revealed similar immunoreactive neuronal and glial intranuclear inclusions, but in much smaller in numbers compared with uNIIs and uGIIs. Electron microscopy showed that such inclusions were composed of granular and filamentous structures. These findings strongly suggest that, in DRPLA, the occurrence of uNIIs and uGIIs is directly related to the causative gene abnormality (an expanded CAG repeat encoding polyglutamine), that neurons are affected much more widely than previously recognized and that glial cells are also involved in the disease process.

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  • The human Musashi homolog 1 (MSI1) gene encoding the homologue of Musashi/Nrp-1, a neural RNA-binding protein putatively expressed in CNS stem cells and neural progenitor cells 査読

    Peter Good, Akinori Yoda, Shin-Ichi Sakakibara, Atsuyo Yamamoto, Takao Imai, Hitoshi Sawa, Takeshi Ikeuchi, Shoji Tsuji, Hitoshi Satoh, Hideyuki Okano

    Genomics52 ( 3 ) 382 - 384   1998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.  

    DOI: 10.1006/geno.1998.5456

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  • A novel long and unstable CAG/CTG trinucleotide repeat on chromosome 17q 査読

    T Ikeuchi, K Sanpei, H Takano, H Sasaki, K Tashiro, G Cancel, A Brice, TD Bird, GD Schellenberg, MA Pericak-Vance, KA Welsh-Bohmer, LN Clark, K Wilhelmsen, S Tsuji

    GENOMICS49 ( 2 ) 321 - 326   1998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:ACADEMIC PRESS INC  

    Using the direct identification of repeat expansion and cloning technique, we cloned a novel long CAG/ CTG trinucleotide repeat on chromosome 17. Using radiation hybrid panels, the CAG/CTG repeat was mapped to chromosome 17q. The CAG/CTG repeat is highly polymorphic, with a heterozygosity of 85%, and exhibits a bimodal distribution (allele S, 10-26 repeat units, and allele L, 50-92 repeat units). The CAG/CTG repeat of allele L exhibited intergenerational instabilities, which are more prominent in maternal transmission than in paternal transmission. Analyses of Northern blot and RT-PCR indicate that the repeat is transcribed. Although the size of the CAG/CTG repeat of allele L is within the range of the expanded CAG repeat of disease-causing genes, we did not detect any association of allele L with various neurodegenerative diseases, including frontotemporal dementia and parkinsonism, mapped to 17q21-q23. (C) 1998 Academic Press.

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  • Multiple system atrophy with severe involvement of the motor cortical areas and cerebral white matter 査読

    K Wakabayashi, T Ikeuchi, A Ishikawa, H Takahashi

    JOURNAL OF THE NEUROLOGICAL SCIENCES156 ( 1 ) 114 - 117   1998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 SCIENCE BV  

    We report multiple system atrophy (MSA) of 14 years' duration in a 75-year-old woman. Postmortem examination revealed pathological changes typical of MSA. Furthermore, neuronal loss with astrocytosis in the primary motor and premotor cortices, especially in the fifth and sixth layers, and extensive myelin and axonal loss in the frontal and parietal white matter were evident. There were numerous ubiquitin-positive oligodendroglial inclusions, which are characteristic of MSA, in these cortical and white matter lesions. These findings suggest that the motor cortical areas and cerebral white matter are sites of significant involvement in the MSA disease process and that inclusion-bearing oligodendroglial alterations contribute to the white matter degeneration. (C) 1998 Elsevier Science B.V.

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  • Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch 査読

    S Igarashi, R Koide, T Shimohata, M Yamada, Y Hayashi, H Takano, H Date, M Oyake, T Sato, A Sato, S Egawa, T Ikeuchi, H Tanaka, R Nakano, K Tanaka, Hozumi, I, T Inuzuka, H Takahashi, S Tsuji

    NATURE GENETICS18 ( 2 ) 111 - 117   1998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 AMERICA INC  

    To elucidate the molecular mechanisms whereby expanded polyglutamine stretches elicit a gain of toxic function, we expressed full-length and truncated DRPLA (dentatorubral-pallidoluysian atrophy) cDNAs with or without expanded CAG repeats in COS-7 cells. We found that truncated DRPLA proteins containing an expanded polyglutamine stretch form filamentous peri-and intranuclear aggregates and undergo apoptosis. The apoptotic cell death was partially suppressed by the transglutaminase inhibitors cystamine and monodansyl cadaverine (but not putrescine), suggesting involvement of a transglutaminase reaction and providing a potential basis for the development of therapeutic measures for GAG-repeat expansion diseases.

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  • Atrophy of the cerebellum and brainstem in dentatorubral pallidoluysian atrophy - Influence of CAG repeat size on MRI findings 査読

    R Koide, O Onodera, T Ikeuchi, R Kondo, H Tanaka, S Tokiguchi, A Tomoda, T Miike, F Isa, H Beppu, N Shimizu, Y Watanabe, Y Horikawa, T Shimohata, K Hirota, A Ishikawa, S Tsuji

    NEUROLOGY49 ( 6 ) 1605 - 1612   1997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:LIPPINCOTT WILLIAMS & WILKINS  

    To elucidate how the size of the expanded CAG repeat of the gene for dentatorubral pallidoluysian atrophy (DRPLA) and other factors affect the atrophy of the brainstem and cerebellum, and the appearance of high-intensity signals on T2-weighted MRI of the cerebral white matter of patients with DRPLA, we quantitatively analyzed the MRI findings of 26 patients with DRPLA, the diagnosis of which was confirmed by molecular analysis of the DRPLA gene. When we classified the patients into two groups based on the size of the expanded CAG repeat of the DRPLA gene (group 1, number of CAG repeat units greater than or equal to 66; group 2, number of CAG repeat units less than or equal to 65), we found strong inverse correlations between the age at MRI and the areas of midsagittal structures of the cerebellum and brainstem in group 1 but not in group 2. Multiple regression analysis, however, revealed that both the patient's age at MRI and the size of the expanded CAG repeat correlated with the areas of midsagittal structures. Involvement of the cerebral white matter as detected on T2-weighted images was observed more frequently in patients belonging to group 2 than in group 1 patients. Furthermore it was demonstrated that high-intensity signals can be detected on T2-weighted images of the cerebral white matter of patients with a largely expanded CAG repeat (group I) in their thirties. These results suggest that patient age as well as the size of the expanded CAG repeat are related to the degree of atrophy of the brainstem and cerebellum, and the white matter changes in patients with DRPLA.

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  • Molecular cloning of murine homologue dentatorubral-pallidoluysian atrophy (DRPLA) cDNA: Strong conservation of a polymorphic CAG repeat in the murine gene 査読

    M Oyake, O Onodera, T Shiroishi, H Takano, Y Takahashi, R Kominami, K Moriwaki, T Ikeuchi, S Igarashi, H Tanaka, S Tsuji

    GENOMICS40 ( 1 ) 205 - 207   1997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:ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

    DOI: 10.1006/geno.1996.4522

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  • Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT 査読

    K Sanpei, H Takano, S Igarashi, T Sato, M Oyake, H Sasaki, A Wakisaka, K Tashiro, Y Ishida, T Ikeuchi, R Koide, M Saito, A Sato, T Tanaka, S Hanyu, Y Takiyama, M Nishizawa, N Shimizu, Y Nomura, M Segawa, K Iwabuchi, Eguchi, I, H Tanaka, H Takahashi, S Tsuji

    NATURE GENETICS14 ( 3 ) 277 - 284   1996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:NATURE PUBLISHING CO  

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant, neurodegenerative disorder that affects the cerebellum and other areas of the central nervous system. We have devised a novel strategy, the direct identification of repeat expansion and cloning technique (DIRECT), which allows selective detection of expanded CAG repeats and cloning of the genes involved. By applying DIRECT, we identified an expanded CAG repeat Of the gene for SCA2. CAG repeats of normal alleles range in size from 15 to 24 repeat units, while those of SCA2 chromosomes are expanded to 35 to 59 repeat units. The SCA2 cDNA is predicted to code for 1,313 amino acids - with the CAG repeats coding for a polyglutamine tract. DIRECT is a robust strategy for identification of pathologically expanded trinucleotide repeats and will dramatically accelerate the search for causative genes of neuropsychiatric diseases caused by trinucleotide repeat expansions.

    DOI: 10.1038/ng1196-277

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  • [How was the gene for dentatorubral-pallidoluysian atrophy discovered?]. 査読

    Tsuji S, Koide R, Ikeuchi T

    No to shinkei = Brain and nerve48 ( 4 ) 323 - 328   1996年4月

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  • Somatic mosaicism of expanded CAG repeats in brains of patients with dentatorubral-pallidoluysian atrophy: Cellular population-dependent dynamics of mitotic instability 査読

    H. Takano, O. Onodera, H. Takahashi, S. Igarashi, M. Yamada, M. Oyake, T. Ikeuchi, R. Koide, H. Tanaka, K. Iwabuchi, S. Tsuji

    American Journal of Human Genetics58 ( 6 ) 1212 - 1222   1996年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease caused by unstable expansion of a CAG repeat in the DRPLA gene. We performed detailed quantitative analysis of the size and the size distribution (range) of the expanded CAG repeats in various regions of the CNS of eight autopsied patients with DRPLA. Expanded alleles (AE) showed considerable variations in size, as well as in range, depending on the region of the CNS, whereas normal alleles did not show such variations, which indicates the occurrence of somatic mosaicism of AE in the CNS. The AE in the cerebellar cortex were consistently smaller by two to five repeat units than those in the cerebellar white matter. Moreover, the AE in the cerebral cortex were smaller by one to four repeat units than those in the cerebral white matter. These results suggest that the smaller AE in the cerebellar and cerebral cortices represent those of neuronal cells. The ranges of the AE in the cerebral cortex, cerebral white matter, and cerebellar white matter showed considerable variation ranging from 9 to 23 repeat units, whereas those in the cerebellar cortex showed little variance and were ~7 repeat units. The ranges of the AE in the cerebral cortex, cerebral white matter, and cerebellar white matter were much broader in patients with higher ages at death than they were in patients with lower ages at death, raising the possibility that the range of AE increases with time, as the result of mitotic instability of AE.

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  • MOLECULAR-CLONING OF A FULL-LENGTH CDNA FOR DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY AND REGIONAL EXPRESSIONS OF THE EXPANDED ALLELES IN THE CNS 査読

    O ONODERA, M OYAKE, H TAKANO, T IKEUCHI, S IGARASHI, S TSUJI

    AMERICAN JOURNAL OF HUMAN GENETICS57 ( 5 ) 1050 - 1060   1995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:UNIV CHICAGO PRESS  

    Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by genetic anticipation and variable combinations of symptoms including myoclonus, epilepsy, cerebellar ataxia, choreoathetosis, and dementia. Recently, we discovered that DRPLA is caused by unstable expansion of a CAG repeat of a gene on the short arm of chromosome 12. We determined the consensus DRPLA cDNA sequence containing the complete coding region for 1,185 amino acids. The CAG repeat, which is expanded in DRPLA, is located 1,462 bp downstream from the putative methionine initiation codon and encodes a poly-glutamine tract. Although poly-serine and proline tracts exist near the CAG repeats, these polyserine or proline tracts did not show any polymorphisms, which is in strong contrast to the high heterogeneity in the length of the CAG repeat. Northern blot analysis revealed a 4.7-kb transcript that is widely expressed in various tissues including heart, lung, kidney, placenta, skeletal muscle, and brain. Reverse transcription-PCR analysis revealed that the expanded alleles are transcribed to levels comparable to those of normal alleles. These results indicate that there is no difference in transcriptional efficiency between expanded and normal alleles. Furthermore, mRNA from cerebellar hemispheres of DRPLA patients showed smaller sizes of CAG repeats compared with other regions of the brain, which reflects somatic mosaicism of the expanded alleles of the DRPLA gene.

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  • DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY - CLINICAL-FEATURES ARE CLOSELY-RELATED TO UNSTABLE EXPANSIONS OF TRINUCLEOTIDE (CAG) REPEAT 査読

    T IKEUCHI, R KOIDE, H TANAKA, O ONODERA, S IGARASHI, H TAKAHASHI, R KONDO, A ISHIKAWA, A TOMODA, T MIIKE, K SATO, Y IHARA, T HAYABARA, F ISA, H TANABE, S TOKIGUCHI, M HAYASHI, N SHIMIZU, F IKUTA, H NAITO, S TSUJI

    ANNALS OF NEUROLOGY37 ( 6 ) 769 - 775   1995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:LITTLE BROWN CO  

    Dentatorubral-pallidoluysian atrophy is an autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy, and dementia as well as a wide range of ages at onset. A specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 was recently identified as the pathogenic mutation for this disease. We investigated how the degree of expansion of the CAG repeat affects the clinical manifestations of dentatorubral-pallidoluysian atrophy. The size of the expanded alleles was well correlated with the age at onset (r = -0.696, p &lt; 0.001). Patients with the progressive myoclonus epilepsy phenotype had larger expansions (62-79 repeats) and an earlier age at onset (onset before age 21). Furthermore, most of the patients with the progressive myoclonus epilepsy phenotype inherited their expanded alleles from their affected fathers. On the other hand, patients with the non-progressive myoclonus epilepsy phenotype showed smaller expansions (54-67 repeats) and a later age at onset (onset at or after age 21). Detailed analyses of clinical features demonstrated that ataxia, involuntary movement of either myoclonus or choreoathetosis, and intellectual decline are cardinal features of dentatorubral-pallidoluysian atrophy, with myoclonus and epilepsy being observed more frequently in patients with an earlier age at onset. Thus the wide variation in clinical manifestations of dentatorubral-pallidoluysian atrophy can now be clearly explained based on the degree of CAG repeat expansion, which strongly indicates that the expanded alleles are intimately involved in the neuronal degeneration in dentatofugal and pallidofugal systems.

