2022/09/29 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   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

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学歴

  • 新潟大学 大学院 医学研究科   Graduate School of Medicine

    1996年4月 - 2000年3月

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  • 新潟大学 医学部 医学科   Faculty of Medicine   School of Medicine

    1984年4月 - 1991年3月

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論文

  • Effects of an essential amino acid mixture on behavioral and psychological symptoms of dementia and executive function in patients with Alzheimer's disease: A double-blind, randomized, placebo-controlled exploratory clinical trial. 国際誌

    Michihiro Takada, Shin Tanaka, Koh Tanaka, Tamao Tsukie, Masako Tsukamoto-Yasui, Katsuya Suzuki, Yasushi Noguchi, Akira Imaizumi, Makoto Ishii, Takeshi Ikeuchi

    International journal of geriatric psychiatry   37 ( 9 )   2022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)  

    BACKGROUND: The increasing number of dementia patients has become a global social problem. Amino acids are known to be used as precursors of neurotransmitters in the brain. Amino acid mixtures as a supplement may be used as a solution to Alzheimer's symptoms. This exploratory study evaluated the efficacy and safety of a mixture containing nine essential amino acids on behavioral and psychological symptoms of dementia (BPSD) and cognitive function in patients with Alzheimer's disease (AD). DESIGN: We conducted a double-blind, randomized, placebo-controlled trial to evaluate the intervention effects of nine essential amino acid mixture for 28 days. A total of 36 patients with AD were enrolled in Japan. BPSD and cognitive function were evaluated by the Neuropsychiatric Inventory-12 item (NPI-12; the primary endpoint), Mini-Mental State Examination (MMSE), Trail Making Test A (TMT-A), Trail Making Test B (TMT-B), Frontal Assessment Battery (FAB), and Clinical Dementia Rating Scale (CDR). RESULTS: Compared with placebo, the amino acid mixture did not improve NPI-12, MMSE, TMT-A and B or CDR scores. However, the analysis of covariance revealed improved FAB scores in the amino acid mixture group as a secondary endpoint. There were four subjects with adverse events in each group. CONCLUSIONS: Our results did not show a beneficial effect of the mixture containing nine essential amino acids on BPSD as a primary endpoint; however, it may improve executive function in patients with AD.

    DOI: 10.1002/gps.5782

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  • Accelerated longitudinal changes and ordering of Alzheimer disease biomarkers across the adult lifespan. 国際誌

    Jingqin Luo, Folasade Agboola, Elizabeth Grant, John C Morris, Colin L Masters, Marilyn S Albert, Sterling C Johnson, Eric M McDade, Anne M Fagan, Tammie L S Benzinger, Jason Hassenstab, Randall J Bateman, Richard J Perrin, Guoqiao Wang, Yan Li, Brian Gordon, Carlos Cruchaga, Gregory S Day, Johannes Levin, Jonathan Vöglein, Takeshi Ikeuchi, Kazushi Suzuki, Ricardo F Allegri, Chengjie Xiong

    Brain : a journal of neurology   2022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)  

    The temporal evolutions and relative orderings of Alzheimer disease biomarkers, including CSF amyloid-β42 (Aβ42), Aβ40, total tau (Tau) and phosphorylated tau181 (pTau181), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar amyloid-β with PET using the 11C-Pittsburgh Compound-B (PiB), MRI-based hippocampal volume and cortical thickness and cognition have been hypothesized but not yet fully tested with longitudinal data for all major biomarker modalities among cognitively normal individuals across the adult lifespan starting from 18 years. By leveraging a large harmonized database from 8 biomarker studies with longitudinal data from 2609 participants in cognition, 873 in MRI biomarkers, 519 in PET PiB imaging and 475 in CSF biomarkers for a median follow-up of 5-6 years, we estimated the longitudinal trajectories of all major Alzheimer disease biomarkers as functions of baseline age that spanned from 18 to 103 years, located the baseline age window at which the longitudinal rates of change accelerated and further examined possible modifying effects of apolipoprotein E (APOE) genotype. We observed that participants 18-45 years at baseline exhibited learning effects on cognition and unexpected directions of change on CSF and PiB biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio (with an increase) and for Tau, and pTau181 (with a decrease) at the next baseline age interval of 45-50 years, followed by an accelerated increase for PiB SUVR at the baseline age of 50-55 years and an accelerated decrease for hippocampal volume at the baseline age of 55-60 years and finally by an accelerated decline for cortical thickness and cognition at the baseline age of 65-70 years. Another acceleration in the rate of change occurred at the baseline age of 65-70 years for Aβ42/Aβ40 ratio, Tau, pTau181, PiB SUVR and hippocampal volume. Accelerated declines in hippocampal volume and cognition continued after 70 years. For participants 18-45 years at baseline, significant increases in Aβ42 and Aβ42/Aβ40 ratio and decreases in PiB SUVR occurred in APOE ɛ4 non-carriers but not carriers. After age 45 years, APOE ɛ4 carriers had greater magnitudes than non-carriers in the rates of change for all CSF biomarkers, PiB SUVR and cognition. Our results characterize the temporal evolutions and relative orderings of Alzheimer disease biomarkers across the adult lifespan and the modification effect of APOE ɛ4. These findings may better inform the design of prevention trials on Alzheimer disease.

    DOI: 10.1093/brain/awac238

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  • Identification of mild cognitive impairment subtypes predicting conversion to Alzheimer’s disease using multimodal data

    Masataka Kikuchi, Kaori Kobayashi, Sakiko Itoh, Kensaku Kasuga, Akinori Miyashita, Takeshi Ikeuchi, Eiji Yumoto, Yuki Kosaka, Yasuto Fushimi, Toshihiro Takeda, Shirou Manabe, Satoshi Hattori, Alzheimer's Disease Neuroimaging Initiative, Akihiro Nakaya, Kenichi Kamijo, Yasushi Matsumura

    Computational and Structural Biotechnology Journal   2022年8月

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

    DOI: 10.1016/j.csbj.2022.08.007

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  • Clinical correlations of cerebrospinal fluid biomarkers including neuron-glia 2 and neurofilament light chain in patients with multiple system atrophy. 国際誌

    Takayoshi Tokutake, Kensaku Kasuga, Tamao Tsukie, Takanobu Ishiguro, Takayoshi Shimohata, Osamu Onodera, Takeshi Ikeuchi

    Parkinsonism & related disorders   102   30 - 35   2022年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder. The usefulness of biomarkers in diagnosing MSA has been recently reported, but few studies have investigated the correlations among cerebrospinal fluid (CSF) biomarkers or the relationship between CSF biomarkers and the clinical parameters of patients with MSA. Thus, this was the aim of our study. METHODS: We performed cross-sectional study of CSF biomarkers in 50 patients with MSA and 20 control subjects. Ten of the patients with MSA were longitudinally followed for a period of 2 ± 1 years (mean ± standard deviation) as a substudy. We quantified CSF biomarkers including α-synuclein (α-syn), β-amyloid42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau), neurofilament light chain (NfL), and neuron-glia2 (NG2), and assessed their relationship with clinical parameters (clinical subtypes, motor symptoms, nonmotor symptoms, and disease progression). RESULTS: The levels of CSF α-syn, Aβ42, and p-tau were significantly lower, while those of NfL were higher in the patients with MSA than in the control subjects. Importantly, we found the significant elevation of soluble NG2 in the CSF of patients with MSA. CSF NfL showed the optimal diagnostic performance for MSA with levels at baseline significantly associated with longitudinal motor progression. With the exception of t-tau, there were no differences in the levels of CSF biomarkers between the MSA-parkinsonism and MSA-cerebellar subtypes. CONCLUSIONS: Our results suggest CSF levels of NG2 and NfL as possible diagnostic and prognostic biomarkers in MSA. Further study is necessary to validate these findings.

    DOI: 10.1016/j.parkreldis.2022.07.007

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  • Covariance-based vs. correlation-based functional connectivity dissociates healthy aging from Alzheimer disease. 国際誌

    Jeremy F Strain, Matthew R Brier, Aaron Tanenbaum, Brian A Gordon, John E McCarthy, Aylin Dincer, Daniel S Marcus, Jasmeer P Chhatwal, Neill R Graff-Radford, Gregory S Day, Christian la Fougère, Richard J Perrin, Stephen Salloway, Peter R Schofield, Igor Yakushev, Takeshi Ikeuchi, Jonathan Vöglein, John C Morris, Tammie L S Benzinger, Randall J Bateman, Beau M Ances, Abraham Z Snyder

    NeuroImage   261   119511 - 119511   2022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)  

    Prior studies of aging and Alzheimer disease have evaluated resting state functional connectivity (FC) using either seed-based correlation (SBC) or independent component analysis (ICA), with a focus on particular functional systems. SBC and ICA both are insensitive to differences in signal amplitude. At the same time, accumulating evidence indicates that the amplitude of spontaneous BOLD signal fluctuations is physiologically meaningful. We systematically compared covariance-based FC, which is sensitive to amplitude, vs. correlation-based FC, which is not, in affected individuals and controls drawn from two cohorts of participants including autosomal dominant Alzheimer disease (ADAD), late onset Alzheimer disease (LOAD), and age-matched controls. Functional connectivity was computed over 222 regions of interest and group differences were evaluated in terms of components projected onto a space of lower dimension. Our principal observations are: (1) Aging is associated with global loss of resting state fMRI signal amplitude that is approximately uniform across resting state networks. (2) Thus, covariance FC measures decrease with age whereas correlation FC is relatively preserved in healthy aging. (3) In contrast, symptomatic ADAD and LOAD both lead to loss of spontaneous activity amplitude as well as severely degraded correlation structure. These results demonstrate a double dissociation between age vs. Alzheimer disease and the amplitude vs. correlation structure of resting state BOLD signals. Modeling results suggest that the AD-associated loss of correlation structure is attributable to a relative increase in the fraction of locally restricted as opposed to widely shared variance.