    DOI: 10.1002/ana.410370610

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  • DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA) - CLOSE CORRELATION OF CAG REPEAT EXPANSIONS WITH THE WIDE SPECTRUM OF CLINICAL PRESENTATIONS AND PROMINENT ANTICIPATION 査読

    T IKEUCHI, O ONODERA, M OYAKE, R KOIDE, H TANAKA, S TSUJI

    SEMINARS IN CELL BIOLOGY6 ( 1 ) 37 - 44   1995年2月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS (LONDON) LTD  

    Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy and dementia as well as various ages of onset. We have identified a specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 as the pathogenic mutation for DRPLA. We investigated how the degree of the expansion of the CAG repeat affects the clinical manifestations of DRPLA. The sires of the expanded alleles were well correlated with the ages of onset (r = -0.6955, P&lt;0.001). Patients with progressive myoclonus epilepsy (PME) phenotype had larger expansions (62-79 repeats) and earlier ages of onset (onset before age 20). Furthermore, most of the patients with PME phenotype inherited their expanded alleles from their affected fathers. On the other hand, patients with non-PME phenotype showed later ages of onset (onset after age 20) and smaller expansions (54-67 repeats). When ages of onset of each clinical symptom are compared with sizes of the CAG repeat, there is again a remarkably high correlation of the sizes of CAG repeat with each of the clinical symptoms. Thus the wide variation in clinical manifestations of DRPLA can now be clearly explained based on-the degree of CAG repeat expansion, which strongly indicates that the expanded alleles are intimately involved in the neuronal degeneration in dentatofugal and pallidofugal systems.

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  • A sporadic dentatorubral-pallidoluysian atrophy (DRPLA) diagnosed by gene analysis 査読

    H. Yoshimoto, M. Sahara, K. Tanaka, T. Ikeuchi, R. Koide, S. Tsuji

    Clinical Neurology35 ( 2 ) 201 - 203   1995年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    We report a 48 year-old woman with dentatorubral-pallidoluysian atrophy (DRPLA). She is the only patient in her 15 family members in two generations. She developed cerebellar ataxia and epilepsy at age 43. On admission at 48, she showed mild dementia and choreic movement in her face and extremities as well as truncal and limb ataxia. Routine laboratory examinations were normal. The point mutations in the tRNA(Lys) gene of mitochondrial DNA specific for MERRF were not found. A cranial CT scan and MRI showed mild atrophy of the cerebellum and prominent atrophy in the pons, especially in the tegmentum. Although she was thought to have DRPLA from the clinical point of view, absence of family history made the diagnosis difficult. Her parents were healthy until their 80's and died of cerebrovascular diseases and her 5 siblings had no symptoms. Hereditary DRPLA is known as an autosomal dominant disorder,with a high rate of penetrance and low rate of new mutation. According to our recent findings of a CAG repeat expansion in the DRPLA gene, this patient was diagnosed as a sporadic DRPLA. Considering the wide varieties of clinical manifestations, it is essential to examine this gene abnormality for diagnosing sporadic DRPLA.

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  • Tubular aggregatesを伴う兄妹発症の家族性ミオパチー 査読

    池内 健, 姉崎利治, 石黒英明, 田中正美, 田中恵子, 辻 省次

    臨床神経35   1016 - 1020   1995年

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    記述言語:日本語  

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  • DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA) - MOLECULAR-BASIS FOR WIDE CLINICAL-FEATURES OF DRPLA 査読

    T IKEUCHI, R KOIDE, O ONODERA, H TANAKA, M OYAKE, H TAKANO, S TSUJI

    CLINICAL NEUROSCIENCE3 ( 1 ) 23 - 27   1995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:WILEY-LISS  

    Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder characterized clinically by various combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis, dementia and psychiatric symptoms. Based on the phenomenon of anticipation, the gene for DRPLA was recently identified. DRPLA is caused by unstable expansion of a CAG repeat in the gene located on the short arm of chromosome 12. As have been observed in Huntington's disease and SCA1, there is a strong correlation between the age of onset and the size of CAG repeats. Furthermore, patients with larger repeats tend to show a PME (progressive myoclonus epilepsy) phenotype as well as earlier ages of onset. More prominent anticipation and larger intergenerational increase of CAG repeats in paternal transmission can be accounted for by the meiotic instability of CAG repeats in male gametogenesis. Comparison of size distributions of CAG repeats in Japanese, African-American and white populations revealed that 7.4% of the Japanese alleles had greater than 19 repeats, whereas none of the whites and 1% of the African-American alleles were of this size. The results may account for the ethnic predilection of DRPLA. (C) 1995 Wiley-Liss, Inc.

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  • 遺伝子 診断が有用であった孤発例と考えられた歯状核赤核淡蒼球ルイ体萎縮症 (DRPLA) の1例 査読

    善本晴子, 佐原正起, 田中恵子, 池内 健, 小出玲爾, 辻 省次

    臨床神経35   201 - 203   1995年

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    記述言語:日本語  

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  • Familial myopathy associated with tubular aggregates: Report of two siblings 査読

    T. Ikeuchi, T. Anezaki, H. Ishiguro, M. Tanaka, K. Tanaka, S. Tsuji

    Clinical Neurology35 ( 9 ) 1016 - 1020   1995年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    We reported two siblings with slowly progressive muscle weakness in proximal and peroneal muscles without atrophy, myalgia, cramps, or episodic weakness. The serum creatine kinase level was moderately elevated. The prominent features of their muscle pathology were accumulation of tubular aggregates in type 2 fibers, predominantly in type 2B fibers, and marked type 1 fiber atrophy. Three to eleven % of muscle fibers contained tubular aggregates. Electron microscopic examination revealed accumulation of double- walled tubular structures. Familial myopathy with tubular aggregates as a hallmark of muscle pathology is considered to be a new clinical form of childhood onset familial myopathies.

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  • UNSTABLE EXPANSION OF CAG REPEAT IN HEREDITARY DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA) 査読

    R KOIDE, T IKEUCHI, O ONODERA, H TANAKA, S IGARASHI, K ENDO, H TAKAHASHI, R KONDO, A ISHIKAWA, T HAYASHI, M SAITO, A TOMODA, T MIIKE, H NAITO, F IKUTA, S TSUJI

    NATURE GENETICS6 ( 1 ) 9 - 13   1994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 CO  

    Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurologic disorder characterized by variable combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. By specifically searching published brain cDNA sequences for the presence of CAG repeats we identified unstable expansion of a CAG in a gene on chromosome 12 in all the 22 DRPLA patients examined. A good correlation between the size of the CAG repeat expansion and the ages of disease onset is found in this group. Patients with earlier onset tended to have a phenotype of progressive myoclonus epilepsy and larger expansions. We propose that the wide variety of clinical manifestations of DRPLA can now be explained by the variable unstable expansion of the CAG repeat.

    DOI: 10.1038/ng0194-9

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▶ 全件表示

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    日本抗加齢医学会総会プログラム・抄録集20回   102 - 102   2020年9月

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    記述言語:日本語   出版者・発行元:(一社)日本抗加齢医学会  

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  • Huntington病の診断、治療、療養の手引き

    中島 健二, 祖父江 元, 長谷川 一子, 饗場 郁子, 青木 正志, 阿部 康二, 池内 健, 小野寺 理, 梶 龍兒, 吉良 潤一, 桑原 聡, 小久保 康昌, 斎藤 加代子, 佐々木 秀直, 佐野 輝, 高橋 良輔, 辻 省次, 戸田 達史, 中川 正法, 野元 正弘, 服部 信孝, 村田 美穂, 村山 繁雄, 望月 秀樹, 森田 光哉, 横田 隆徳, 吉田 眞理, 渡辺 保裕, 保住 功, Huntington病の診断、治療、療養の手引きガイドライン作成委員会

    神経治療学37 ( 1 ) 61 - 104   2020年1月

  • FTLD-Jから見た本邦前頭側頭型認知症の臨床特徴

    桝田 道人, 渡辺 宏久, 大嶽 れい子, 加藤 隼康, 小倉 礼, 勝野 雅央, 新井 哲明, 池内 健, 和泉 唯信, 繁信 和恵, 品川 俊一郎, 横田 修, 渡辺 保裕, 中島 健二, 池田 学, 祖父江 元

    臨床神経学59 ( Suppl. ) S328 - S328   2019年11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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  • 家族性アルツハイマー病で同定された新規PSEN1遺伝子変異の病的意義の検討

    三浦 健, 目崎 直実, Zhu Bin, 村上 涼太, Liu Lixin, 樋口 陽, 石黒 敬信, 月江 珠緒, 原 範和, 春日 健作, 宮下 哲典, 小野寺 理, 池内 健

    臨床神経学59 ( Suppl. ) S352 - S352   2019年11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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  • 脳脊髄液バイオマーカーによるAlzheimer's clinical syndromeの検討

    春日 健作, 月江 珠緒, 原 範和, 樋口 陽, 石黒 敬信, 徳武 孝允, 宮下 哲典, 小野寺 理, 池内 健

    臨床神経学59 ( Suppl. ) S217 - S217   2019年11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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  • LMNB1関連常染色体優性遺伝性白質脳症の本邦例と既報例の比較

    目崎 直実, 三浦 健, 野崎 洋明, 今野 卓哉, 春日 健作, 小野寺 理, 池内 健

    臨床神経学59 ( Suppl. ) S327 - S327   2019年11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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  • 大脳皮質基底核変性症における多角的診断の重要性

    齊藤 祐子, 饗場 郁子, 佐野 輝典, 小松 奏子, 池内 健, 長谷川 成人, 徳丸 阿耶, 村山 繁雄, 日本神経病理学会ブレインバンク委員会

    臨床神経学59 ( Suppl. ) S303 - S303   2019年11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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  • 多系統萎縮症における脳脊髄液バイオマーカーの検討

    徳武 孝允, 春日 健作, 月江 珠緒, 石黒 敬信, 樋口 陽, 下畑 享良, 小野寺 理, 池内 健

    臨床神経学59 ( Suppl. ) S276 - S276   2019年11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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  • 【認知症の遺伝子研究のこれまでとこれから】各論 アルツハイマー病に関与する遺伝子 ゲノムワイド関連解析で見いだされた感受性遺伝子

    宮下 哲典, 原 範和, 劉 李きん, 春日 健作, 池内 健

    老年精神医学雑誌30 ( 11 ) 1226 - 1235   2019年11月

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    記述言語:日本語   出版者・発行元:(株)ワールドプランニング  

    アルツハイマー病(AD)は糖尿病などと同じく「ありふれた疾患」である。遺伝的素因を背景にさまざまな環境要因が加わって潜行性に発症し、緩徐に不可逆的に進行する。ADは認知症全体のおよそ6〜7割を占め、最も頻度が高い。加齢が最大のリスク要因ではあるが、遺伝要因の寄与率はおよそ6割と見積もられている。これは、先天的な疾患感受性要因としてバリアント情報を軽視できないことを意味している。本稿では、AD感受性遺伝子について最新の知見を概説した。(著者抄録)

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  • パーキンソン病患者における軽度認知障害(PD-MCI)の検討

    黒羽 泰子, 吉野 美穂子, 荒井 祐生, 金山 武史, 青山 あずさ, 長谷川 有香, 高橋 哲哉, 松原 奈絵, 春日 健作, 池内 健, 小池 亮子

    臨床神経学59 ( Suppl. ) S354 - S354   2019年11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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  • 日本人集団におけるABCA7機能喪失型変異とアルツハイマー病発症リスクとの関連

    原範和, 宮下哲典, LIU Lixin, 樋口陽, 朱斌, 月江珠緒, 春日健作, 桑野良三, 岩坪威, 池内健

    Dementia Japan33 ( 4 ) 547   2019年10月

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    記述言語:日本語  

    J-GLOBAL

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  • 日本人におけるAPOEのコモン・レアバリアント解析

    宮下哲典, 原範和, 春日健作, LIU Lixin, 樋口陽, ZHU Bin, 月江珠緒, 石黒敬信, 村上涼太, 菊地正隆, 中谷明弘, 尾崎浩一, 新飯田俊平, 赤澤宏平, 桑野良三, 桑野良三, 岩坪威, 岩坪威, 池内健

    Dementia Japan33 ( 4 ) 519   2019年10月

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    記述言語:日本語  

    J-GLOBAL

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  • SORL1レアバリアントとアルツハイマー病発症リスクとの遺伝的関連

    月江珠緒, 原範和, 宮下哲典, LIU Lixin, 樋口陽, ZHU Bin, 春日健作, 桑野良三, 桑野良三, 岩坪威, 池内健

    Dementia Japan33 ( 4 ) 524   2019年10月

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    記述言語:日本語  

    J-GLOBAL

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  • ALSP患者において同定されたCSF1R変異の機能アッセイ

    朱斌, LIU Lixin, 三浦健, 樋口陽, 原範和, 月江珠緒, 今野卓哉, 春日健作, 宮下哲典, 池内健

    Dementia Japan33 ( 4 ) 548   2019年10月

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    記述言語:日本語  

    J-GLOBAL

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  • 日本人集団におけるアルツハイマー病ポリジェニック解析

    菊地正隆, 宮下哲典, 原範和, 重水大智, 尾崎浩一, 新飯田俊平, 池内健, 中谷明弘

    Dementia Japan33 ( 4 ) 562   2019年10月

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    記述言語:日本語  

    J-GLOBAL

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  • 培養細胞を用いたAβ過剰産生がタウの細胞外分泌へ及ぼす影響の検討

    石黒 敬信, 春日 健作, 樋口 陽, 目崎 直実, 三浦 健, 徳武 孝允, 小野寺 理, 池内 健

    Dementia Japan33 ( 4 ) 545 - 545   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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  • 血漿炎症系サイトカインと脳脊髄液バイオマーカーとの関連

    樋口 陽, 春日 健作, Bin Zhu, Lixin Liu, 石黒 敬信, 徳武 孝允, 宮下 哲典, 小野寺 理, 池内 健

    Dementia Japan33 ( 4 ) 548 - 548   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  

    J-GLOBAL

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  • ヒト死後脳におけるAPP・APOEの遺伝子発現解析

    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 Japan33 ( 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  

    J-GLOBAL

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  • 多系統萎縮症における脳脊髄液バイオマーカーと認知機能の検討

    徳武 孝允, 春日 健作, 月江 珠緒, 石黒 敬信, 樋口 陽, 下畑 享良, 小野寺 理, 池内 健

    Dementia Japan33 ( 4 ) 531 - 531   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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  • 【認知症の早期発見と進展防止-超早期の介入に向けて】遺伝要因とバイオマーカー

    池内 健

    カレントテラピー37 ( 8 ) 761 - 766   2019年8月

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    記述言語:日本語   出版者・発行元:(株)ライフメディコム  

    認知症の根本治療を目指した疾患修飾薬の開発がアルツハイマー病を中心に活発に進められているが、第III相試験により有用性が証明された薬剤は未だない。治験が不成功におわった理由としては、薬剤介入時期が遅かったこと、適切な評価項目が不足していたこと、また複合的な背景をもつ被検者を均一の集団として組み入れたこと、などが挙げられる。疾患修飾薬の効果を最大限に引き出すためには、被検者を遺伝的要因とバイオマーカー変化を用いて層別化し、病態と病期に応じた薬剤選択と治験デザインを構築することが求められる。本稿では、アルツハイマー病に関する遺伝的要因としてのAPOE多型とポリジェニックリスクスコア、そして脳内病理変化を反映するバイオマーカー研究の動向を概説し、認知症・超早期における介入に向けた展望を概説する。(著者抄録)

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  • 神経心理学の臨床現場にインパクトを与える医療の進歩 認知症医療におけるバイオマーカーの必要性

    池内 健

    日本神経心理学会総会プログラム・予稿集43回   50 - 50   2019年7月

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    記述言語:日本語   出版者・発行元:日本神経心理学会  

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  • ローマ字書字の際に母音が脱落する特異な書字障害を呈した神経変性疾患の一例

    丸山 志織, 和泉 美和子, 田中 晋, 池内 健, 今村 徹

    日本神経心理学会総会プログラム・予稿集43回   67 - 67   2019年7月

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    記述言語:日本語   出版者・発行元:日本神経心理学会  

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  • Microbleedsを伴ったAdult-onset leukoencephalopathy with axonal spheroids and pigmented gliaの一例

    石川 亮, 山下 理英子, 増田 慶一, 板垣 圭, 和田 健, 池内 健

    精神神経学雑誌 ( 2019特別号 ) S435 - S435   2019年6月

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    記述言語:日本語   出版者・発行元:(公社)日本精神神経学会  

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  • MAPT intron 10+14変異を伴うFTDP-17の一剖検例

    渡辺 亮平, 河上 緒, 池内 健, 村山 繁雄, 秋山 治彦, 新井 哲明, 女屋 光基, 長谷川 成人

    精神神経学雑誌 ( 2019特別号 ) S655 - S655   2019年6月

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    記述言語:日本語   出版者・発行元:(公社)日本精神神経学会  

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  • 自閉スペクトラム症の経過中に右優位の意味性認知症が明らかになった1例

    下島 里音, 横山 裕一, 吉田 悠里, 徳武 孝允, 池内 健, 染矢 俊幸

    精神神経学雑誌 ( 2019特別号 ) S486 - S486   2019年6月

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    記述言語:日本語   出版者・発行元:(公社)日本精神神経学会  

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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

    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 = Clinical psychiatry61 ( 5 ) 595 - 603   2019年5月

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    記述言語:日本語   出版者・発行元:医学書院  

    CiNii Article

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  • シアニジン分解物のアミロイドβ誘導性神経細胞死抑制効果

    石橋実学, 梅田将実, 原崇, 池内健, 中村澄子, 城斗志夫, 西澤正豊, 山崎彬, 小林篤, 大坪研一

    日本農芸化学会大会講演要旨集(Web)2019   ROMBUNNO.1B4p07 (WEB ONLY)   2019年3月

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    記述言語:日本語  

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  • Clinical and psychometric characteristics of preclinical Alzheimer’s disease in the J‐ADNI

    IHARA Ryoko, IHARA Ryoko, IWATA Atsushi, SUZUKI Kazushi, IKEUCHI Takeshi, KUWANO Ryozo, IWATSUBO Takeshi

    日本神経学会学術大会プログラム・抄録集60th   539   2019年

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    記述言語:英語  

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  • CSF biomarkers in J‐ADNI: diagnostic accuracy in AD and predictability of cognitive decline in MCI

    SUZUKI Kazushi, IHARA Ryoko, IWATA Atsushi, IWATSUBO Takeshi, ISHII Kenji, IKEUCHI Takeshi, KUWANO Ryozo

    日本神経学会学術大会プログラム・抄録集60th   500   2019年

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    記述言語:英語  

    J-GLOBAL

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  • 「大脳皮質基底核変性症(CBD)mimics」の背景病理 日本人を対象としたCBD検証研究(Background pathology of 'corticobasal degeneration(CBD) mimics': Japanese validation study of CBD)

    下畑 享良, 饗場 郁子, 吉田 眞理, 豊島 靖子, 村山 繁雄, 内原 俊記, 新井 哲明, 齋藤 由扶子, 矢部 一郎, 長谷川 隆文, 齊藤 祐子, 瀧川 洋史, 長谷川 一子, 池内 健, 長谷川 成人, 小森 隆司, 若林 孝一, 徳丸 阿耶, 櫻井 圭太, 中島 健二, J-VAC study group

    臨床神経学58 ( Suppl. ) S239 - S239   2018年12月

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    記述言語:英語   出版者・発行元:(一社)日本神経学会  

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  • COX10変異とPMP22欠失を伴った白質脳症の一家系 分子遺伝学的解析

    石黒 敬信, 黒羽 泰子, 原 範和, 目崎 直実, 三浦 健, 春日 健作, 長谷川 有香, 谷 卓, 高橋 哲哉, 松原 奈絵, 他田 真理, 河内 泉, 柿田 明美, 小野寺 理, 小池 亮子, 池内 健

    臨床神経学58 ( Suppl. ) S327 - S327   2018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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  • COX10変異とPMP22欠失を伴った白質脳症の一家系 臨床病理学的解析

    黒羽 泰子, 石黒 敬信, 長谷川 有香, 谷 卓, 高橋 哲哉, 松原 奈絵, 他田 真理, 河内 泉, 柿田 明美, 小野寺 理, 池内 健, 小池 亮子

    臨床神経学58 ( Suppl. ) S327 - S327   2018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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  • PSP Rating Scaleによる進行性核上性麻痺の経時的変化に関する検討

    瀧川 洋史, 池内 健, 饗場 郁子, 森田 光哉, 小野寺 理, 下畑 享良, 徳田 隆彦, 村山 繁雄, 長谷川 一子, 古和 久典, 花島 律子, 中島 健二, JALPACコンソーシアム

    臨床神経学58 ( Suppl. ) S261 - S261   2018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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  • アルツハイマー病の原因遺伝子と感受性遺伝子:我々の取り組みと国内外の最新情報

    宮下哲典, 原範和, 菊地正隆, 月江珠緒, 春日健作, 中谷明弘, 池内健

    Dementia Japan32 ( 3 ) 365   2018年9月

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    記述言語:日本語  

    J-GLOBAL

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  • 脳脊髄液バイオマーカーAT(N)systemをもちいた認知症関連疾患の再考

    春日健作, 月江珠緒, 石黒敬信, 石黒敬信, 三浦健, 目崎直実, 徳武孝允, 宮下哲典, 小野寺理, 池内健

    Dementia Japan32 ( 3 ) 417   2018年9月

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    記述言語:日本語  

    J-GLOBAL

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  • 認知症性疾患のバイオリソースの構築と活用:新潟大学脳研究所における取り組み

    宮下哲典, 月江珠緒, 原範和, 廣瀬美香, 小林智子, 佐藤怜奈, 河合麗子, 平井香織, 高殿恵子, 春日健作, 池内健

    Dementia Japan32 ( 3 ) 450   2018年9月

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    記述言語:日本語  

    J-GLOBAL

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  • アルツハイマー病剖検脳を用いたAPOE遺伝型とミエリン関連遺伝子発現との関連

    原範和, 宮下哲典, 柿田明美, 池内健

    Dementia Japan32 ( 3 ) 429   2018年9月

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  • ポリジェニックハザードスコアを用いたアルツハイマー病発症年齢解析

    菊地正隆, 宮下哲典, 池内健, 中谷明弘

    Dementia Japan32 ( 3 ) 433   2018年9月

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  • 認知症臨床ゲノム情報データベース構築に関する開発研究

    池内健, 新飯田俊平, 佐々木貴史, 宮下哲典, 尾崎浩一, 広瀬信義, 中谷明弘, 柿田明美, 鈴木一詩, 齋藤祐子, 村山繁雄, 橋詰良夫, 寺田整司, 吉田真理, 嶋田裕之, 三村将, 岡野栄之, 岩坪威, 秋山治彦, 森啓

    Dementia Japan32 ( 3 ) 462   2018年9月

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  • いま注目のトピックを掘り下げる アルツハイマー病における脳脊髄液バイオマーカーの新展開

    池内 健

    Medical Technology46 ( 9 ) 917 - 920   2018年9月

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    記述言語:日本語   出版者・発行元:医歯薬出版(株)  

    アルツハイマー病の脳脊髄液バイオマーカーの最近の動向は以下のとおりである。・認知症の鑑別診断を目的とした脳脊髄液中のリン酸化タウ測定が保険診療として臨床応用されている。・疾患修飾薬の実用化を視野に入れた早期診断ツールとして脳脊髄液バイオマーカーの役割が期待されている。・脳脊髄液バイオマーカー測定の自動化・高速化を可能にする次世代のアッセイ法が開発されている。(著者抄録)

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  • APOE遺伝型はAPPの遺伝子発現量に影響を及ぼすか? ヒト死後脳における検証

    村上 涼太, 朱 斌, 原 範和, 菊地 正隆, 月江 珠緒, 春日 健作, 宮下 哲典, 中谷 明弘, 赤津 裕康, 柿田 明美, 村山 繁雄, 池内 健

    Dementia Japan32 ( 3 ) 429 - 429   2018年9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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  • 多数例のエクソーム解析データに基づいた新規アルツハイマー病関連遺伝子の同定

    田中 真生, 新見 淳, 石浦 浩之, 三井 純, 宮下 哲典, 桑野 良三, 池内 健, 辻 省次

    Dementia Japan32 ( 3 ) 449 - 449   2018年9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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  • γセクレターゼ切断産物p3-Alcβペプチドの加齢およびAD発症による産生変化

    羽田 沙緒里, 木村 彩乃, 木村 展之, 池内 健, 春日 健作, 藁谷 正明, 西村 正樹, 鈴木 利治

    Dementia Japan32 ( 3 ) 423 - 423   2018年9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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  • MCIの進行における性差と教育程度の関与

    岩田 淳, 岩坪 威, 井原 涼子, 鈴木 一詩, 松山 裕, 冨田 尚希, 荒井 啓行, 石井 賢二, 千田 道雄, 伊藤 健吾, 池内 健, 桑野 良三, 松田 博史

    Dementia Japan32 ( 3 ) 445 - 445   2018年9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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  • 超硬質米および黒米を配合した高圧処理包装米飯の機能性

    大坪 研一, 中村 澄子, 前田 聡, 小林 篤, 池内 健, 春日 健作, 原 崇, 平山 匡男, 渡辺 賢一, 後藤 博, 小出 頼子, 山口 修, 山崎 彬

    応用糖質科学8 ( 3 ) 32 - 32   2018年8月

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    記述言語:日本語   出版者・発行元:(一社)日本応用糖質科学会  

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  • PSEN1にc.367G>A変異を認めた遺伝性アルツハイマー病の1家系