    DOI: 10.1016/j.neuroimage.2022.119511

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  • [Neuropsychological and regional cerebral blood flow of posterior parietal area features in patients with Parkinson's disease with mild cognitive impairment].

    Yasuko Kuroha, Tetsuya Takahashi, Yuki Arai, Mihoko Yoshino, Kensaku Kasuga, Arika Hasegawa, Nae Matsubara, Ryoko Koike, Takeshi Ikeuchi

    Rinsho shinkeigaku = Clinical neurology   62 ( 7 )   532 - 540   2022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)  

    This study aimed to clarify associations between neuropsychological scales and regional cerebral blood flow (rCBF) of on ‍123I-IMP-SPECT in patients with Parkinson's disease with mild cognitive impairment (PD-MCI). Forty-two participants (mean age, 65.5 ± 8.9 years; mean disease duration, 11.1 ±5.7 years) were evaluated using the Wechsler Adult Intelligence Scale, third edition (WAIS-III), Wechsler Memory Scale, revised (WMS-R), Stroop test, Category word fluency, Auditory verbal learning test, Raven colored progressive matrices, Trail Making Test-B, and Clock drawing test. Participants were classified into PD-MCI and PD non-demented (PD-ND) using ten of these scales or its subtests. The rCBF of the posterior cingulate gyrus, precuneus, and parietal lobes was evaluated by ‍123I-IMP-SPECT using the easy Z-‍score imaging system (eZIS analysis). Extent was the extent index of voxels showing z-score > 2, and Severity was mean z-score in those regions on eZIS analysis. Cingulate island sign score (CIScore) was the ratio of integrated z-scores of the posterior cingulate gyrus to those of the posterior cortex.Twenty-three participants were diagnosed with PD-MCI (55%). The rCBF indices were significantly increased in the PD-MCI group compared to the PD-ND group (Extent: P = 0.047; CIScore: P = 0.006). These indices were significantly correlated with WAIS-III Processing Speed (Extent: P = 0.041, R = -0.317; Severity: P = 0.047, R = -0.309), Stroop effect (Extent: P = 0.003, R = 0.443; Severity: P = 0.004, R = 0.437), WMS-R Visual memory (Extent: P = 0.019, R = -0.361; Severity: P = 0.014, R = -0.375), and Delayed memory score (Extent: P = 0.005, R = -0.423; Severity: P = 0.044, R = -0.312). The rCBF indices showed no correlations with the number of impaired cognitive domains. Collectively, decreased posterior parietal area rCBF and lower scores on selective neuropsychological scales might be helpful to detect a transition period from PD-MCI to PD-D.

    DOI: 10.5692/clinicalneurol.cn-001709

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  • The use of lumbar puncture and safety recommendations in Alzheimer's disease: a plain language summary. 国際誌

    Harald Hampel, Aya Elhage, Leslie M Shaw, Paul Aisen, Christopher Chen, Alberto Lleó, Takeshi Iwatsubo, Atsushi Iwata, Masahito Yamada, Takeshi Ikeuchi, Jianping Jia, Huali Wang, Charlotte E Teunissen, Elaine Peskind, Kaj Blennow, Jeffrey Cummings, Andrea Vergallo

    Neurodegenerative disease management   2022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)  

    WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of an article published in Alzheimer's & Dementia. It looks at a type of test called a lumbar puncture (also known as spinal tap) used in people suspected of having Alzheimer's disease or some other form of dementia. This summary focuses on how to do a lumbar puncture safely. WHY IS THIS IMPORTANT?: Alzheimer's disease is a progressive condition, which means it gets worse over time. This leads to difficulties with thinking and memory. People with Alzheimer's disease show a build up of proteins called amyloid-β and tau in the brain. This is followed by a gradual loss of brain cells and brain function. The changes in the brain are thought to occur years before symptoms appear. Lumbar puncture is a medical procedure during which samples of cerebrospinal fluid are collected. In Alzheimer's disease, it is used to examine cerebrospinal fluid biomarkers that can help diagnose disease. Lumbar puncture is traditionally considered as a painful and invasive procedure with frequent side effects. However, multiple studies indicate that a lumbar puncture can be performed safely. Side effects are typically mild and do not require specialist intervention. WHAT ARE THE KEY TAKEAWAYS?: Despite the low risk of serious complications associated with a lumbar puncture, physicians and their patients may be reluctant to recommend or undergo this procedure. Patient education, specialist training, as well as new methods concerning patient safety are important factors to support the widespread use of lumbar puncture in Alzheimer's disease.

    DOI: 10.2217/nmt-2022-0012

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  • 【神経核内封入体病・白質脳症】HDLS(hereditary diffuse leukoencephalopathy with spheroids)

    今野 卓哉, 池内 健, 小野寺 理

    脳神経内科   97 ( 1 )   101 - 109   2022年7月

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    記述言語:日本語   出版者・発行元:(有)科学評論社  

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  • Four-repeat tauopathies and late-onset psychiatric disorders: Etiological relevance or incidental findings? 国際誌

    Osamu Yokota, Tomoko Miki, Hideki Ishizu, Takashi Haraguchi, Yuki Kishimoto, Shintaro Takenoshita, Norikazu Hara, Akinori Miyashita, Takeshi Ikeuchi, Seishi Terada, Norihito Yamada

    Neuropathology : official journal of the Japanese Society of Neuropathology   2022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)  

    Argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) and corticobasal degeneration are four-repeat (4R) tauopathies that develop in the presenium or later. Whether these diseases are associated with the occurrence of late-onset psychiatric disorders remains unclear. To facilitate the accumulation of clinicopathological findings regarding this issue, we here present a selected series of 11 cases that clinically developed psychotic disorder (n = 7; age at onset: 41-75 years), depressive disorder (n = 1; 49 years), bipolar disorder (n = 2; 32 and 37 years) and somatoform disorder (n = 1; 88 years), and had at least one pathological hallmark of these tauopathies. The mean age at death was 74.3 years. No case showed dementia, at least in the early stage of the course. Nine cases had AGD. Granular fuzzy astrocytes in the amygdala were noted in all AGD cases and one non-AGD case. Two AGD cases had tufted astrocytes (TAs) in the amygdala but not in the frontal cortex and striatum. Three AGD and two non-AGD cases had TAs in the frontal cortex and/or striatum but not in the amygdala. One AGD case had a small number of astrocytic plaques in the frontal cortex, striatum and globus pallidus. Only one case was diagnosed as atypical PSP according to the NINDS-PSP neuropathological criteria. No case had high-level Alzheimer's disease pathology, Lewy body disease or limbic-predominant age-related TDP-43 encephalopathy. Two cases had mild neuronal loss in the hippocampus and substantia nigra, respectively. Clinicopathological studies focusing especially on early changes of 4R tauopathies, as well as the development of surrogate markers of these diseases, may be necessary for better understanding of the pathogenic backgrounds of late-onset psychiatric disorders.

    DOI: 10.1111/neup.12820

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  • Frontotemporal Lobar Degeneration With Unclassifiable 4-Repeat Tauopathy Mimicking Globular Glial Tauopathy. 国際誌

    Ai Shimizu, Akio Akagi, Chiho Ishida, Kenji Sakai, Kiyonobu Komai, Mitsuru Kawamura, Masato Hasegawa, Takeshi Ikeuchi, Masahito Yamada

    Journal of neuropathology and experimental neurology   81 ( 7 )   581 - 584   2022年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/jnen/nlac039

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  • CDiP technology for reverse engineering of sporadic Alzheimer’s disease

    Takayuki Kondo, Yuichiro Yada, Takeshi Ikeuchi, Haruhisa Inoue

    Journal of Human Genetics   2022年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Abstract

    Alzheimer’s disease (AD) is a neurodegenerative disease that causes cognitive impairment for which neither treatable nor preventable approaches have been confirmed. Although genetic factors are considered to contribute to sporadic AD, for the majority of AD patients, the exact causes of AD aren’t fully understood. For AD genetics, we developed cellular dissection of polygenicity (CDiP) technology to identify the smallest unit of AD, i.e., genetic factors at a cellular level. By CDiP, we found potential therapeutic targets, a rare variant for disease stratification, and polygenes to predict real-world AD by using the real-world data of AD cohort studies (Alzheimer’s Disease Neuroimaging Initiative: ADNI and Japanese Alzheimer’s Disease Neuroimaging Initiative: J-ADNI). In this review, we describe the components and results of CDiP in AD, induced pluripotent stem cell (iPSC) cohort, a cell genome-wide association study (cell GWAS), and machine learning. And finally, we discuss the future perspectives of CDiP technology for reverse engineering of sporadic AD toward AD eradication.