    長岡 敦子, 飯國 洋一郎, 門脇 傑, 森松 暁史, 白田 明子, 山根 清美, 池内 健

    臨床神経学58 ( 8 ) 538 - 538   2018年8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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  • 認知症と遺伝子の関係 ゲノム医療への展望

    池内 健

    日本早期認知症学会誌11 ( 3 ) 50 - 50   2018年8月

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    記述言語:日本語   出版者・発行元:日本早期認知症学会  

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  • 野生型及び変異α synuclein凝集体の分子特性に関するin vitro及びin vivoでの比較検討

    早川 英規, 馬場 孝輔, 池中 建介, 仲谷 利栄, Aguirre Cesar, 鐘 其静, 津田 浩史, 長野 清一, 永井 義隆, 池内 健, 望月 秀樹

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集12回   74 - 74   2018年7月

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    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

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  • 【最新遺伝医学研究と遺伝カウンセリング(シリーズ3) 最新 多因子遺伝性疾患研究と遺伝カウンセリング】 (第4章)多因子疾患の遺伝カウンセリングの実際(ケーススタディ) アルツハイマー病(家族性でないもの)

    池内 健

    遺伝子医学MOOK別冊 ( 最新多因子遺伝性疾患研究と遺伝カウンセリング ) 236 - 241   2018年6月

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    記述言語:日本語   出版者・発行元:(株)メディカルドゥ  

    アルツハイマー病の大部分は、遺伝的要因と後天的要因が複合的に交絡して発症する多因子疾患である。アルツハイマー病の最大の遺伝的要因はAPOE多型である。APOEε4はアルツハイマー病の発症リスクを上昇させる一方、ε2は防御的に作用する。APOEε4は、アレル数に依存して脳内アミロイド沈着の早発化を促進する。APOE多型は強力な遺伝学的リスクであるが、診断を目的としたAPOE検査は推奨されない。APOE以外の感受性遺伝子も報告されているが、発症への影響は小さく、個々の症例での臨床的な意味づけは難しい。高い遺伝的リスクを有する未発症者を対象とした予防的臨床試験が海外で行われている。(著者抄録)

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  • 鏡現象を呈した大脳皮質基底核症候群の一例

    丸山 志織, 和泉 美和子, 田中 晋, 池内 健, 今村 徹

    日本神経心理学会総会プログラム・予稿集42回   86 - 86   2018年6月

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    記述言語:日本語   出版者・発行元:日本神経心理学会  

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  • アミロイドβ誘導性神経細胞死に対するシアニジン‐3‐グルコシドの抑制効果

    石橋実学, 池田彩, 原崇, 池内健, 中村澄子, 城斗志夫, 西澤正豊, 山崎彬, 小林篤, 大坪研一

    日本農芸化学会大会講演要旨集(Web)2018   ROMBUNNO.2B06p12 (WEB ONLY)   2018年3月

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    記述言語:日本語  

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  • 【ニューロジェネティクス新時代 次世代シークエンサーが拓く新しい世界】 筋疾患・神経疾患のジェネティクス アルツハイマー病

    原 範和, 宮下 哲典, 池内 健

    Clinical Neuroscience36 ( 2 ) 222 - 226   2018年2月

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    記述言語:日本語   出版者・発行元:(株)中外医学社  

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  • 長期間精神症状が先行した、PSEN1遺伝子変異を有する早期発症型家族性アルツハイマー病の1剖検例

    竹島 明, 他田 真理, 鈴木 正博, 春日 健作, 池内 健, 小野寺 理, 高橋 均, 柿田 明美, 伊古田 勇人

    信州医学雑誌66 ( 1 ) 110 - 111   2018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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  • 常染色体劣性遺伝性が疑われる若年発症 緩徐進行性小脳失調症の1剖検例

    齋藤 理恵, 他田 真理, 若林 允甫, 小野寺 理, 高橋 均, 池内 健, 柿田 明美, 横尾 英明

    信州医学雑誌66 ( 1 ) 111 - 112   2018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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  • 長期間精神症状が先行した、PSEN1遺伝子変異を有する早期発症型家族性アルツハイマー病の1剖検例

    竹島 明, 他田 真理, 鈴木 正博, 春日 健作, 池内 健, 小野寺 理, 高橋 均, 柿田 明美, 伊古田 勇人

    信州医学雑誌66 ( 1 ) 110 - 111   2018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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  • 【実施診療のための最新認知症学-検査・治療・予防・支援-】アルツハイマー病の先進医療とRegistry DIAN-J研究登録事業

    森 啓, 嶋田 裕之, 東海林 幹夫, 池内 健, 鈴木 一詩, 千田 道雄, 石井 賢二, 松田 博史, 岩田 敦, 井原 涼子, 岩坪 威, 武藤 香織, 中澤 栄輔, 関島 良樹, 森 悦朗, 池田 学, 池田 将樹, 川勝 忍, 中西 亜紀, 橋本 衛, 布村 明彦, 松原 悦朗, 福井 充, 白戸 朋代, 平井 香織, 坂本 昌子, 藤井 比佐子, 石井 一成, 西郷 和真

    日本臨床76 ( 増刊1 実施診療のための最新認知症学 検査・治療・予防・支援 ) 258 - 265   2018年1月

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    記述言語:日本語   出版者・発行元:(株)日本臨床社  

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  • Presenilin 1(PSEN1)の新規遺伝子変異による家族性アルツハイマー型認知症の一家系

    佐藤大祐, 斎藤尚宏, 伊関千書, 飛田宗重, 川勝忍, 池内健, 桑野良三, 鈴木匡子

    日本神経学会学術大会プログラム・抄録集59th   335   2018年

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  • 【臨床検査の最前線-将来の検査を展望する】 神経 アルツハイマー型認知症のバイオマーカー

    池内 健

    医学のあゆみ263 ( 13 ) 1185 - 1188   2017年12月

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    記述言語:日本語   出版者・発行元:医歯薬出版(株)  

    アルツハイマー病(AD)の診断ツールとしてのバイオマーカーの重要性が高まっている。ADの脳内病理を反映する脳脊髄液バイオマーカーは、改訂診断基準(2011年)に取り入れられ、認知症の診断学は、症候学や画像形態を中心とした病型診断から、背景分子病理を重視した病型診断へと移行しつつある。病型診断における重要性に加え、認知機能障害が出現する前の無症候期(プレクリニカル期)での早期診断、軽度認知障害からADへのコンバート予測、疾患修飾薬の薬剤効果判定など、脳脊髄液バイオマーカーの応用範囲が広がっている。低侵襲性、汎用性の面から期待されている血液バイオマーカー候補が同定されており、実用化に向けた開発が進んでいる。(著者抄録)

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  • アルツハイマー病関連ノンコーディングバリアントの染色体高次構造解析

    菊地 正隆, 原 範和, 長谷川 舞衣, 宮下 哲典, 桑野 良三, 池内 健, 中谷 明弘

    生命科学系学会合同年次大会2017年度   [2P - 1343]   2017年12月

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    記述言語:日本語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • SNORD118遺伝子に複合ヘテロ変異を認めた、leukoencephalopathy with calcifications and cystsの女性例

    岩崎 靖, 三室 マヤ, 吉田 眞理, 川合 圭成, 伊藤 益美, 森 恵子, 星野 賢一郎, 月江 珠緒, 池内 健

    臨床神経学57 ( 12 ) 802 - 802   2017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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  • 神経疾患治療ノート 神経軸索スフェロイドを伴う遺伝性びまん性白質脳症

    池内 健

    Clinical Neuroscience35 ( 11 ) 1354 - 1355   2017年11月

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    記述言語:日本語   出版者・発行元:(株)中外医学社  

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  • ポルトガル語と日本語のバイリンガルに生じた意味性認知症の一例

    平井 香織, 徳武 孝允, 池内 健

    Dementia Japan31 ( 4 ) 587 - 587   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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  • 認知症疾患におけるアルツハイマー病関連脳脊髄液バイオマーカーの解析

    春日 健作, 徳武 孝允, 三浦 健, 目崎 直実, 石黒 敬信, 小野寺 理, 池内 健

    Dementia Japan31 ( 4 ) 610 - 610   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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  • 遺伝子異常を同定し得た家族性アルツハイマー病の新規家系

    中瀬 泰然, 長田 乾, 佐藤 雄一, 前田 哲也, 池内 健, 宮田 元

    Dementia Japan31 ( 4 ) 605 - 605   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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  • Lamin B1関連常染色体優性遺伝性白質脳症 コピー数多型と臨床的特徴

    目崎 直実, 三浦 健, 大垣 光太郎, 江里口 誠, 水野 裕理, 小松 研一, 山崎 博輝, 末次 南月, 河尻 澄宏, 山崎 亮, 野崎 洋明, 春日 健作, 大熊 泰之, 吉良 潤一, 原 英夫, 小野寺 理, 池内 健

    Dementia Japan31 ( 4 ) 596 - 596   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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  • HDLS患者におけるCSF1R新規ミスセンス変異の同定及び変異CSF1R機能解析

    三浦 健, 目崎 直実, 石黒 敬信, 徳武 孝允, 春日 健作, 今野 卓哉, 野崎 洋明, 小野寺 理, 池内 健

    Dementia Japan31 ( 4 ) 595 - 595   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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  • エクソーム解析データに基づく孤発性アルツハイマー病における疾患関連遺伝子の検討

    新見 淳, 田中 真生, 石浦 浩之, 三井 純, 宮下 哲典, 桑野 良三, 池内 健, 辻 省次

    Dementia Japan31 ( 4 ) 612 - 612   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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  • エクソーム解析データに基づくY染色体欠失の検出とアルツハイマー病との関連性の検討

    田中 真生, 石浦 浩之, 三井 純, 宮下 哲典, 桑野 良三, 池内 健, 辻 省次

    Dementia Japan31 ( 4 ) 612 - 612   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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  • 尿プロテオミクスによるアルツハイマー病バイオマーカー探索

    渡邊 裕美, 平尾 嘉利, 春日 健作, 徳武 孝允, 池内 健, 中村 和利, 山本 格

    Dementia Japan31 ( 4 ) 611 - 611   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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  • 認知症を呈する白質脳症 分子遺伝学を基盤とした成人発症大脳白質脳症の理解

    池内 健

    Dementia Japan31 ( 4 ) 532 - 532   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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  • ADのリスク遺伝子とその分子病態 アルツハイマー病の遺伝的因子と新規リスク遺伝子の探索

    池内 健

    Dementia Japan31 ( 4 ) 495 - 495   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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  • アルツハイマー病剖検脳を用いたRNA-seq解析

    原 範和, 宮下 哲典, 菊地 正隆, 中谷 明弘, 柿田 明美, 池内 健

    Dementia Japan31 ( 4 ) 571 - 571   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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  • アルツハイマー病GWASデータを用いたポリジェニック解析

    菊地 正隆, 宮下 哲典, 池内 健, 中谷 明弘

    Dementia Japan31 ( 4 ) 570 - 570   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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  • 神経細胞興奮がβ-amyloid precursor protein(APP) processingへ及ぼす影響

    石黒 敬信, 春日 健作, 斎藤 健智, 目崎 直実, 三浦 健, 小野寺 理, 池内 健

    Dementia Japan31 ( 4 ) 560 - 560   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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  • FTDP-17患者由来iPS細胞を用いたin vitro病態モデルの確立及び表現型解析

    中村 真理, 渡部 博貴, 塩澤 誠司, 久永 眞市, 佐原 成彦, 木村 妙子, 宮坂 知宏, 高島 明彦, 池内 健, 岡野 栄之

    Dementia Japan31 ( 4 ) 555 - 555   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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  • パーキンソン病患者の認知機能およびADL低下と脳血流SPECT変化

    黒羽 泰子, 長谷川 有香, 谷 卓, 高橋 哲哉, 松原 奈絵, 春日 健作, 池内 健, 小池 亮子

    Dementia Japan31 ( 4 ) 582 - 582   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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  • 意味性認知症の画像所見とバイオマーカーの検討

    徳武 孝允, 春日 健作, 三浦 健, 目崎 直実, 平井 香織, 小野寺 理, 池内 健

    Dementia Japan31 ( 4 ) 590 - 590   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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  • 【プレシジョン・メディシンとアンチエイジング】 アルツハイマー病のプレシジョン・メディシン

    池内 健

    アンチ・エイジング医学13 ( 5 ) 657 - 662   2017年10月

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    記述言語:日本語   出版者・発行元:(株)メディカルレビュー社  

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  • MRI拡散強調像(DWI)で散在性の高信号が続いている遺伝性びまん性白質脳症(HDLS)の一例

    大喜多 賢治, 水野 将行, 川嶋 将司, 豊田 剛成, 大村 眞弘, 松川 則之, 櫻井 圭太, 池内 健

    臨床神経学57 ( 10 ) 615 - 615   2017年10月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 認知症疾患におけるアルツハイマー病関連脳脊髄液バイオマーカーの解析

    春日 健作, 徳武 孝允, 三浦 健, 目崎 直実, 石黒 敬信, 小野寺 理, 池内 健

    Dementia Japan31 ( 4 ) 610 - 610   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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  • Lamin B1関連常染色体優性遺伝性白質脳症 コピー数多型と臨床的特徴

    目崎 直実, 三浦 健, 大垣 光太郎, 江里口 誠, 水野 裕理, 小松 研一, 山崎 博輝, 末次 南月, 河尻 澄宏, 山崎 亮, 野崎 洋明, 春日 健作, 大熊 泰之, 吉良 潤一, 原 英夫, 小野寺 理, 池内 健

    Dementia Japan31 ( 4 ) 596 - 596   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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  • HDLS患者におけるCSF1R新規ミスセンス変異の同定及び変異CSF1R機能解析

    三浦 健, 目崎 直実, 石黒 敬信, 徳武 孝允, 春日 健作, 今野 卓哉, 野崎 洋明, 小野寺 理, 池内 健

    Dementia Japan31 ( 4 ) 595 - 595   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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  • 意味性認知症の画像所見とバイオマーカーの検討

    徳武 孝允, 春日 健作, 三浦 健, 目崎 直実, 平井 香織, 小野寺 理, 池内 健

    Dementia Japan31 ( 4 ) 590 - 590   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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  • 糖尿病および認知症の複合予防効果の期待される米飯開発の試み

    大坪 研一, 池内 健, 春日 健作, 原 崇, 山崎 彬, 小林 篤, 前田 聡, 大原 絵里, 後藤 博, 平山 匡男, 小出 頼子, 渡辺 賢一, 野呂 渉, 大坪 貞規, 中村 澄子

    応用糖質科学7 ( 3 ) 34 - 34   2017年8月

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    記述言語:日本語   出版者・発行元:(一社)日本応用糖質科学会  

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  • 【認知症 発症前治療のために解明すべき分子病態は何か?】 (第3章)遺伝的視点 アルツハイマー病のゲノミクス リスク遺伝子と防御的遺伝子

    原 範和, 池内 健

    実験医学35 ( 12 ) 2023 - 2029   2017年8月

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    記述言語:日本語   出版者・発行元:(株)羊土社  

    数万人規模のゲノムワイド関連解析によりアルツハイマー病(Alzheimer&#039;s disease:AD)に関するリスク遺伝子の探索が行われたが、APOEに匹敵するエフェクトをもつ感受性遺伝子は検出されなかった。しかし、次世代シークエンサーによる網羅的なゲノム情報が効率的に得られるようになり、APOEに匹敵するADリスク遺伝子が同定されている。これまで同定が困難であった低頻度のレアバリアントが、AD発症の新たなリスクとなることが判明している。一方で、防御的効果を有するレアバリアントが見出されており、ADの先制医療の観点から注目されている。本稿ではAPOEに加え、次世代シークエンサー(NGS)により同定されたAD関連遺伝子を紹介し、AD発症の危険因子と防御因子の両面からAD病態を再考する。(著者抄録)

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  • 【あしたのアルツハイマー病治療】DIAN/DIAN-J/DIAN-TU

    嶋田 裕之, 東海林 幹夫, 池内 健, 鈴木 一詩, 千田 道雄, 石井 賢二, 松田 博史, 岩田 淳, 井原 涼子, 岩坪 威, 武藤 香織, 中澤 栄輔, 関島 良樹, 森 悦朗, 池田 学, 池田 将樹, 川勝 忍, 中西 亜紀, 橋本 衛, 布村 明彦, 松原 悦朗, 福井 充, 白戸 朋代, 平井 香織, 坂本 昌子, 藤井 比佐子, 森 啓

    BRAIN and NERVE: 神経研究の進歩69 ( 7 ) 701 - 709   2017年7月

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    記述言語:日本語   出版者・発行元:(株)医学書院  

    DIAN観察研究は,家族性アルツハイマー病患者のバイオマーカーの変化を明らかにした。われわれは日本においても同様の研究を行うべく,ワシントン大学と交渉し,国際共同研究としてのDIAN-J研究を開始した。しかしそれは米国での基準を満たさなければならず,大きな困難を伴うものであった。米国では2013年からDIAN-TUという治療介入研究が始まっている。2017年からは次期のDIAN-TU研究が始まる予定であり,日本も参加すべく準備中である。(著者抄録)

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  • アルツハイマー病の遺伝学的リスク (特集 認知症の発症,病状進行,治療反応性に関与するさまざまな因子) 招待

    宮下 哲典, 原 範和, 春日 健作, 菊地 正隆, 中谷 明弘, 池内 健

    老年精神医学雑誌28 ( 7 ) 754 - 765   2017年7月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)   出版者・発行元:ワールドプランニング  

    CiNii Article

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  • Progression of milestones by clinical types in progressive supranuclear palsy: a longitudinal observational study of a cohort of patients with PSP/CBD (the JALPAC project)

    I. Aiba, T. Ikeuchi, H. Takigawa, T. Shimohata, T. Tokuda, M. Morita, O. Onodera, S. Murayama, K. Hasegawa, K. Nakashima

    MOVEMENT DISORDERS32   2017年6月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY  

    Web of Science

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  • 6.中毒・代謝疾患 1 糖尿病と認知症

    徳武孝允, 笠原壮, 池内健

    Annual Review 神経2017   191‐199   2017年1月

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    記述言語:日本語  

    J-GLOBAL

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  • 各種疾患 中毒・代謝疾患 糖尿病と認知症

    徳武 孝允, 笠原 壮, 池内 健

    Annual Review神経2017   191 - 199   2017年1月

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    記述言語:日本語   出版者・発行元:(株)中外医学社  

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  • KIF1Aの新規変異によるSPG30とSCA31とを併せ持つ1家系にみられた、臨床的遺伝的特徴

    長谷川 有香, 小池 亮子, 黒羽 泰子, 谷 卓, 松原 奈絵, 川上 明男, 高 紀信, 瀧山 嘉久, 池内 健

    臨床神経学56 ( Suppl. ) S487 - S487   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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  • 成人発症白質脳症におけるLaminB1関連常染色体優性白質脳症 遺伝子変異と臨床的特徴

    目崎 直実, 三浦 健, 野崎 洋明, 大垣 光太郎, 河尻 澄宏, 大熊 泰之, 小野 南月, 原 英夫, 春日 健作, 小野寺 理, 西澤 正豊, 池内 健

    臨床神経学56 ( Suppl. ) S444 - S444   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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  • 若年性アルツハイマー病の臨床早期にみられた非典型的進行性失語について

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    Dementia Japan30 ( 4 ) 537 - 537   2016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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  • 意味性認知症の臨床症状・画像的特徴・脳脊髄液バイオマーカーの検討

    徳武 孝允, 春日 健作, 三浦 健, 目崎 直実, 平井 香織, 西澤 正豊, 小野寺 理, 池内 健

    Dementia Japan30 ( 4 ) 583 - 583   2016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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  • 意味性認知症の臨床症状・画像的特徴・脳脊髄液バイオマーカーの検討

    徳武 孝允, 春日 健作, 三浦 健, 目崎 直実, 平井 香織, 西澤 正豊, 小野寺 理, 池内 健

    Dementia Japan30 ( 4 ) 583 - 583   2016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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  • 地域総合病院通院患者における透析療法と認知機能スケールとの関連 PROST

    渡邊 裕美, 北村 香織, 若杉 三奈子, 横関 明男, 三瓶 一弘, 小野寺 理, 池内 健, 百都 健, 成田 一衛, 遠藤 直人

    Dementia Japan30 ( 4 ) 550 - 550   2016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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  • 末梢血・網羅的RNA-Seq解析により示されたアルツハイマー病に特徴的な遺伝子発現変動

    原 範和, 石黒 敬信, 目崎 直実, 三浦 健, 春日 健作, 月江 珠緒, 宮下 哲典, 池内 健

    Dementia Japan30 ( 4 ) 599 - 599   2016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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  • 地域総合病院通院患者における透析療法と認知機能スケールとの関連 PROST

    渡邊 裕美, 北村 香織, 若杉 三奈子, 横関 明男, 三瓶 一弘, 小野寺 理, 池内 健, 百都 健, 成田 一衛, 遠藤 直人

    Dementia Japan30 ( 4 ) 550 - 550   2016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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  • LaminB1関連常染色体優性遺伝性白質脳症 遺伝子重複と臨床的特徴

    目崎 直実, 三浦 健, 野崎 洋明, 大垣 光太郎, 河尻 澄宏, 大熊 泰之, 小野 南月, 原 英夫, 小野寺 理, 池内 健

    Dementia Japan30 ( 4 ) 541 - 541   2016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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  • LaminB1関連常染色体優性遺伝性白質脳症 遺伝子重複と臨床的特徴

    目崎 直実, 三浦 健, 野崎 洋明, 大垣 光太郎, 河尻 澄宏, 大熊 泰之, 小野 南月, 原 英夫, 小野寺 理, 池内 健

    Dementia Japan30 ( 4 ) 541 - 541   2016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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  • Barthel IndexならびにPSPRS-Jによる進行性核上性麻痺症例のADL評価に関する検討

    瀧川 洋史, 池内 健, 森田 光哉, 饗場 郁子, 小野寺 理, 下畑 享良, 徳田 隆彦, 村山 繁雄, 中島 健二, JALPAC研究グループ

    神経治療学33 ( 5 ) S229 - S229   2016年10月

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    記述言語:日本語   出版者・発行元:日本神経治療学会  

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  • 病理診断されたGlobular Glial Tauopathyの臨床的特徴 自験2例と既報39例のまとめ

    三浦 健, 目崎 直実, 三瓶 一弘, 青木 賢樹, 竹内 亮子, 田中 英智, 豊島 靖子, 柿田 明美, 小野寺 理, 池内 健

    Dementia Japan30 ( 4 ) 542 - 542   2016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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  • Barthel IndexならびにPSPRS-Jによる進行性核上性麻痺症例のADL評価に関する検討

    瀧川 洋史, 池内 健, 森田 光哉, 饗場 郁子, 小野寺 理, 下畑 享良, 徳田 隆彦, 村山 繁雄, 中島 健二, JALPAC研究グループ

    神経治療学33 ( 5 ) S229 - S229   2016年10月

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    記述言語:日本語   出版者・発行元:日本神経治療学会  

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  • 病理計断されたGlobular Glial Tauopathyの臨床的特徴 自験2例と既報39例のまとめ

    三浦 健, 目崎 直実, 三瓶 一弘, 青木 賢樹, 竹内 亮子, 田中 英智, 豊島 靖子, 柿田 明美, 小野寺 理, 池内 健

    Dementia Japan30 ( 4 ) 542 - 542   2016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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  • アルツハイマー型認知症診療のBreakthrough アルツハイマー型認知症の遺伝子解析とバイオインフォマティクス

    菊地正隆, 原範和, 中谷明弘, 池内健

    Pharma Medica34 ( 7 ) 19‐24 - 24   2016年7月

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    記述言語:日本語   出版者・発行元:(株)メディカルレビュー社  

    J-GLOBAL

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  • 【認知症の危険因子と防御因子】アポリポ蛋白E遺伝子(APOE) 査読

    徳武 孝允, 春日 健作, 原 範和, 池内 健

    BRAIN and NERVE: 神経研究の進歩68 ( 7 ) 703 - 712   2016年7月

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    記述言語:日本語   出版者・発行元:(株)医学書院  

    アポリポ蛋白E遺伝子(APOE)はアルツハイマー病(AD)の強力な感受性遺伝子である。APOEε4はAD発症リスクとなる一方,ε2は防御的に作用する。遺伝的リスクとしてのAPOEの役割に加え,APOE多型は健常者の認知機能,画像・バイオマーカー所見に関与する。APOEε4保因者では脳内アミロイド蓄積が早発化することから,ε4はADの病態早期に作用する可能性がある。APOEε4陽性の健常高齢者をAD発症の高リスク者として抽出し,予防介入を試みる探索的治験が海外で行われている。(著者抄録)

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  • A longitudinal observational study of a cohort of patients with PSP/CBD: The JALPAC project

    T. Tokuda, T. Ikeuchi, H. Takigawa, I. Aiba, T. Shimohata, M. Morita, O. Onodera, S. Murayama, K. Nakashima

    MOVEMENT DISORDERS31   S59 - S59   2016年6月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY-BLACKWELL  

    Web of Science

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  • 【認知症の診断と治療:最近の進歩】ゲノム解析による認知症の臨床・病態解明

    原 範和, 春日 健作, 宮下 哲典, 池内 健

    臨床精神医学45 ( 4 ) 395 - 403   2016年4月

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    記述言語:日本語   出版者・発行元:(株)アークメディア  

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    The Alzheimer's Disease Cooperative Study (ADCS) started in 1991 as part of an agreement between the National Institute on Aging (NIA) and the University of California, San Diego, is a major clinical activity for treating Alzheimer's disease (AD). As part of the NIA Division, the ADCS supports all activities for AD treatment, including the discovery and evaluation of new diagnostic methods, drugs, and devices for patients with AD, as well as the prevention of AD.