    DOI: 10.1038/s10038-022-01047-8

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    その他リンク: https://www.nature.com/articles/s10038-022-01047-8

  • Genetics of Alzheimer’s disease: an East Asian perspective 査読

    Akinori Miyashita†, Masataka Kikuchi†, Norikazu Hara†, Takeshi Ikeuchi

    Journal of Human Genetics   2022年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Abstract

    Alzheimer’s disease (AD) is an age-related multifactorial neurodegenerative disorder. Advances in genome technology, including next generation sequencing have uncovered complex genetic effects in AD by analyzing both common and rare functional variants. Multiple lines of evidence suggest that the pathogenesis of AD is influenced by multiple genetic components rather than single genetic factor. Previous genetic studies on AD have predominantly included European ancestry cohorts; hence, the non-European population may be underrepresented, potentially leading to reduced diversity in AD genetic research. Additionally, ethnic diversity may result in dissimilar effects of genetic determinants in AD. APOE genotypes are a well-established genetic risk factor in AD, with the East Asian population having a higher risk of AD associated with the APOE ε4 allele. To date, seven genome-wide association studies (GWAS) have been conducted in East Asians, which report a total of 26 AD-associated loci. Several rare variants, including the p.H157Y variant in TREM2, and the p.G186R and p.R274W variants in SHARPIN are associated with risk of AD in East Asians. Extending genetic studies to diverse populations, including East Asians is necessary, which could yield more comprehensive insights into AD, and here we review the recent findings regarding the genetic determinants of AD from an East Asian perspective.

    DOI: 10.1038/s10038-022-01050-z

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    その他リンク: https://www.nature.com/articles/s10038-022-01050-z

  • Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology. 国際誌

    Koyo Tsujikawa, Kohei Hamanaka, Yuichi Riku, Yuki Hattori, Norikazu Hara, Yohei Iguchi, Shinsuke Ishigaki, Atsushi Hashizume, Satoko Miyatake, Satomi Mitsuhashi, Yu Miyazaki, Mayumi Kataoka, Li Jiayi, Keizo Yasui, Satoshi Kuru, Haruki Koike, Kenta Kobayashi, Naruhiko Sahara, Norio Ozaki, Mari Yoshida, Akiyoshi Kakita, Yuko Saito, Yasushi Iwasaki, Akinori Miyashita, Takeshi Iwatsubo, Takeshi Ikeuchi, Takaki Miyata, Gen Sobue, Naomichi Matsumoto, Kentaro Sahashi, Masahisa Katsuno

    Science advances   8 ( 21 )   eabm5029   2022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)  

    While amyloid-β lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.

    DOI: 10.1126/sciadv.abm5029

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  • Pattern and implications of neurological examination findings in autosomal dominant Alzheimer disease 国際誌

    Jonathan Vöglein, Nicolai Franzmeier, John C Morris, Marianne Dieterich, Eric McDade, Mikael Simons, Oliver Preische, Anna Hofmann, Jason Hassenstab, Tammie L Benzinger, Anne Fagan, James M Noble, Sarah B Berman, Neill R Graff-Radford, Bernardino Ghetti, Martin R Farlow, Jasmeer P Chhatwal, Stephen Salloway, Chengjie Xiong, Celeste M Karch, Nigel Cairns, Richard J Perrin, Gregory Day, Ralph Martins, Raquel Sanchez-Valle, Hiroshi Mori, Hiroyuki Shimada, Takeshi Ikeuchi, Kazushi Suzuki, Peter R Schofield, Colin L Masters, Alison Goate, Virginia Buckles, Nick C Fox, Patricio Chrem, Ricardo Allegri, John M Ringman, Igor Yakushev, Christoph Laske, Mathias Jucker, Günter Höglinger, Randall J Bateman, Adrian Danek, Johannes Levin

    Alzheimer's & dementia : the journal of the Alzheimer's Association   2022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)  

    INTRODUCTION: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD. METHODS: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers. RESULTS: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time. DISCUSSION: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.

    DOI: 10.1002/alz.12684

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  • Autosomal dominant and sporadic late onset Alzheimer disease share a common in vivo pathophysiology. 国際誌

    John C Morris, Michael Weiner, Chengjie Xiong, Laurel Beckett, Dean Coble, Naomi Saito, Paul S Aisen, Ricardo Allegri, Tammie L S Benzinger, Sarah B Berman, Nigel J Cairns, Maria C Carrillo, Helena C Chui, Jasmeer P Chhatwal, Carlos Cruchaga, Anne M Fagan, Martin Farlow, Nick C Fox, Bernardino Ghetti, Alison M Goate, Brian A Gordon, Neill Graff-Radford, Gregory S Day, Jason Hassenstab, Takeshi Ikeuchi, Clifford R Jack, William J Jagust, Mathias Jucker, Johannes Levin, Parinaz Massoumzadeh, Colin L Masters, Ralph Martins, Eric McDade, Hiroshi Mori, James M Noble, Ronald C Petersen, John M Ringman, Stephen Salloway, Andrew J Saykin, Peter R Schofield, Leslie M Shaw, Arthur W Toga, John Q Trojanowski, Jonathan Vöglein, Stacie Weninger, Randall J Bateman, Virginia D Buckles

    Brain : a journal of neurology   2022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)  

    The extent to which the pathophysiology of autosomal dominant Alzheimer disease corresponds to the pathophysiology of "sporadic" late onset Alzheimer disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer disease to late onset Alzheimer disease. We compared brain magnetic resonance imaging and amyloid positron emission tomography data, as well as cerebrospinal fluid concentrations of amyloid-beta-42, amyloid-beta-40, tau, and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer disease from the Dominantly Inherited Alzheimer Network with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and cerebrospinal fluid samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer disease and late onset Alzheimer disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by positron emission tomography was greater after symptomatic onset in autosomal dominant Alzheimer disease than in late onset Alzheimer disease participants, cerebrospinal fluid assays of amyloid-beta-42, amyloid-beta-40, tau, and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer disease and late onset Alzheimer disease, supporting a shared pathobiological construct.

    DOI: 10.1093/brain/awac181

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  • Differences in age at diagnosis of ovarian cancer for each BRCA mutation type in Japan: optimal timing to carry out risk-reducing salpingo-oophorectomy. 国際誌

    Masayuki Sekine, Takayuki Enomoto, Masami Arai, Hiroki Den, Hiroyuki Nomura, Takeshi Ikeuchi, Seigo Nakamura

    Journal of gynecologic oncology   2022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)  

    OBJECTIVE: BRCA1 and BRCA2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) by age 40 and 45, respectively. However, the carriers have a different way of thinking about their life plan. We aimed to investigate the distribution of age at diagnosis of ovarian cancer (OC) patients to examine the optimal timing of RRSO in the carriers. METHODS: We examined a correlation between age at diagnosis of OC and common mutation types in 3,517 probands that received BRCA genetic testing. Among them, germline BRCA1 mutation (gBRCA1m), germline BRCA2 mutation (gBRCA2m) and germline BRCA wild-type (gBRCAwt) were found in 185, 42 and 241 OC patients, respectively. RESULTS: The average age at diagnosis of OC in gBRCA1m and gBRCA2m was 51.3 and 58.3 years, respectively, and the difference from gBRCAwt (53.8 years) was significant. The gBRCA2m carriers did not develop OC under the age of 40. The average age was 50.1 years for L63X and 52.8 years for Q934X in BRCA1, and 55.1 years for R2318X and 61.1 years for STOP1861 in BRCA2. The age at diagnosis in L63X or R2318X carriers was relatively younger than other BRCA1 or BRCA2 carriers, however their differences were not significant. With L63X and R2318X carriers, 89.4% (42/47) and 100% (7/7) of women were able to prevent the development of OC, respectively, when RRSO was performed at age 40. CONCLUSION: There appears to be no difference in the age at diagnosis of OC depending on the type of BRCA common mutation. Further analysis would be needed.

    DOI: 10.3802/jgo.2022.33.e46

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  • Possibility for Prevention of Type 2 Diabetes Mellitus and Dementia Using Three Kinds of Brown Rice Blends after High-Pressure Treatment. 国際誌

    Sumiko Nakamura, Takeshi Ikeuchi, Aki Araki, Kensaku Kasuga, Kenichi Watanabe, Masao Hirayama, Mitsutoshi Ito, Ken'ichi Ohtsubo

    Foods (Basel, Switzerland)   11 ( 6 )   2022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)  

    As it has been reported that type 2 diabetes mellitus increases the risk of Alzheimer's disease, we investigated how to prevent type 2 diabetes and dementia using biofunctional boiled rice. We adopted unpolished super-hard rice (SHBR) for diabetes and wax-free unpolished black rice (WFBBR) for dementia and blended those with ordinary non-polished rice (KBR) (blending ratio 4:4:2), adding 2.5% waxy black rice bran (WBB) and 0.3% rice oil after high-pressure treatment (HPT) (WFBSK) to improve its palatability. This boiled rice is rich in dietary fiber, anthocyanin, free ferulic acid and β-secretase inhibitory activity. A randomized, parallel-group comparison study was conducted for 12 weeks with 24 subjects, using Cognitrax to evaluate their cognitive function primarily. Furthermore, as the secondary purpose, we performed a single-dose test for postprandial blood glucose and insulin secretion at the end of the human intervention test. After 12 weeks, consumers of the WFBSK rice exhibited significant improvement in language memory by cognitive test battery compared with those who consumed the control white rice (p < 0.05). Moreover, subjects who consumed the WFBSK rice had lower insulin secretion levels than those who consumed the control polished rice (p < 0.05).