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

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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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    野崎 洋明, 原 賢寿, 志賀 篤, 三井 純, 高橋 祐二, 石黒 英明, 四茂野 はるみ, 栗崎 博司, 後藤 順, 池内 健, 辻 省次, 西澤 正豊, 小野寺 理

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    記述言語:日本語   出版者・発行元:(一社)日本臨床神経生理学会  

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    記述言語:日本語   出版者・発行元:国立精神・神経センター  

    Rimmed vacuole型遠位型ミオパチー(DMRV)の候補領域にマップされ,筋細胞に発現する4個のexpressed sequence tag(EST)についてcDNA cloningを行った.その結果,各dynein,rabbit ubiquitin conjugating enzyme E2(32k),ubiquitin associated proteinと高い相同性を認めた.残りの一つは未知遺伝子と考えられた.ubiquitin associated proteinと相同性を認めたクローンは全長2.7kbで骨格筋と心筋に強い発現を認めた.Southern解析ではホモ接合体を呈すべきDMRV家系においてヘテロ接合体と考えられる結果であった.以上より,ubiquitin associated proteinの遺伝子座はDMRVの原因遺伝子ではなく,候補領域外に存在するものと考えられた

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  • Rimmed vacuole型遠位型ミオパチーの臨床・分子遺伝学的研究

    田中 恵子, 新井 亜希, 五十嵐 修一, 小林 央, 池内 健, 辻 省次

    厚生労働省精神・神経疾患研究委託費研究報告書 筋ジストロフィー及び関連疾患の臨床病態解明と治療法開発に関する研究平成11〜13年度   75 - 76   2002年3月

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    記述言語:日本語   出版者・発行元:厚生労働省精神・神経疾患研究班  

    rimmedvacuole型遠位型ミオパチー(DMRV)症例のUDP-N acetylglucosamine 2-epimerase/N-acetylmannosamine kinase(GNE)geneにおける変異について検索し,原因遺伝子としての可能性を検討した.これによりDMRVとhereditary inclusion body myopathy(HIBM)の臨床遺伝学的特徴について考察し,創始者効果についても検討した.DMRV 7家系を用い,GNEgeneの翻訳領域の直接塩基配列決定を行ったが,HIBMで報告された変異は見られず,全ての家系においてGNEgene exon 10でvalineからleucineへ置換する新たな変異を認めた.連鎖不平衡について検討したところ,共通するハプロタイプを認め,強い創始者効果を認めた

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  • Rimmed vacuole型遠位型ミオパチーの候補遺伝子解析

    新井 亜希, 小林 央, 田中 恵子, 池内 健, 辻 省次

    臨床神経学41 ( 11 ) 874 - 874   2001年11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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  • 常染色体優性遺伝形式をとるミトコンドリア病家系の臨床及び分子遺伝学的解析

    福島 隆男, 中野 亮一, 菊川 公紀, 池内 健, 小出 隆司, 辻 省次, 丹野 芳範

    臨床神経学40 ( 12 ) 1481 - 1481   2000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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  • 筋ジストロフィー及び関連疾患の臨床病態解明と治療法開発に関する研究 Rimmed vacuole型遠位型ミオパチーの候補遺伝子解析

    田中 恵子, 小林 央, 池内 健, 辻 省次

    厚生省精神・神経疾患研究委託費による研究報告集平成11年度   515 - 515   2000年12月

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    記述言語:日本語   出版者・発行元:国立精神・神経センター  

    DMRVの候補領域にマップされ,筋細胞に発現する各ESTとしてcDNAクローニングを行い,現在迄に4個のクローンが得られ,そのうち2個は遺伝子配列を確認した.一つはミオシンと共に筋運動分子として重要なダイニンであった.この分子は最近Primary ciliary dyskinesiaの原因遺伝子であることが報告された.もう一方はホモロジーサーチで相同のものがなく,現時点では未知の遺伝子と考えられた.今後,順次各ESTをプローブとしてcDNAのクローニングを行い,各クローンについてその構造を明らかにし,DMRVの原因遺伝子であるかどうかの解析を行う

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  • 常染色体優性遺伝形式が疑われた常染色体劣性若年性パーキンソニズム(AR-JP)の1家系

    斎藤 正明, 石川 厚, 丸山 美枝子, 池内 健, 辻 省次

    臨床神経学40 ( 12 ) 1394 - 1394   2000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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  • Multiple system atrophy剖検脳におけるα-synuclein mRNA発現量の検討

    小澤 鉄太郎, 奥泉 薫, 池内 健, 辻 省次, 若林 孝一, 高橋 均

    臨床神経学40 ( 12 ) 1343 - 1343   2000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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  • 既知の遺伝子異常がなく家族歴を有する脊髄小脳失調症についての遺伝子学的検討

    池田 賢一, 中川 正法, 梅原 藤雄, 有村 公良, 納 光弘, 園田 健, 平田 圭子, 末原 雅人, 池内 健, 辻 省次

    臨床神経学40 ( 12 ) 1346 - 1346   2000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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  • Rimmed vacuole型遠位型ミオパチーの候補遺伝子の解析

    新井 亜希, 田中 恵子, 小林 央, 池内 健, 辻 省次

    臨床神経学40 ( 12 ) 1424 - 1424   2000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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  • 神経疾患の分子生物学的病態解明研究 既知の遺伝子異常がなく家族歴を有する脊髄小脳失調症についての遺伝子学的検討

    納 光弘, 池田 賢一, 中川 正法, 園田 健, 梅原 藤雄, 有村 公良, 末原 雅人, 平田 圭子, 池内 健, 辻 省次

    厚生省精神・神経疾患研究委託費による研究報告集平成11年度   574 - 574   2000年12月

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    記述言語:日本語   出版者・発行元:国立精神・神経センター  

    南九州・沖縄地方においては未知の遺伝子異常による脊髄小脳萎縮症家系例が比較的多いことが示唆された.末梢神経障害を伴い表現促進現象を認めた1家系について,遺伝子学的検討を行い,未知の遺伝子異常であることを明らかにした

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  • 神経変性疾患の病因遺伝子の遺伝子クローニング

    池内 健, 小出 玲爾, 辻 省次, 三瓶 一弘

    新潟県医師会報 ( 601 ) 2 - 7   2000年4月

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    記述言語:日本語   出版者・発行元:新潟県医師会  

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  • SCA6は他のポリグルタミン病と同一の疾患か? MRIからの検討

    小野寺 理, 池内 健, 五十嵐 修一, 辻 省次

    臨床神経学39 ( 12 ) 1427 - 1427   1999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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  • 早期発症捻転ジストニー(DYT1)本邦例の臨床像

    野村 芳子, 下平 雅之, 八森 啓, 瀬川 昌也, 池内 健, 辻 省次, 楢林 博太郎

    臨床神経学39 ( 12 ) 1372 - 1372   1999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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  • Multiple system atrophy剖検脳におけるα-synuclein遺伝子の全コード領域の解析

    小澤 鉄太郎, 高野 弘基, 小野寺 理, 小林 央, 池内 健, 小出 玲爾, 奥泉 薫, 下畑 享良, 辻 省次, 若林 孝一

    臨床神経学39 ( 12 ) 1336 - 1336   1999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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  • 常染色体劣性若年性パーキンソニズム(AR-JP)5家系におけるparkin遺伝子の変異解析

    斎藤 正明, 丸山 美枝子, 石川 厚, 近藤 浩, 湯浅 龍彦, 池内 健, 辻 省次

    臨床神経学39 ( 12 ) 1308 - 1308   1999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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  • TATA-binding protein(TBP)のCAGリピート増大に伴う神経変性疾患

    小出 玲爾, 下畑 享良, 池内 健, 丸山 美枝子, 斎藤 正明, 辻 省次, 小林 繁一

    臨床神経学39 ( 12 ) 1428 - 1428   1999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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  • DMRV病因遺伝子の候補領域にマップされるEST(expressed sequence tag)の解析

    長谷川 有香, 池内 健, 田中 恵子, 辻 省次

    臨床神経学39 ( 12 ) 1442 - 1442   1999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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  • 二次元電気泳動を用いたDIRECTの開発(2D-DIRECT) 新規トリプレットリピート病の同定に向けて

    池内 健, 小出 玲爾, 辻 省次, 三瓶 一弘

    臨床神経学39 ( 12 ) 1394 - 1394   1999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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  • Mutational analyses and comparison of clinical phenotypes of six families with autosomal recessive juvenile parkinsonism (AR-JP).

    M Saito, M Maruyama, T Ikeuchi, H Kondo, A Ishikawa, S Tsuji

    AMERICAN JOURNAL OF HUMAN GENETICS65 ( 4 ) A489 - A489   1999年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:UNIV CHICAGO PRESS  

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  • A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease?

    R Koide, S Kobayashi, T Shimohata, T Ikeuchi, M Maruyama, M Saito, M Yamada, H Takahashi, S Tsuji

    HUMAN MOLECULAR GENETICS8 ( 11 ) 2047 - 2053   1999年10月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:OXFORD UNIV PRESS  

    To investigate whether the expansion of CAG repeats of the TATA-binding protein (TBP) gene is involved in the pathogenesis of neurodegenerative diseases, we have screened 118 patients with various forms of neurological disease and identified a sporadic-onset patient with unique neurologic symptoms consisting of ataxia and intellectual deterioration associated with de novo expansion of the CAG repeat of the TBP gene, The mutant TBP with an expanded polyglutamine stretch (63 glutamines) was demonstrated to be expressed in lymphoblastoid cell lines at a level comparable with that of wild-type TBP, The CAG repeat of the TBP gene consists of impure CAG repeat and the de novo expansion involves partial duplication of the CAG repeat. The present study provides new insights into sporadic-onset trinucleotide repeat diseases that involve de novo CAG repeat expansion.

    DOI: 10.1093/hmg/8.11.2047

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  • A neurological disease caused by the expanded trinucleotide repeat in the TATA-binding protein gene: A new polyglutamine disease

    R Koide, S Kobayashi, T Shimohata, T Ikeuchi, M Maruyama, M Saito, S Tsuji

    NEUROLOGY52 ( 6 ) A114 - A114   1999年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Rimmed vacuole型遠位型ミオパチーの遺伝子解析

    田中 恵子, 池内 健, 斎藤 正明, 田中 一, 樋口 砂里, 辻 省次, 浅賀 知也, 高守 正治

    厚生省精神・神経疾患研究委託費研究報告書 筋ジストロフィー及び関連疾患の臨床病態と治療法に関する研究平成8〜10年度   124 - 125   1999年3月

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    記述言語:日本語   出版者・発行元:厚生省精神・神経疾患研究班  

    DMRV9家系について連鎖解析を行い,本症の原因遺伝子がマイクロサテライト多型マーカーのD9S1868からD9S1788迄の間の12.3cMに存在し,ハプロタイプ解析からD9S1804からD9S1859の1.5cM周辺が候補領域として有望であることを示した.この領域にマップされるexpressed sequence tag(EST)から筋細胞に発現する10個のESTを選択し,DMRV生検筋から抽出したRNAについて,TaqMan probeを用いて定量的PCRを行い,本候補領域に存在するESTはタイプ 1線維に発現の多い遺伝子である可能性を示した

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  • Rimmed-vacuole型遠位型ミオパチーの遺伝子解析

    高守 正治, 浅賀 知也, 沖野 惣一, 滝沢 泰樹, 駒井 清暢, 新田 永俊, 池内 健, 斉藤 正明, 田中 一, 田中 恵子, 辻 省次

    厚生省精神・神経疾患研究委託費研究報告書 筋ジストロフィー及び関連疾患の臨床病態と治療法に関する研究平成8〜10年度   126 - 128   1999年3月

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    記述言語:日本語   出版者・発行元:厚生省精神・神経疾患研究班  

    まずrefined mappingを行い,homozygosity mapping,2点連鎖解析,haplotype分析及び連鎖不均衡の検討よりDMRVの疾患遺伝子がマイクロサテライト多型DNAマーカーD9S1878-D9S1859間の1.5cMに存在することを示した.更にD9S1878-D9S1859近傍にはβトロポミオシン遺伝子(TPM2)がmappingされていることから,TPM2異常の有無について検討した.その結果,1家系においてexon6Bのsplicing enhancer配列にA to Gのpoint mutationを認めたが,他のDMRV症例にはTPM2の変異は認められず,TPM2はDMRVの疾患遺伝子ではないものと考えられた

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  • 脊髄小脳失調症6型(SCA6)における電位依存性Ca2+チャネルα1Aサブユニット遺伝子のCAGリピートの伸長と経過年数に着目した臨床徴候の多様性

    池内 健, 高野 弘基, 小出 玲爾, 田中 一, 辻 省次, 高橋 均, 堀川 楊, 大西 洋司, 本間 義章, 中尾 直樹

    臨床神経学39 ( 1 ) 123 - 123   1999年1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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  • SCA6の電気生理学的所見 multimodality evoked potentialによる検討

    本間 篤, 佐藤 正久, 寺島 健史, 磯田 昌岐, 池内 健, 辻 省次, 近藤 浩, 原山 尋実

    臨床神経学39 ( 1 ) 147 - 147   1999年1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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  • DIRECT法で検出される伸長CAG/CTGリピートの健常者における頻度

    三瓶 一弘, 池内 健, 高野 弘基, 五十嵐 修一, 辻 省次

    臨床神経学39 ( 1 ) 150 - 150   1999年1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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  • ポリグルタミンとglyceraldehyde-3-phosphate dehydrogenaseの蛋白間相互作用の検討

    姉崎 利治, 小出 玲爾, 下畑 享良, 池内 健, 佐藤 晶, 五十嵐 修一, 田中 恵子, 辻 省次

    臨床神経学39 ( 1 ) 149 - 149   1999年1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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  • Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients(共著) 査読

    Human Molecular Genetics8 ( 1 ) 99 - 106   1999年

  • Close associations between prevalences of dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations

    H Takano, G Cancel, T Ikeuchi, D Lorenzetti, R Mawad, G Stevanin, O Didierjean, A Durr, M Oyake, T Shimohata, R Sasaki, R Koide, S Igarashi, S Hayashi, Y Takiyama, M Nishizawa, H Tanaka, H Zoghbi, A Brice, S Tsuji

    AMERICAN JOURNAL OF HUMAN GENETICS63 ( 4 ) 1060 - 1066   1998年10月

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    記述言語:英語   出版者・発行元:UNIV CHICAGO PRESS  

    To test the hypothesis that the frequencies of normal alleles (ANs) with a relatively large number of CAG repeats (large ANs) are related to the prevalences of the dominant spinocerebellar ataxias (SCAs)-SCA types 1, 2, 3 (Machado-Joseph disease), 6, and dentatorubral-pallidoluysian atrophy (DRPLA)-we investigated the relative prevalences of these diseases in 202 Japanese and 177 Caucasian families and distributions of the number of CAG repeats of ANs at these disease loci in normal individuals in each population. The relative prevalences of SCA1 and SCA2 were significantly higher in Caucasian pedigrees (15% and 14%, respectively) than in Japanese pedigrees (3% and 5%, respectively), corresponding to the observation that the frequencies of large ANs of SCA1 (alleles &gt;30 repeats) and of SCA2 (alleles &gt;22 repeats) were significantly higher in Caucasians than in Japanese. The relative prevalences of MJD/SCA3, SCA6, and DRPLA were significantly higher in Japanese pedigrees (43%, 11%, and 20%, respectively) than in Caucasian pedigrees (30%, 5%, and 0%, respectively), corresponding to the observation that the frequencies of large ANs of MJD/SCAS (&gt;27 repeats), SCA6 (&gt;13 repeats), and DRPLA (&gt;17 repeats) were significantly higher in Japanese than in Caucasians. The close correlations of the relative prevalences of the dominant SCAs with the distributions of large ANs strongly support the assumption that large ANs contribute to generation of expanded alleles (AEs) and the relative prevalences of the dominant SCAs.

    DOI: 10.1086/302067

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  • 筋ジストロフィー及び関連疾患の臨床病態と治療法に関する研究 Distal myopathy with rimmed vacuoles(DMRV)の遺伝子解析

    浅賀 知也, 沖野 惣一, 瀧澤 泰樹, 駒井 清暢, 新田 永俊, 高守 正治, 池内 健, 斎藤 正明, 田中 一, 田中 恵子, 辻 省次

    厚生省精神・神経疾患研究委託費による研究報告集平成9年度   68 - 68   1998年8月

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    記述言語:日本語   出版者・発行元:国立精神・神経センター  

    DMRVについてホモ接合マッピングや連鎖不均衡の検討をはじめとする解析を行った結果,本疾患が9p13上の約3cMの間に疾患遺伝子座を有することが明かとなった.本疾患の本態はまだ明かではないが,今後同部位に存在する既知の遺伝子の検討やより詳細なマッピングによって検討を進めていく必要がある

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  • 筋ジストロフィー及び関連疾患の臨床病態と治療法に関する研究 常染色体劣性遺伝性rimmed vacuole型遠位型ミオパチーの病因遺伝子のfine mapping

    田中 恵子, 池内 健, 斉藤 正明, 田中 一, 齋田 恭子, 浅賀 知也, 高守 正治, 宇山 英一郎, 水澤 英洋, 福原 信義, 辻 省次

    厚生省精神・神経疾患研究委託費による研究報告集平成9年度   72 - 73   1998年8月

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    記述言語:日本語   出版者・発行元:国立精神・神経センター  

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  • Phenotype variation correlates with CAG repeat length in SCA2 - A study of 28 Japanese patients

    H Sasaki, A Wakisaka, K Sanpei, H Takano, S Igarashi, T Ikeuchi, K Iwabuchi, T Fukazawa, T Hamada, T Yuasa, S Tsuji, K Tashiro

    JOURNAL OF THE NEUROLOGICAL SCIENCES159 ( 2 ) 202 - 208   1998年8月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    Spinocerebellar ataxia-2 (SCA2) is an autosomal dominant ataxia caused by an abnormal CAG repeat expansion in a novel gene on chromosome 12q24.1. The size of the mutant allele is unstable during transmission, and correlates inversely with age at onset. We studied eight Japanese SCA2 families,:including 28 patients, to assess the effect of repeat length on the phenotype features of SCA2. Frequencies of slow eye movements (SEM), reflex activity, dementia, choreiform movements, and axial tremor correlated significantly with CAG repeat size. Parkinsonism was seen in a man homozygote for SCA2 mutation. The clinical variety of SCA2 is apparently influenced by the size of the mutant allele, as is the case in other CAG repeat disorders. (C) 1998 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S0022-510X(98)00166-X

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  • Autosomal dominant cerebellar ataxia (SCA6): clinical, genetic and neuropathological study in a family

    H Takahashi, T Ikeuchi, Y Honma, S Hayashi, S Tsuji

    ACTA NEUROPATHOLOGICA95 ( 4 ) 333 - 337   1998年4月

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    記述言語:英語   出版者・発行元:SPRINGER VERLAG  

    We describe a family with dominantly inherited ataxia of late adult onset. Expansion of a CAG repeat in the gene encoding the alpha(1A) voltage-dependent calcium channel was identified at autopsy in one patient, a 65-year-old woman with a disease duration of 11 years. In this patient, pathological changes were confined to the cerebellar cortex and inferior olivary complex, The cerebellar cortex showed severe loss of Purkinje cells with proliferation of Bergmann's glia, being more pronounced in the superior parts of the vermis and hemispheres. In the inferior olivary complex, a reduced neuronal cell population, which could be interpreted as a change secondary to the cerebellar cortical lesion, was evident. We conclude that the pathological phenotype of this newly classified autosomal dominant cerebellar ataxia, SCA6, is cerebello-olivary atrophy, or more strictly cerebellar cortical atrophy.

    DOI: 10.1007/s004010050807

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  • 【イオンチャネルとレセプター 生理と病態】 電位依存性Ca2+チャネル遺伝子と遺伝性神経筋疾患

    池内 健, 五十嵐 修一, 辻 省次

    神経研究の進歩42 ( 2 ) 255 - 262   1998年4月

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    記述言語:日本語   出版者・発行元:(株)医学書院  

    DOI: 10.11477/mf.1431900842

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  • 神経・筋疾患の遺伝子研究と遺伝子診断用のデータベースシステムの確立とそれを用いた本邦優性遺伝性脊髄小脳変性症の頻度に関する研究

    辻 省次, 高野 弘基, 池内 健, 小宅 陸郎, 下畑 享良, 五十嵐 修一, 田中 一, 林 森太郎, 佐々木 良元

    厚生省精神・神経疾患研究委託費研究報告書 神経・筋疾患の遺伝子診断システムの確立と遺伝子バンクの樹立に関する研究平成7〜9年度   45 - 46   1998年3月

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    記述言語:日本語   出版者・発行元:国立精神・神経センター  

    1988年より開始したNGDは,1994年より軌道にのり,年間350-500の新規のサンプルが登録されている.1997年9月29日迄の総数は,1826(1206家系)であり,研究目的が33%,診断目的が57%であった.遺伝子診断の延べ数では3038件で,71%は3塩基繰り返し配列の増大に基づく疾患であり,その大半は優性遺伝性脊髄小脳変性症の遺伝子診断であった.優性遺伝性脊髄小脳変性症に関する頻度分析をNGDを用いて検索したところ,2世代以上に渡って発症者がいる優性遺伝性と考えられる家系は202家系あり,北海道と宮城県を除きほぼ全国からの家系が含まれていた.これらのうち,MJD/SCA3の頻度が最も高く43%を占めていた.続いて,DRPLA,SCA6が各々20%,11%と多く,SCA1,SCA2は各々3%,5%と比較的少なかった.これら以外の未知の優性遺伝性脊髄小脳変性症が16%あった

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  • 【分子筋肉病学】 進行性筋ジストロフィー その他の進行性筋ジストロフィー諸型の分子遺伝学的研究の現況 Rimmed vacuole型遠位型ミオパチー(DMRV)

    池内 健, 辻 省次

    日本臨床55 ( 12 ) 3195 - 3199   1997年12月

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    記述言語:日本語   出版者・発行元:(株)日本臨床社  

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  • Spinocerebellar ataxia type 6: CAG repeat expansion in alpha(1A) voltage-dependent calcium channel gene and clinical variations in Japanese population

    T Ikeuchi, H Takano, R Koide, Y Horikawa, Y Honma, Y Onishi, S Igarashi, H Tanaka, N Nakao, K Sahashi, H Tsukagoshi, K Inoue, H Takahashi, S Tsuji

    ANNALS OF NEUROLOGY42 ( 6 ) 879 - 884   1997年12月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Autosomal dominant spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. Recently, mild CAG repeat expansion in the alpha(1A) voltage-dependent calcium channel gene has been found to be associated with a type of autosomal dominant SCA (SCA6). We analyzed 98 Japanese families with autosomal dominant SCAs, for whom CAG repeat expansions of the SCA1, SCA2, Machado-Joseph disease/SCA3, and dentatorubral-pallidoluysian atrophy genes were excluded, and 5 apparently sporadic cases of cortical cerebellar atrophy. The diagnosis of SCA6 was confirmed in 30 families (31%) comprising 47 affected individuals and 1 sporadic case. The size of expanded CAG repeats ranged from 21 to 26 repeat units and was found to be correlated inversely with age at onset. We identified 2 SCA6 patients homozygous for expanded CAG repeats, whose ages at onset were earlier than the 95% lower confidence level, suggesting the presence of a gene dosage effect of expanded CAG repeat. Ataxia is the most common initial symptom found in 45 of the 48 patients. Patients with a prolonged disease course showed other accompanying clinical features including dystonic postures, involuntary movements, and abnormalities in tendon reflexes.

    DOI: 10.1002/ana.410420609

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  • Prevalence rates of dominant spinocerebellar ataxias (SCAs) tightly correlate with the frequencies of intermediate alleles (Al) in the corresponding ethnic populations.

    H Takano, G Cancel, A Durr, T Ikeuchi, D Lorenzetti, R Mawad, M Oyake, R Sasaki, S Igarashi, S Hayashi, R Koide, Y Takiyama, M Nishizawa, H Tanaka, H Zoghbi, A Brice, ST Tsuji

    AMERICAN JOURNAL OF HUMAN GENETICS61 ( 4 ) A213 - A213   1997年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:UNIV CHICAGO PRESS  

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  • CAG repeat expansion in alpha(1A)-voltage-dependent calcium channel gene and clinical variations in spinocerebellar ataxia type 6

    T Ikeuchi, H Takano, R Koide, Y Horikawa, Y Honma, Y Onishi, S Igarashi, H Tanaka, N Nakao, K Sahashi, H Tsukagoshi, K Inoue, H Takahashi, S Tsuji

    AMERICAN JOURNAL OF HUMAN GENETICS61 ( 4 ) A311 - A311   1997年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:UNIV CHICAGO PRESS  

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  • A significant proportion of Japanese families with autosomal dominant pure cerebellar ataxia (ADPCA) is associated with mild CAG repeat expansions in the alpha 1A voltage-dependent calcium channel gene.

    K Ishikawa, M Watanabe, H Tanaka, T Ikeuchi, M Takashima, S Shoji, S Tsuji, H Mizusawa

    AMERICAN JOURNAL OF HUMAN GENETICS61 ( 4 ) A52 - A52   1997年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:UNIV CHICAGO PRESS  

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  • Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1

    K Ishikawa, H Tanaka, M Saito, N Ohkoshi, T Fujita, K Yoshizawa, T Ikeuchi, M Watanabe, A Hayashi, Y Takiyama, M Nishizawa, Nakano, I, K Matsubayashi, M Miwa, S Shoji, Kanazawa, I, S Tsuji, H Mizusawa

    AMERICAN JOURNAL OF HUMAN GENETICS61 ( 2 ) 336 - 346   1997年8月

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    記述言語:英語   出版者・発行元:UNIV CHICAGO PRESS  

    Autosomal dominant cerebellar ataxia is a group of clinically and genetically heterogeneous disorders, We carried out genomewide linkage analysis in 15 families with autosomal dominant pure cerebellar ataxia (ADPCA). Evidence for linkage to chromosome 19p markers was found in nine families, and combined multipoint analysis refined the candidate region to a 13.3-cM interval in 19p13.1-p13.2. The remaining six families were excluded for this region. Analysis of GAG-repeat expansion in the alpha1A-voltage-dependent calcium channel (CACNL1A4) gene lying in 19p13.1, recently identified among 8 small American kindreds with ADPCA (spino-cerebellar ataxia type 6 [SCA6]), revealed that 8 of the 15 families studied had similar, very small expansion in this gene: all affected individuals had larger alleles (range of CAG repeats 21-25), compared with alleles observed in neurologically normal. Japanese (range 5-20 repeats). Inverse correlation between the GAG-repeat number and the age at onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proved in the SCA6 families that we studied, We conclude that more than half of Japanese cases of ADPCA map to 19p13.1-p13.2 and are strongly associated with the mild CAG expansion in the SCAG/CACNL1A4 gene.