    DOI: 10.3390/foods11060818

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  • Motor neuron TDP-43 proteinopathy in progressive supranuclear palsy and corticobasal degeneration. 査読 国際誌

    Yuichi Riku, Yasushi Iwasaki, Shinsuke Ishigaki, Akio Akagi, Masato Hasegawa, Kenya Nishioka, Yuanzhe Li, Miho Riku, Takeshi Ikeuchi, Yusuke Fujioka, Hiroaki Miyahara, Jun Sone, Nobutaka Hattori, Mari Yoshida, Masahisa Katsuno, Gen Sobue

    Brain : a journal of neurology   2022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)  

    Transactive response DNA-binding protein 43 kDa (TDP-43) is mislocalized from the nucleus and aggregates within the cytoplasm of affected neurons in amyotrophic lateral sclerosis (ALS) cases. TDP-43 pathology has also been found in brain tissues under non-ALS conditions, suggesting mechanistic links between TDP-43-related ALS (ALS-TDP) and various neurological disorders. This study aimed to assess TDP-43 pathology in the spinal cord motor neurons of tauopathies. We examined 106 spinal cords from consecutively autopsied cases with progressive supranuclear palsy (PSP, n = 26), corticobasal degeneration (CBD, n = 12), globular glial tauopathy (GGT, n = 5), Alzheimer's disease (AD, n = 21), or Pick disease (PiD, n = 6) and neurologically healthy controls (n = 36). Ten of the PSP cases (38%) and seven of the CBD cases (58%) showed mislocalization and cytoplasmic aggregation of TDP-43 in spinal cord motor neurons, which was prominent in the cervical cord. TDP-43-aggregates were found to be skein-like, round-shaped, granular, or dot-like and contained insoluble C-terminal fragments showing blotting pattern of ALS or frontotemporal lobar degeneration (FTLD). The lower motor neurons also showed cystatin-C aggregates, although Bunina bodies were absent in hematoxylin-eosin staining. The spinal cord TDP-43 pathology was often associated with TDP-43 pathology of the primary motor cortex. Positive correlations were shown between the severities of TDP-43 and 4-repeat (4R)-tau aggregates in the cervical cord. TDP-43 and 4R-tau aggregates burdens positively correlated with microglial burden in anterior horn. TDP-43 pathology of spinal cord motor neuron did not develop in an age-dependent manner and was not found in the AD, PiD, GGT, and control groups. Next, we assessed splicing factor proline/glutamine rich (SFPQ) expression in spinal cord motor neurons; SFPQ is a recently-identified regulator of ALS/FTLD pathogenesis, and it is also reported that interaction between SFPQ and fused-in-sarcoma (FUS) regulates splicing of microtubule-associated protein tau exon 10. Immunofluorescent and proximity-ligation assays revealed altered SFPQ/FUS-interactions in the neuronal nuclei of PSP, CBD, and ALS-TDP cases but not in AD, PiD, and GGT cases. Moreover, SFPQ expression was depleted in neurons containing TDP-43 or 4R-tau aggregates of PSP and CBD cases. Our results indicate that PSP and CBD may have properties of systematic motor neuron TDP-43 proteinopathy, suggesting mechanistic links with ALS-TDP. SFPQ dysfunction, arising from altered interaction with FUS, may be a candidate of the common pathway.

    DOI: 10.1093/brain/awac091

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  • PROS1 variant in sudden death case of pulmonary embolism caused by calcification in the inferior vena cava: The importance of postmortem genetic analysis. 国際誌

    Aya Miura, Kazuhisa Funayama, Hiromi Nyuzuki, Naoya Takahashi, Takuma Yamamoto, Akihide Koyama, Takeshi Ikeuchi, Hisakazu Takatsuka, Hajime Nishio

    Legal medicine (Tokyo, Japan)   55   102029 - 102029   2022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)  

    A Japanese man in his 30s died suddenly. Postmortem computed tomography and autopsy revealed a pulmonary embolism from an organizing thrombus in the inferior vena cava as the cause of death. Genomic analysis of congenital thrombophilia-related genes (i.e., SERPINC1, PROC, PROS1, F2, F5, PLG, and MTHFR) revealed a heterozygous variant of PROS1 (p.A139V), which has been reported in patients with congenital protein S deficiency. After a genetic conference that included forensic pathologists, molecular scientists, genetic researchers, genetic clinicians, and clinical physicians, the results of the genetic analysis were explained to the family. Biochemical analyses of protein S (PS) activity and total PS antigen levels were performed with samples from the deceased's family and genetic analysis was not performed until clinical symptoms appear. Herein we demonstrate the importance of genetic background in cases of a sudden death due to pulmonary embolism.

    DOI: 10.1016/j.legalmed.2022.102029

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  • Focal striatal amyloid deposition in Alzheimer's disease caused by APP p.V717I mutation: Longitudinal positron emission tomography study.

    Ryota Kobayashi, Shinobu Kawakatsu, Hiroshi Hayashi, Daichi Morioka, Norikazu Hara, Takeshi Ikeuchi, Koichi Otani

    Geriatrics & gerontology international   2022年2月

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    記述言語:英語  

    DOI: 10.1111/ggi.14361

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  • Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. 国際誌

    Sadequl Islam, Yang Sun, Yuan Gao, Tomohisa Nakamura, Arshad Ali Noorani, Tong Li, Philip C Wong, Noriyuki Kimura, Etsuro Matsubara, Kensaku Kasuga, Takeshi Ikeuchi, Taisuke Tomita, Kun Zou, Makoto Michikawa

    The Journal of neuroscience : the official journal of the Society for Neuroscience   42 ( 8 )   1574 - 1586   2022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)  

    Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β (Aβ) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aβ, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENT Familial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-β 42 (Aβ42)/Aβ40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aβ clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretion in vitro and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.

    DOI: 10.1523/JNEUROSCI.2039-21.2021

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  • Efficacy of BRAF inhibitor and anti-EGFR antibody in colorectal neuroendocrine carcinoma.

    Mae Nakano, Yoshifumi Shimada, Yoshifumi Matsumoto, Takuro Saiki, Qiliang Zhou, Kenta Sasaki, Masato Moriyama, Kosuke Yoshihara, Manabu Natsumeda, Yoko Kuriyama, Yasumasa Takii, Gen Watanabe, Hajime Umezu, Shujiro Okuda, Takeshi Ikeuchi, Toshifumi Wakai, Yasuo Saijo

    Clinical journal of gastroenterology   2022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)  

    Neuroendocrine neoplasms of the colon and rectum are colorectal epithelial neoplasms with neuroendocrine differentiation. A platinum regimen used for small cell lung cancer is the currently recommended chemotherapy for gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), regardless of the organ. The BRAF V600E mutation has been recently reported as a druggable driver mutation in colorectal NECs. In BRAF V600E mutant colorectal cancer, a combination of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody, with or without a MEK inhibitor, is recommended. Here, we report the case of 77-year-old man who had lymph node recurrence after surgery for primary ascending colonic NEC. Two cytotoxic regimens, cisplatin plus irinotecan and modified FOLFOX6, were administered as first- and second-line chemotherapies with no remarkable response observed. At this point, genetic analysis confirmed the tumor harbored a BRAF V600E mutation. Thus, a regimen of BRAF inhibitor plus anti-EGFR antibody was administered. After commencing this regimen, carcinoembryonic antigen levels decreased within normal range, and there was dramatic shrinkage of the lymph node metastases observed by chest and abdominal computed tomography scans. To our knowledge, this is the first reported case of a colorectal NEC responding to a BRAF inhibitor and anti-EGFR antibody.

    DOI: 10.1007/s12328-022-01599-4

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  • Four Swedish cases of CSF1R-related leukoencephalopathy: Visualization of clinical phenotypes. 国際誌

    Igal Rosenstein, Oluf Andersen, Daniel Victor, Elisabet Englund, Tobias Granberg, Carola Hedberg-Oldfors, Katarina Jood, Yusran Ady Fitrah, Takeshi Ikeuchi, Virginija Danylaité Karrenbauer

    Acta neurologica Scandinavica   2022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)  

    Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rare, genetic disease caused by heterozygous mutations in the CSF1R gene with rapidly progressive neurodegeneration, behavioral, cognitive, motor disturbances. OBJECTIVE: To describe four cases of CSF1R-related leukoencephalopathy from three families with two different pathogenic mutations in the tyrosine kinase domain of CSF1R and to develop an integrated presentation of inter-individual diversity of clinical presentations. METHODS: This is an observational study of a case series. Patients diagnosed with CSF1R encephalopathy were evaluated with standardized functional estimation scores and subject to analysis of cerebrospinal fluid biomarkers. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were evaluated. We performed a functional phosphorylation assay to confirm the dysfunction of mutated CSF1R protein. RESULTS: Two heterozygous missense mutations in the CSF1R gene were identified, c.2344C>T; p.Arg777Trp and c.2329C>T; p.Arg782Cys. A phosphorylation assay in vitro showed markedly reduced autophosphorylation in cells expressing mutations. According to ACMG criteria, both mutations were pathogenic. A radiological investigation revealed typical white matter lesions in all cases. There was inter-individual diversity in the loss of cognitive, motor-neuronal, and extrapyramidal functions. CONCLUSIONS: Including the present cases, currently three CSF1R mutations are known in Sweden. We present a visualization tool to describe the clinical diversity, with potential use for longitudinal follow-up for this and other leukoencephalopathies.

    DOI: 10.1111/ane.13589

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  • Development of a Novel Nutrition-Related Multivariate Biomarker for Mild Cognitive Impairment Based on the Plasma Free Amino Acid Profile. 国際誌

    Takeshi Ikeuchi, Yuki Yano, Wataru Sato, Fumiyoshi Morikawa, Shuta Toru, Chika Nishimura, Nobuhiko Miyazawa, Yasuko Kuroha, Ryoko Koike, Shin Tanaka, Kumiko Utsumi, Kensaku Kasuga, Takayoshi Tokutake, Kenjiro Ono, Satoshi Yano, Satoshi Naruse, Ryuji Yajima, Tadanori Hamano, Yuri Yokoyama, Akihiko Kitamura, Eiji Kaneko, Minoru Yamakado, Kenji Nagao

    Nutrients   14 ( 3 )   2022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)  

    Nutritional epidemiology has shown the importance of protein intake for maintaining brain function in the elderly population. Mild cognitive impairment (MCI) may be associated with malnutrition, especially protein intake. We explored blood-based biomarkers linking protein nutritional status with MCI in a multicenter study. In total, 219 individuals with MCI (79.5 ± 5.7 year) from 10 institutions and 220 individuals who were cognitively normal (CN, 76.3 ± 6.6 year) in four different cities in Japan were recruited. They were divided into the training (120 MCI and 120 CN) and validation (99 MCI and 100 CN) groups. A model involving concentrations of PFAAs and albumin to discriminate MCI from CN individuals was constructed by multivariate logistic regression analysis in the training dataset, and the performance was evaluated in the validation dataset. The concentrations of some essential amino acids and albumin were significantly lower in MCI group than CN group. An index incorporating albumin and PFAA discriminated MCI from CN participants with the AUC of 0.705 (95% CI: 0.632-0.778), and the sensitivities at specificities of 90% and 60% were 25.3% and 76.8%, respectively. No significant association with BMI or APOE status was observed. This cross-sectional study suggests that the biomarker changes in MCI group may be associated with protein nutrition.

    DOI: 10.3390/nu14030637

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  • Dissection of the polygenic architecture of neuronal Aβ production using a large sample of individual iPSC lines derived from Alzheimer’s disease patients