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  • 大脳白質の広範な淡明化に加え,視床・橋にも対称性の病変を認めた歯状核赤核淡蒼球ルイ体萎縮症(DRPLA)の1剖検例

    柿田 明美, 登木口 進, 池内 健, 辻 省次, 高橋 均

    NEUROPATHOLOGY17 ( Suppl. ) 82 - 82   1997年5月

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    記述言語:日本語   出版者・発行元:John Wiley & Sons Australia, Ltd  

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  • Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9

    T Ikeuchi, T Asaka, M Saito, H Tanaka, S Higuchi, K Tanaka, K Saida, E Uyama, H Mizusawa, N Fukuhara, Nonaka, I, M Takamori, S Tsuji

    ANNALS OF NEUROLOGY41 ( 4 ) 432 - 437   1997年4月

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    記述言語:英語   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

    Distal myopathy with rimmed vacuoles is an autosomal recessive muscular disorder, characterized clinically by weakness of the distal muscles in the lower limbs in early adulthood. Recently, the gene locus for familial vacuolar myopathy with autosomal recessive inheritance (hereditary inclusion body myopathy) was mapped to chromosome 9 by genome-wide linkage analysis of nine Persian-Jewish families. Since both disease conditions share similar clinical, genetic, and histopathological features, we analyzed seven families with distal myopathy with rimmed vacuoles using ten microsatellite markers within the region of the hereditary inclusion body myopathy locus. Significantly high cumulative pairwise lod scores were obtained with three markers: D9S248 (Z(max) = 5.90 at Theta = 0), D9S43 (Z(max) = 5.25 at Theta = 0), and D9S50 (Z(max) = 4.23 at Theta = 0). Detection of obligate recombination events as well as multipoint linkage analysis revealed that the most likely location of the distal myopathy with rimmed vacuoles gene is in a 23.3-cM interval defined by D9S319 and D9S276 on chromosome 9. The results raise the possibility that distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy in Persian Jews are allelic diseases.

    DOI: 10.1002/ana.410410405

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  • A molecular genetic study on autosomal-dominant ataxias in Japanese. Comparison of the prevalences and CAG repeat expansions among spinocerebellar ataxia (SCA1), spinocerebellar ataxia type 2 (SCA2), Machado-Joseph disease (MJD) and dentatorubral-pallidoluysian atrophy (DRPLA)

    H Takano, T Ikeuchi, S Igarashi, M Oyake, R Koide, R Sasaki, K Sanpei, H Sasaki, A Wakisaka, K Tashiro, K Iwabuchi, Y Takiyama, M Nishizawa, H Tanaka

    NEUROLOGY48 ( 3 ) 26002 - 26002   1997年3月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

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  • A sporadic case of dentatorubral pallidoluysian atrophy (DRPLA) with CAG repeat expansion but no clinical abnormalities in the father

    N Shimizu, T Yamami, M Nakayama, T Ikeuchi, R Koide, S Tsuji

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY61 ( 1 ) 113 - 114   1996年7月

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    記述言語:英語   掲載種別:速報,短報,研究ノート等(学術雑誌)   出版者・発行元:BRITISH MED JOURNAL PUBL GROUP  

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  • Non-Mendelian transmission in Dentatorubral-Pallidoluysian atrophy and Machado-Joseph disease: The mutant allele is preferentially transmitted in male meiosis

    T Ikeuchi, S Igarashi, Y Takiyama, O Onodera, M Oyake, H Takano, R Koide, H Tanaka, S Tsuji

    AMERICAN JOURNAL OF HUMAN GENETICS58 ( 4 ) 730 - 733   1996年4月

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    記述言語:英語   出版者・発行元:UNIV CHICAGO PRESS  

    Autosomal dominant dentatorubral-pallidoluysian atrophy (DRPLA) and Machado-Joseph disease (MJD) are neurodegenerative disorders caused by CAG trinucleotide repeat expansions. An inverse correlation of age at onset with the length of the expanded CAG trinucleotide repeats has been demonstrated, and the intergenerational instability of the length of the CAG trinucleotide repeats, which is more prominent in paternal than in maternal transmissions, has been shown to underlie the basic mechanisms of anticipation in DRPLA and MJD. Our previous observations on DRPLA and MJD pedigrees, as well as a review of the literature, have suggested that the numbers of affected offspring exceed those of unaffected offspring, which is difficult to explain by the Mendelian principle of random segregation of alleles. In the present study, we analyzed the segregation patterns in 211 transmissions in 24 DRPLA pedigrees and 80 transmissions in 7 MJD pedigrees, with the diagnoses confirmed by molecular testing. Significant distortions in favor of transmission of the mutant alleles were found in male meiosis, where the mutant alleles were transmitted to 62% of all offspring in DRPLA (chi(2) = 7.69; P &lt; .01) and 73% in MJD (chi(2) = 6.82; P &lt; .01). The results were consistent with meiotic drive in DRPLA and MJD. Since more prominent meiotic instability of the length of the CAG trinucleotide repeats is observed in male meiosis than in female meiosis and meiotic drive is observed only in male meiosis, these results raise the possibility that a common molecular mechanism underlies the meiotic drive and the meiotic instability in male meiosis.

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  • 内藤・小柳病(DRPLA)のgene huntingの軌跡

    辻 省次, 小出 玲爾, 池内 健

    脳と神経48 ( 4 ) 323 - 328   1996年4月

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    記述言語:日本語   出版者・発行元:(株)医学書院  

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  • Rimmed Vacuoleを伴う遠位型ミオパチーに対するhomozygosity mappingを用いた分子遺伝学的研究

    辻 省次, 池内 健, 樋口 砂里

    厚生省精神・神経疾患研究委託費研究報告書 筋ジストロフィー及び類縁疾患の病態と治療法に関する研究平成7年度   91 - 94   1996年3月

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    記述言語:日本語   出版者・発行元:厚生省精神・神経疾患研究班  

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  • 遺伝性脊髄小脳変性症の遺伝子変異と臨床像

    池内 健, 五十嵐 修一, 辻 省次

    Brain Medical8 ( 1 ) 13 - 19   1996年3月

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    記述言語:日本語   出版者・発行元:(株)メディカルレビュー社  

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  • トリプレットリピート病における,非メンデル遺伝学的現象とその分子機構について

    辻 省次, 池内 健, 五十嵐 修一

    厚生省精神・神経疾患研究委託費研究報告書 神経疾患の病態解明に関する分子遺伝学的研究平成6〜7年度   89 - 92   1996年3月

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    記述言語:日本語   出版者・発行元:厚生省精神・神経疾患研究班  

    本研究で示したDRPLAとMJDにおける非メンデル遺伝現象と,世代間でCAG repeatが顕著に不安定になる現象とも,父親から遺伝子が伝わる時に認めているので,この両者には共通の分子機構が存在している可能性が示唆された

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  • 歯状核赤核・淡蒼球ルイ体萎縮症(DRPLA)の分子遺伝学的検討

    辻 省次, 池内 健, 小出 玲爾

    厚生省精神・神経疾患研究委託費研究報告書 神経疾患の病態解明に関する分子遺伝学的研究平成6〜7年度   81 - 84   1996年3月

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    記述言語:日本語   出版者・発行元:厚生省精神・神経疾患研究班  

    CAG repeatの延長の程度が,DRPLAの多彩な臨床像に強く相関していることを示した

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  • Non-Mendelian transmission in dentatorubral-pallidoluysian atrophy and Machado-Joseph disease

    T Ikeuchi, S Igarashi, Y Takiyama, O Onodera, M Oyake, H Takano, R Koide, H Tanaka, S Tsuji

    NEUROLOGY46 ( 2 ) 30005 - 30005   1996年2月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LITTLE BROWN CO  

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  • SOMATIC MOSAICISM OF THE CAG REPEAT EXPANSION IN THE CENTRAL-NERVOUS-SYSTEM AS A REFLECTION OF PROGRESSIVE NEURONAL CELL LOSS IN DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA)

    H TAKANO, O ONODERA, H TAKAHASHI, S IGARASHI, M YAMADA, M OYAKE, T IKEUCHI, R KOIDE, H TANAKA, K IWABUCHI, S TSUJI

    AMERICAN JOURNAL OF HUMAN GENETICS57 ( 4 ) 39 - 39   1995年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:UNIV CHICAGO PRESS  

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  • DOES HOMOZYGOSITY ADVANCE THE ONSET OF DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY

    K SATO, K KASHIHARA, S OKADA, T IKEUCHI, S TSUJI, T SHOMORI, K MORIMOTO, T HAYABARA

    NEUROLOGY45 ( 10 ) 1934 - 1936   1995年10月

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    記述言語:英語   掲載種別:記事・総説・解説・論説等(学術雑誌)   出版者・発行元:LITTLE BROWN CO  

    We confirmed a homozygous type of relatively small expansion of CAG triplet repeats (57 repeats) in the short arm of chromosome 12 in a male patient with dentatorubral-pallidoluysian atrophy (DRPLA) by polymerase chain reaction. He showed early onset (age, 17 years) of DRPLA. There was good correlation of the age of onset with the number of triplet repeats. The homozygous state of the expansion of the triplet repeats was responsible for the early onset and severity of his DRPLA.

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  • 進行性ミオクローヌスてんかんの分子遺伝学

    池内 健, 丹野 芳範, 辻 省次

    MEDICO26 ( 10 ) 11 - 15   1995年10月

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    記述言語:日本語   出版者・発行元:千代田開発(株)  

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  • 神経細胞死 Up to Date 3塩基リピートの異常を示す遺伝性神経変性疾患

    辻 省次, 池内 健

    Dementia9 ( 4 ) 393 - 400   1995年10月

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    記述言語:日本語   出版者・発行元:エースアート(株)  

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  • 神経疾患の遺伝子診断

    池内 健, 辻 省次

    Biotherapy9 ( 9 ) 1084 - 1095   1995年9月

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    記述言語:日本語   出版者・発行元:(株)癌と化学療法社  

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  • 遺伝性歯状核赤核淡蒼球ルイ体萎縮症(DRPLA):分子遺伝学の立場から

    小出 玲爾, 池内 健, 小野寺 理

    新潟医学会雑誌109 ( 4 ) 185 - 189   1995年4月

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    記述言語:日本語   出版者・発行元:新潟医学会  

    DRPLAは第12染色体上のCTG B37という名で呼ばれる遺伝子のCAGリピートの増大が原因であり,発症年齢やその多彩な病型はCAGリピート数と相関していることが明らかとなった

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  • Triplet repeat異常と遺伝性神経筋疾患

    池内 健, 辻 省次

    Annual Review神経1995   1 - 12   1995年1月

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    記述言語:日本語   出版者・発行元:(株)中外医学社  

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  • UNSTABLE EXPANSION OF CAG TRINUCLEOTIDE REPEATS AND THE IMPLICATION FOR NEURONAL DEGENERATION

    S TSUJI, T IKEUCHI, H TAKANO, S IGARASHI, Y TAKIYAMA, R KOIDE, H TANAKA

    JOURNAL OF NEUROCHEMISTRY65   S72 - S72   1995年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

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  • DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY AND HAW-RIVER-SYNDROME

    AR BURKE, T IKEUCHI, R KOIDE, S TSUJI, M YAMADA, MA PERICAKVANCE, JM VANCE

    LANCET344 ( 8938 ) 1711 - 1712   1994年12月

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    記述言語:英語   掲載種別:速報,短報,研究ノート等(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • 遺伝性脊髄小脳変性症の遺伝子診断

    池内 健, 辻 省次

    日本内科学会雑誌83 ( 11 ) 2000 - 2006   1994年11月

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    記述言語:日本語   出版者・発行元:(一社)日本内科学会  

    DOI: 10.2169/naika.83.2000

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  • 歯状核赤核淡蒼球ルイ体萎縮症(DRPLA)の分子遺伝学 CAGリピート病と遺伝子同定への新しい戦略

    池内 健, 小出 玲爾, 辻 省次

    医学のあゆみ171 ( 4 ) 256 - 257   1994年10月

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    記述言語:日本語   出版者・発行元:医歯薬出版(株)  

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  • 歯状核赤核淡蒼球ルイ体萎縮症(DRPLA)の分子遺伝学 CAGリピートの増大はDRPLAの臨床像と深く相関する

    池内 健, 小出 玲爾, 辻 省次

    医学のあゆみ170 ( 6 ) 640 - 643   1994年8月

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    記述言語:日本語   出版者・発行元:医歯薬出版(株)  

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  • 神経変性疾患 最近の話題 歯状核赤核淡蒼球ルイ体萎縮症(DRPLA)

    池内 健, 小出 玲爾, 辻 省次

    Modern Physician14 ( 6 ) 811 - 814   1994年6月

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    記述言語:日本語   出版者・発行元:(株)新興医学出版社  

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  • UNSTABLE EXPANSION OF CAG REPEAT IN HEREDITARY DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA)

    T IKEUCHI, R KOIDE, O ONODERA, H TANAKA, S IGARASHI, K ENDO, S TSUJI, H TAKAHASHI, F IKUTA, R KONDO, A ISHIKAWA, T HAYASHI, M SAITO, H NAITO, A TOMODA, T MIIKE

    NEUROLOGY44 ( 4 ) A360 - A360   1994年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LITTLE BROWN CO  

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