    Takayuki Kondo, Norikazu Hara, Satoshi Koyama, Yuichiro Yada, Kayoko Tsukita, Ayako Nagahashi, Takeshi Ikeuchi, Kenji Ishii, Takashi Asada, Tetsuaki Arai, Ryo Yamada, Michael W. Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, John Morris, Leslie M. Shaw, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Beccera, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, John C. Morris, Maria Carroll, Mary L. Creech, Erin Franklin, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, Randall Griffith, David Clark, David Geldmacher, John Brockington, Erik Roberson, Marissa Natelson Love, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Daniel Varon, Maria T. Greig, Peggy Roberts, Marilyn Albert, Chiadi Onyike, Daniel D’Agostino, Stephanie Kielb, James E. Galvin, Brittany Cerbone, Christina A. Michel, Dana M. Pogorelec, Henry Rusinek, Mony J. de Leon, Lidia Glodzik, Susan De Santi, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Ruth A. Mulnard, Gaby Thai, Catherine Mc-Adams-Ortiz, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H. S. Silverman, Po H. Lu, George Bartzokis, Neill R. Graff-Radford, Francine Parfitt, Tracy Kendall, Heather Johnson, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Cynthia Hunt, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Howard Feldman, Benita Mudge, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek Marsel Mesulam, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T.-Y. Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Steven G. Potkin, Adrian Preda, Dana Nguyen, Pierre Tariot, Anna Burke, Nadira Trncic, Adam Fleisher, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Anahita Adeli, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Leslie Gordineer, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Henry Querfurth, Geoffrey Tremont, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Norman Relkin, Gloria Chaing, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Takeshi Iwatsubo, Takashi Asada, Hiroyuki Arai, Morihiro Sugishita, Hiroshi Matsuda, Kengo Ito, Michio Senda, Kenji Ishii, Ryozo Kuwano, Takeshi Ikeuchi, Noriko Sato, Hajime Sato, Shun Shimohama, Masaki Saitoh, Rika Yamauchi, Takashi Hayashi, Seiju Kobayashi, Norihito Nakano, Junichiro Kanazawa, Takeshi Ando, Chiyoko Takanami, Masato Hareyama, Masamitsu Hatakenaka, Eriko Tsukamoto, Shinji Ochi, Mikio Shoji, Etsuro Matsubara, Takeshi Kawarabayashi, Yasuhito Wakasaya, Takashi Nakata, Naoko Nakahata, Shuichi Ono, Yoshihiro Takai, Satoshi Takahashi, Hisashi Yonezawa, Junko Takahashi, Masako Kudoh, Makoto Sasaki, Yutaka Matsumura, Yohsuke Hirata, Tsuyoshi Metoki, Susumu Hayakawa, Yuichi Sato, Masayuki Takeda, Toshiaki Sasaki, Koichiro Sera, Kazunori Terasaki, Yoshihiro Saitoh, Shoko Goto, Kuniko Ueno, Hiromi Sakashita, Kuniko Watanabe, Ken Nagata, Yuichi Sato, Tetsuya Maeda, Yasushi Kondoh, Takashi Yamazaki, Daiki Takano, Mio Miyata, Hiromi Komatsu, Mayumi Watanabe, Tomomi Sinoda, Rena Muraoka, Kayoko Kikuchi, Hitomi Ito, Aki Sato, Toshibumi Kinoshita, Hideyo Toyoshima, Kaoru Sato, Shigeki Sugawara, Isao Ito, Fumiko Kumagai, Hiroyuki Arai, Katsutoshi Furukawa, Masaaki Waragai, Naoki Tomita, Nobuyuki Okamura, Mari Ootsuki, Katsumi Sugawara, Satomi Sugawara, Shunji Mugikura, Atsushi Umetsu, Takanori Murata, Tatsuo Nagasaka, Yukitsuka Kudo, Manabu Tashiro, Shoichi Watanuki, Masatoyo Nishizawa, Takeshi Ikeuchi, Takayoshi Tokutake, Saeri Ishikawa, Emiko Kishida, Nozomi Sato, Mieko Hagiwara, Kumi Yamanaka, Takeyuki Watanabe, Taeko Takasugi, Shoichi Inagawa, Kenichi Naito, Masanori Awaji, Tsutomu Kanazawa, Kouiti Okamoto, Masaki Ikeda, Tsuneo Yamazaki, Yuiti Tasiro, Syunn Nagamine, Shiori Katsuyama, Sathiko Kurose, Sayuri Fukushima, Etsuko Koya, Makoto Amanuma, Noboru Oriuti, Kouiti Ujita, Kazuhiro Kishi, Kazuhisa Tuda, Takashi Asada, Katsuyoshi Mizukami, Tetsuaki Arai, Etsuko Nakajima, Katsumi Miyamoto, Kousaku Saotome, Tomoya Kobayashi, Saori Itoya, Jun Ookubo, Toshiya Akatsu, Yoshiko Anzai, Junya Ikegaki, Yuuichi Katou, Kaori Kimura, Ryou Kuchii, Hajime Saitou, Kazuya Shinoda, Satoka Someya, Hiroko Taguchi, Kazuya Tashiro, Masaya Tanaka, Tatsuya Nemoto, Ryou Wakabayashi, Daisuke Watanabe, Harumasa Takano, Tetsuya Suhara, Hitoshi Shinoto, Hitoshi Shimada, Makoto Higuchi, Takaaki Mori, Hiroshi Ito, Takayuki Obata, Yoshiko Fukushima, Kazuko Suzuki, Izumi Izumida, Katsuyuki Tanimoto, Takahiro Shiraishi, Hitoshi Shinotoh, Hitoshi Shimada, Junko Shiba, Hiroaki Yano, Miki Satake, Aimi Nakui, Yae Ebihara, Tomomi Hasegawa, Yasumasa Yoshiyama, Mami Kato, Yuki Ogata, Hiroyuki Fujikawa, Nobuo Araki, Yoshihiko Nakazato, Takahiro Sasaki, Tomokazu Shimadu, Kimiko Yoshimaru, Hiroshi Matsuda, Etsuko Imabayashi, Asako Yasuda, Etuko Yamamoto, Natsumi Nakamata, Noriko Miyauchi, Keiko Ozawa, Rieko Hashimoto, Taishi Unezawa, Takafumi Ichikawa, Hiroki Hayashi, Masakazu Yamagishi, Tunemichi Mihara, Masaya Hirano, Shinichi Watanabe, Junichiro Fukuhara, Hajime Matsudo, Nobuyuki Saito, Atsushi Iwata, Hisatomo Kowa, Toshihiro Hayashi, Ryoko Ihara, Toji Miyagawa, Mizuho Yoshida, Yuri Koide, Eriko Samura, Kurumi Fujii, Kaori Watanabe, Nagae Orihara, Toshimitsu Momose, Akira Kunimatsu, Harushi Mori, Miwako Takahashi, Takuya Arai, Yoshiki Kojima, Masami Goto, Takeo Sarashina, Syuichi Uzuki, Seiji Katou, Yoshiharu Sekine, Yukihiro Takauchi, Chiine Kagami, Kazutomi Kanemaru, Shigeo Murayama, Yasushi Nishina, Kenji Ishii, Maria Sakaibara, Yumiko Okazaki, Rieko Okada, Maki Obata, Yuko Iwata, Mizuho Minami, Yasuko Hanabusa, Hanae Shingyouji, Kyoko Tottori, Aya Tokumaru, Makoto Ichinose, Kazuya Kume, Syunsuke Kahashi, Kunimasa Arima, Tadashi Tukamoto, Shin Tanaka, Yuko Nagahusa, Masuhiro Sakata, Mitsutoshi Okazaki, Yuko Saito, Maki Yamada, Tiine Kodama, Maki Obata, Tomoko Takeuchi, Keiichiro Ozawa, Yuko Iwata, Hanae Shingyouji, Yasuko Hanabusa, Yoshiko Kawaji, Kyouko Tottori, Noriko Sato, Yasuhiro Nakata, Satoshi Sawada, Makoto Mimatsu, Daisuke Nakkamura, Takeshi Tamaru, Shunichirou Horiuchi, Heii Arai, Tsuneyoshi Ota, Aiko Kodaka, Yuko Tagata, Tomoko Nakada, Eizo Iseki, Kiyoshi Sato, Hiroshige Fujishiro, Norio Murayama, Masaru Suzuki, Satoshi Kimura, Masanobu Takahashi, Haruo Hanyu, Hirofumi Sakurai, Takahiko Umahara, Hidekazu Kanetaka, Kaori Arashino, Mikako Murakami, Ai Kito, Seiko Miyagi, Kaori Doi, Kazuyoshi Sasaki, Mineo Yamazaki, Akiko Ishiwata, Yasushi Arai, Akane Nogami, Sumiko Fukuda, Kyouko Tottori, Mizuho Minami, Yuko Iwata, Koichi Kozaki, Yukiko Yamada, Sayaka Kimura, Ayako Machida, Kuninori Kobayashi, Hidehiro Mizusawa, Nobuo Sanjo, Mutsufusa Watanabe, Takuya Ohkubo, Hiromi Utashiro, Yukiko Matsumoto, Kumiko Hagiya, Yoshiko Miyama, Takako Shinozaki, Haruko Hiraki, Hitoshi Shibuya, Isamu Ohashi, Akira Toriihara, Shinichi Ohtani, Toshifumi Matsui, Yu Hayasaka, Tomomi Toyama, Hideki Sakurai, Kumiko Sugiura, Hirofumi Taguchi, Shizuo Hatashita, Akari Imuta, Akiko Matsudo, Daichi Wakebe, Hideki Hayakawa, Mitsuhiro Ono, Takayoshi Ohara, Yukihiko Washimi, Yutaka Arahata, Akinori Takeda, Yoko Konagaya, Akiko Yamaoka, Masashi Tsujimoto, Hideyuki Hattori, Takashi Sakurai, Miura Hisayuki, Hidetoshi Endou, Syousuke Satake, Young Jae Hong, Katsunari Iwai, Kenji Yoshiyama, Masaki Suenaga, Sumiko Morita, Teruhiko Kachi, Kenji Toba, Rina Miura, Takiko Kawai, Ai Honda, Kengo Itou, Takashi Kato, Ken Fujiwara, Rikio Katou, Mariko Koyama, Naohiko Fukaya, Akira Tsuji, Hitomi Shimizu, Hiroyuki Fujisawa, Tomoko Nakazawa, Satoshi Koyama, Takanori Sakata, Masahito Yamada, Mitsuhiro Yoshita, Miharu Samuraki, Kenjiro Ono, Moeko Shinohara, Yuki Soshi, Kozue Niwa, Chiaki Doumoto, Mariko Hata, Miyuki Matsushita, Mai Tsukiyama, Nozomi Takeda, Sachiko Yonezawa, Ichiro Matsunari, Osamu Matsui, Fumiaki Ueda, Yasuji Ryu, Masanobu Sakamoto, Yasuomi Ouchi, Yasuomi Ouchi, Madoka Chita, Yumiko Fujita, Rika Majima, Hiromi Tsubota, Umeo Shirasawa, Masashi Sugimori, Wataru Ariya, Yuuzou Hagiwara, Yasuo Tanizaki, Hidenao Fukuyama, Ryosuke Takahashi, Hajime Takechi, Chihiro Namiki, Kengo Uemura, Takeshi Kihara, Hiroshi Yamauchi, Shizuko Tanaka-Urayama, Emiko Maeda, Natsu Saito, Shiho Satomi, Konomi Kabata, Shin-Ichi Urayama, Tomohisa Okada, Koichi Ishizu, Shigeto Kawase, Satoshi Fukumoto, Masanori Nakagawa, Takahiko Tokuda, Masaki Kondo, Fumitoshi Niwa, Toshiki Mizuno, Yoko Oishi, Mariko Yamazaki, Daisuke Yamaguchi, Kyoko Ito, Yoku Asano, Chizuru Hamaguchi, Kei Yamada, Chio Okuyama, Kentaro Akazawa, Shigenori Matsushima, Takamasa Matsuo, Toshiaki Nakagawa, Takeshi Nii, Takuji Nishida, Kuniaki Kiuchi, Masami Fukusumi, Hideyuki Watanabe, Toshiaki Taoka, Akihiro Nogi, Masatoshi Takeda, Toshihisa Tanaka, Naoyuki Sato, Hiroaki Kazui, Kenji Yoshiyama, Takashi Kudo, Masayasu Okochi, Takashi Morihara, Shinji Tagami, Noriyuki Hayashi, Masahiko Takaya, Tamiki Wada, Mikiko Yokokoji, Hiromichi Sugiyama, Daisuke Yamamoto, Shuko Takeda, Keiko Nomura, Mutsumi Tomioka, Eiichi Uchida, Yoshiyuki Ikeda, Mineto Murakami, Takami Miki, Hiroyuki Shimada, Suzuka Ataka, Motokatsu Kanemoto, Jun Takeuchi, Akitoshi Takeda, Rie Azuma, Yuki Iwamoto, Naomi Tagawa, Junko Masao, Yuka Matsumoto, Yuko Kikukawa, Hisako Fujii, Junko Matsumura, Susumu Shiomi, Joji Kawabe, Yoshihiro Shimonishi, Yukio Miki, Mitsuji Higashida, Tomohiro Sahara, Takashi Yamanaga, Shinichi Sakamoto, Hiroyuki Tsushima, Kiyoshi Maeda, Yasuji Yamamoto, Toshio Kawamata, Kazuo Sakai, Haruhiko Oda, Takashi Sakurai, Taichi Akisaki, Mizuho Adachi, Masako Kuranaga, Sachi Takegawa, Yoshihiko Tahara, Seishi Terada, Takeshi Ishihara, Hajime Honda, Osamu Yokota, Yuki Kishimoto, Naoya Takeda, Nao Imai, Mayumi Yabe, Kentaro Ida, Daigo Anami, Seiji Inoue, Toshi Matsushita, Reiko Wada, Shinsuke Hiramatsu, Hiromi Tonbara, Reiko Yamamoto, Kenji Nakashima, Kenji Wada-Isoe, Saori Yamasaki, Eijiro Yamashita, Yu Nakamura, Ichiro Ishikawa, Sonoko Danjo, Tomomi Shinohara, Miyuki Ueno, Yuka Kashimoto, Yoshihiro Nishiyama, Yuka Yamamoto, Narihide Kimura, Kazuo Ogawa, Yasuhiro Sasakawa, Takashi Ishimori, Yukito Maeda, Tatsuo Yamada, Shinji Ouma, Aika Fukuhara-Kaneumi, Nami Sakamoto, Rie Nagao, Kengo Yoshimitsu, Yasuo Kuwabara, Ryuji Nakamuta, Minoru Tanaka, Manabu Ikeda, Mamoru Hashimoto, Keiichirou Kaneda, Yuusuke Yatabe, Kazuki Honda, Naoko Ichimi, Fumi Akatuka, Mariko Morinaga, Miyako Noda, Mika Kitajima, Toshinori Hirai, Shinya Shiraishi, Naoji Amano, Shinsuke Washizuka, Toru Takahashi, Shin Inuzuka, Tetsuya Hagiwara, Nobuhiro Sugiyama, Yatsuka Okada, Tomomi Ogihara, Takehiko Yasaki, Minori Kitayama, Tomonori Owa, Akiko Ryokawa, Rie Takeuchi, Satoe Goto, Keiko Yamauchi, Mie Ito, Tomoki Kaneko, Hitoshi Ueda, Shuichi Ikeda, Masaki Takao, Ban Mihara, Hirofumi Kubo, Akiko Takano, Gou Yasui, Masami Akuzawa, Kaori Yamaguchi, Toshinari Odawara, Megumi Shimamura, Mikiko Sugiyama, Atsushi Watanabe, Naomi Oota, Shigeo Takebayashi, Yoshigazu Hayakawa, Mitsuhiro Idegawa, Noriko Toya, Kazunari Ishii, Haruhisa Inoue

    Nature Aging   2 ( 2 )   125 - 139   2022年2月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    DOI: 10.1038/s43587-021-00158-9

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    その他リンク: https://www.nature.com/articles/s43587-021-00158-9

  • Correlation between the risk of ovarian cancer and BRCA recurrent pathogenic variants in Japan. 国際誌

    Masayuki Sekine, Takayuki Enomoto, Masami Arai, Shiro Yokoyama, Hiroyuki Nomura, Koji Nishino, Takeshi Ikeuchi, Yoko Kuriyama, Seigo Nakamura

    Journal of human genetics   2022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)  

    We previously reported that L63X and Q934X are BRCA1 common founder variants in Japan. So far, there have been no reports of a correlation between such BRCA common variants and the risk of BRCA-related cancers. In this analysis, we investigated the correlation between the risk of ovarian cancer (OC) and BRCA recurrent pathogenic variants. We examined the database of the Japanese organization of hereditary breast and ovarian cancer. The database contained 3517 probands who underwent BRCA genetic testing. Among them, 11.1% (392/3517) had germline BRCA1 pathogenic variant, and 8.3% (293/3517) had BRCA2 pathogenic variant. We calculated the OC prevalence, breast cancer (BC) prevalence, and the ratio of OC to BC within second-degree relatives. The ratio of OC to BC in Q934X family members was significantly higher than that in the overall BRCA1 family members (0.80 vs.0.52: p = 0.038), and the ratio in STOP799 was 0.42, which was relatively lower than the overall BRCA1 value. Both Q934X and STOP799 are located in the ovarian cancer cluster region (OCCR), however there seems to be a difference in the risk of OC. R2318X family members had a significant higher ratio of OC to BC at 0.32 than the overall BRCA2 value of 0.13 (p = 0.012). R2318X is known to be located in the OCCR. This is the first report to investigate the correlation between BRCA recurrent variants and the risk of OC in Japan. The family members of probands with Q934X or R2318X have a higher risk of OC than that with other BRCA variants.

    DOI: 10.1038/s10038-021-01002-z

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  • White Matter Lesions May Aid in Differentiating Idiopathic Normal Pressure Hydrocephalus and Alzheimer's Disease. 国際誌

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

    Journal of Alzheimer's disease : JAD   85 ( 2 )   851 - 862   2022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 often misdiagnosed as Alzheimer's disease (AD) due to overlapping pathophysiology and similar imaging characteristics, including ventricular enlargement and increased white matter lesions (WMLs). OBJECTIVE: To compare the extent and distribution of WMLs directly between iNPH and AD and examine the association with underlying pathophysiology. METHODS: Twelve patients with iNPH (mean age: 78.08 years; 5 females), 20 with AD (mean age: 75.40 years; 13 females), and 10 normal cognition (NC) participants (mean age: 76.60 years; 7 females) were recruited. The extent and distribution of WMLs and the lateral ventricular volume (LV-V) were evaluated on MRI using voxel-based morphometry analysis. Concentrations of cerebrospinal fluid biomarkers, such as amyloid-β protein (Aβ)42, Aβ40, Aβ38, and tau species, were also measured. Risk factors for small vessel disease (SVD) were assessed by blood examination and medical records. RESULTS: The periventricular WML volume (PWML-V) and deep WML volume (DWML-V) were significantly larger in iNPH than in AD and NC. The DWML-V was dominant in iNPH, while the PWML-V was dominant in AD and NC. GM-V was significantly smaller in AD than in iNPH and NC. The LV-V positively correlated with WML-V in all participants. There was a significant negative correlation between LV-V and Aβ38 in iNPH. Furthermore, there was no significant difference in SVD risk factors between the groups. CONCLUSION: The differences in the extent and distribution of WMLs between iNPH and AD, especially predominance of DWML-V over PWML-V in iNPH, may reflect decreased fluid and Aβ clearance.

    DOI: 10.3233/JAD-215187

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  • Clinical application of CSF biomarkers for Alzheimer's disease: From rationale to ratios. 国際誌

    Femke H Bouwman, Giovanni B Frisoni, Sterling C Johnson, Xiaochun Chen, Sebastiaan Engelborghs, Takeshi Ikeuchi, Claire Paquet, Craig Ritchie, Sasha Bozeat, Frances-Catherine Quevenco, Charlotte Teunissen

    Alzheimer's & dementia (Amsterdam, Netherlands)   14 ( 1 )   e12314   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Biomarker testing is recommended for the accurate and timely diagnosis of Alzheimer's disease (AD). Using illustrative case narratives we consider how cerebrospinal fluid (CSF) biomarker tests may be used in different presentations of cognitive impairment to facilitate timely and differential diagnosis, improving diagnostic accuracy, providing prognostic information, and guiding personalized management in diverse scenarios. Evidence shows that (1) CSF ratios are superior to amyloid beta (Aβ)1-42 alone; (2) concordance of CSF ratios to amyloid positron emission tomography (PET) is better than Aβ1-42 alone; and (3) phosphorylated tau (p-tau)/Aβ1-42 ratio is superior to p-tau alone. CSF biomarkers are recommended for the exclusion of AD as the underlying cause of cognitive impairment, diagnosis of AD at an early stage, differential diagnosis of AD in individuals presenting with other neuropsychiatric symptoms, accurate diagnosis of AD in an atypical presentation, and for clinical trial enrichment. Highlights:  Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker testing may be underused outside specialist centers.CSF biomarkers improve diagnostic accuracy, guiding personalized management of AD.CSF ratios (amyloid beta [Aβ]1-42/Aβ1-40 and phosphorylated tau/Aβ1-42) perform better than single markers.CSF ratios produce fewer false-negative and false-positive results than individual markers.CSF biomarkers should be included in diagnostic work-up of AD and mild cognitive impairment due to AD.

    DOI: 10.1002/dad2.12314

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  • Different AT(N) profiles and clinical progression classified by two different N markers using total tau and neurofilament light chain in cerebrospinal fluid. 国際誌

    Kensaku Kasuga, Masataka Kikuchi, Tamao Tsukie, Kazushi Suzuki, Ryoko Ihara, Atsushi Iwata, Norikazu Hara, Akinori Miyashita, Ryozo Kuwano, Takeshi Iwatsubo, Takeshi Ikeuchi

    BMJ neurology open   4 ( 2 )   e000321   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: The AT(N) classification was proposed for categorising individuals according to biomarkers. However, AT(N) profiles may vary depending on the markers chosen and the target population. Methods: We stratified 177 individuals who participated in the Japanese Alzheimer's Disease Neuroimaging Initiative by AT(N) classification according to cerebrospinal fluid (CSF) biomarkers. We compared the frequency of AT(N) profiles between the classification using total tau and neurofilament light chain (NfL) as N markers (AT(N)tau and AT(N)NfL). Baseline characteristics, and longitudinal biological and clinical changes were examined between AT(N) profiles. Results: We found that 9% of cognitively unimpaired subjects, 49% of subjects with mild cognitive impairment, and 61% of patients with Alzheimer's disease (AD) dementia had the biological AD profile (ie, A+T+) in the cohort. The frequency of AT(N) profiles substantially differed between the AT(N)tau and AT(N)NfL classifications. When we used t-tau as the N marker (AT(N)tau), those who had T- were more frequently assigned to (N)-, whereas those who had T+were more frequently assigned to (N)+ than when we used NfL as the N marker (AT(N)NfL). During a follow-up, the AD continuum group progressed clinically and biologically compared with the normal biomarker group in both the AT(N)tau and AT(N)NfL classifications. More frequent conversion to dementia was observed in the non-AD pathological change group in the AT(N)tau classification, but not in the AT(N)NfL classification. Conclusions: AT(N)tau and AT(N)NfL in CSF may capture different aspects of neurodegeneration and provide a different prognostic value. The AT(N) classification aids in understanding the AD continuum biology in various populations.

    DOI: 10.1136/bmjno-2022-000321

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  • Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview. 国際誌

    Constance Delaby, Charlotte E Teunissen, Kaj Blennow, Daniel Alcolea, Ivan Arisi, Elodie Bouaziz Amar, Anne Beaume, Aurélie Bedel, Giovanni Bellomo, Edith Bigot-Corbel, Maria Bjerke, Marie-Céline Blanc-Quintin, Mercè Boada, Olivier Bousiges, Miles D Chapman, Mari L DeMarco, Mara D'Onofrio, Julien Dumurgier, Diane Dufour-Rainfray, Sebastiaan Engelborghs, Hermann Esselmann, Anne Fogli, Audrey Gabelle, Elisabetta Galloni, Clémentine Gondolf, Frédérique Grandhomme, Oriol Grau-Rivera, Melanie Hart, Takeshi Ikeuchi, Andreas Jeromin, Kensaku Kasuga, Ashvini Keshavan, Michael Khalil, Peter Körtvelyessy, Agnieszka Kulczynska-Przybik, Jean-Louis Laplanche, Piotr Lewczuk, Qiao-Xin Li, Alberto Lleó, Catherine Malaplate, Marta Marquié, Colin L Masters, Barbara Mroczko, Léonor Nogueira, Adelina Orellana, Markus Otto, Jean-Baptiste Oudart, Claire Paquet, Federico Paolini Paoletti, Lucilla Parnetti, Armand Perret-Liaudet, Katell Peoc'h, Koen Poesen, Albert Puig-Pijoan, Isabelle Quadrio, Muriel Quillard-Muraine, Benoit Rucheton, Susanna Schraen, Jonathan M Schott, Leslie M Shaw, Marc Suárez-Calvet, Magda Tsolaki, Hayrettin Tumani, Chinedu T Udeh-Momoh, Lucie Vaudran, Marcel M Verbeek, Federico Verde, Lisa Vermunt, Jonathan Vogelgsang, Jens Wiltfang, Henrik Zetterberg, Sylvain Lehmann

    Alzheimer's & dementia : the journal of the Alzheimer's Association   2021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)  

    INTRODUCTION: The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. METHODS: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. RESULTS: The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. DISCUSSION: This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD.

    DOI: 10.1002/alz.12545

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  • Transcriptional downregulation of FAM3C/ILEI in the Alzheimer's brain. 国際誌

    Naoki Watanabe, Masaki Nakano, Yachiyo Mitsuishi, Norikazu Hara, Tatsuo Mano, Atsushi Iwata, Shigeo Murayama, Toshiharu Suzuki, Takeshi Ikeuchi, Masaki Nishimura

    Human molecular genetics   31 ( 1 )   122 - 132   2021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)  

    Amyloid-β (Aβ) accumulation in the brain triggers the pathogenic cascade for Alzheimer's disease (AD) development. The secretory protein FAM3C (also named ILEI) is a candidate for an endogenous suppressor of Aβ production. In this study, we found that FAM3C expression was transcriptionally downregulated in the AD brain. To determine the transcriptional mechanism of the human FAM3C gene, we delineated the minimal 5'-flanking sequence required for basal promoter activity. From a database search for DNA-binding motifs, expression analysis using cultured cells, and promoter DNA-binding assays, we identified SP1 and EBF1 as candidate basal transcription factors for FAM3C, and found that SMAD1 was a putative inducible transcription factor and KLF6 was a transcription repressor for FAM3C. Genomic deletion of the basal promoter sequence from HEK293 and Neuro-2a cells markedly reduced endogenous expression of FAM3C and abrogated SP1- or EBF1-mediated induction of FAM3C. Nuclear protein extracts from AD brains contained lower levels of SP1 and EBF1 than did those from control brains, although the relative mRNA levels of these factors did not differ significantly between the groups. Additionally, the ability of nuclear SP1 and EBF1 in AD brains to bind with the basal promoter sequence-containing DNA probe was reduced compared with the binding ability of these factors in control brains. Thus, the transcriptional downregulation of FAM3C in the AD brain is attributable to the reduced nuclear levels and genomic DNA binding of SP1 and EBF1. An expressional decline in FAM3C may be a risk factor for Aβ accumulation and eventually AD development.

    DOI: 10.1093/hmg/ddab226

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  • Brain TDP-43 pathology in corticobasal degeneration: Topographical correlation with neuronal loss. 国際誌

    Makoto Sainouchi, Mari Tada, Yusran Ady Fitrah, Norikazu Hara, Kou Tanaka, Jiro Idezuka, Izumi Aida, Takashi Nakajima, Akinori Miyashita, Kohei Akazawa, Takeshi Ikeuchi, Osamu Onodera, Akiyoshi Kakita

    Neuropathology and applied neurobiology   e12786   2021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)  

    AIMS: Neuronal and glial inclusions comprising transactive response DNA-binding protein of 43 kDa (TDP-43) have been identified in the brains of patients with corticobasal degeneration (CBD), and a possible correlation between the presence of these inclusions and clinical phenotypes has been speculated. However, the significance of TDP-43 pathology in the pathomechanism of CBD has remained unclear. Here, we investigated the topographical relationship between TDP-43 inclusions and neuronal loss in CBD. METHODS: We estimated semi-quantitatively neuronal loss and TDP-43 pathology in the form of neuronal cytoplasmic inclusions (NCIs), astrocytic inclusions (AIs), oligodendroglial cytoplasmic inclusions (GCIs), and dystrophic neurites in 22 CNS regions in 10 patients with CBD. Then, the degree of correlation between the severity of neuronal loss and the quantity of each type of TDP-43 inclusion was assessed. We also investigated tau pathology in a similar manner. RESULTS: TDP-43 pathology was evident in nine patients. The putamen and globus pallidus were the regions most frequently affected (80%). NCIs were the most prominent form, and their quantity was significantly correlated with the severity of neuronal loss in more than half of the regions examined. The quantities of TDP-43 NCIs and tau NCIs were correlated in only a few regions. The number of regions where the quantities of TDP-43 AIs and GCIs were correlated with the severity of neuronal loss was apparently small in comparison with that of NCIs. CONCLUSIONS: TDP-43 alterations in neurons, not closely associated with tau pathology, may be involved in the pathomechanism underlying neuronal loss in CBD. There was a significant topographical correlation between neuronal cytoplasmic aggregation of TDP-43 and neuronal loss in CBD, suggesting that TDP-43 protein aberration might be associated with neuronal degeneration in CBD. There was no close correlation between the burden of TDP-43 and that of tau in neurons.

    DOI: 10.1111/nan.12786

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  • Neuronal Intranuclear Inclusion Disease Presenting with Voice Tremor

    Tomone Taneda, Masato Kanazawa, Yo Higuchi, Hironori Baba, Aiko Isami, Masahiro Uemura, Takuya Konno, Arata Horii, Takeshi Ikeuchi, Osamu Onodera

    Movement Disorders Clinical Practice   2021年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1002/mdc3.13382

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  • A functional variant of SHARPIN confers increased risk of late-onset Alzheimer's disease. 国際誌

    Yuya Asanomi, Daichi Shigemizu, Shintaro Akiyama, Akinori Miyashita, Risa Mitsumori, Norikazu Hara, Takeshi Ikeuchi, Shumpei Niida, Kouichi Ozaki

    Journal of human genetics   2021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)  

    Late-onset Alzheimer's disease (LOAD) is the most common form of dementia, and its pathogenesis is multifactorial. We previously reported a rare functional variant of SHARPIN (rs572750141, NP_112236.3:p.Gly186Arg) that was significantly associated with LOAD. In addition, several recent studies have suggested the potential role of SHARPIN in AD pathogenesis. In this study, we sought to identify additional functional variants of SHARPIN in Japanese population. Six highly deleterious variants of SHARPIN, comprising four missense variants, one frameshift variant, and one stop-gain variant were detected from whole-genome sequencing data for 180 patients with LOAD and 184 with mild cognitive impairment. One of these candidate variants (rs77359862, NP_112236.3:p.Arg274Trp) was significantly associated with an increased risk of LOAD in 5043 LOAD cases and 11984 controls (P = 0.0016, odds ratio = 1.43). Furthermore, this variant SHARPIN showed aberrant cellular localization and reduced the activation of NF-κB, a central mediator of inflammatory and immune responses. Further investigation of the physiologic role of SHARPIN may reveal the mechanism of onset of LOAD.

    DOI: 10.1038/s10038-021-00987-x

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  • Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. 国際誌

    Nobuto Kakuda, Mako Takami, Masayasu Okochi, Kensaku Kasuga, Yasuo Ihara, Takeshi Ikeuchi

    Translational psychiatry   11 ( 1 )   558 - 558   2021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)  

    Presenilin (PS) with a genetic mutation generates abundant β-amyloid protein (Aβ) 43. Senile plaques are formed by Aβ43 in the cerebral parenchyma together with Aβ42 at middle ages. These brains cause the early onset of Alzheimer's disease (AD), which is known as familial Alzheimer's disease (FAD). Based on the stepwise processing model of Aβ generation by γ-secretase, we reassessed the levels of Aβs in the cerebrospinal fluid (CSF) of FAD participants. While low levels of Aβ38, Aβ40, and Aβ42 were generated in the CSF of FAD participants, the levels of Aβ43 were unchanged in some of them compared with other participants. We sought to investigate why the level of Aβ43 was unchanged in FAD participants. These characteristics of Aβ generation were observed in the γ-secretase assay in vitro using cells, which express FAD mutations in PS1. Aβ38 and Aβ40 generation from their precursors, Aβ42 and Aβ43, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF. Both the ratios of Aβ38/Aβ42 and Aβ40/Aβ43 in PS1 mutants were lower than those in the WT. However, the ratio of Aβ43/amyloid precursor protein intracellular domain (AICD) increased in the PS1 mutants in an onset age dependency, while other Aβ/AICD ratios were decreased or unchanged. Importantly, liquid chromatography-mass spectrometry found that the generation of Aβ43 was stimulated from Aβ48 in PS1 mutants. This result indicates that PS1 mutants switched the Aβ43 generating line, which reflects the level of Aβ43 in the CSF and forming senile plaques.

    DOI: 10.1038/s41398-021-01684-1

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  • Structure-based classification of tauopathies. 国際誌

    Yang Shi, Wenjuan Zhang, Yang Yang, Alexey G Murzin, Benjamin Falcon, Abhay Kotecha, Mike van Beers, Airi Tarutani, Fuyuki Kametani, Holly J Garringer, Ruben Vidal, Grace I Hallinan, Tammaryn Lashley, Yuko Saito, Shigeo Murayama, Mari Yoshida, Hidetomo Tanaka, Akiyoshi Kakita, Takeshi Ikeuchi, Andrew C Robinson, David M A Mann, Gabor G Kovacs, Tamas Revesz, Bernardino Ghetti, Masato Hasegawa, Michel Goedert, Sjors H W Scheres

    Nature   598 ( 7880 )   359 - 363   2021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)  

    The ordered assembly of tau protein into filaments characterizes several neurodegenerative diseases, which are called tauopathies. It was previously reported that, by cryo-electron microscopy, the structures of tau filaments from Alzheimer's disease1,2, Pick's disease3, chronic traumatic encephalopathy4 and corticobasal degeneration5 are distinct. Here we show that the structures of tau filaments from progressive supranuclear palsy (PSP) define a new three-layered fold. Moreover, the structures of tau filaments from globular glial tauopathy are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs, instead resembling the four-layered fold of corticobasal degeneration. The AGD fold is also observed in ageing-related tau astrogliopathy. Tau protofilament structures from inherited cases of mutations at positions +3 or +16 in intron 10 of MAPT (the microtubule-associated protein tau gene) are also identical to those from AGD, suggesting that relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, the structures of tau filaments from cases of familial British dementia and familial Danish dementia are the same as those from cases of Alzheimer's disease and primary age-related tauopathy. These findings suggest a hierarchical classification of tauopathies on the basis of their filament folds, which complements clinical diagnosis and neuropathology and also allows the identification of new entities-as we show for a case diagnosed as PSP, but with filament structures that are intermediate between those of globular glial tauopathy and PSP.

    DOI: 10.1038/s41586-021-03911-7

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  • 正常圧水頭症とアルツハイマー型認知症の大脳白質病変の比較

    黒田 岳志, 松岡 馨, イズデプスキ 彬子, 久保田 怜美, 渡辺 慶子, 森 友紀子, 二村 明徳, 春日 健作, 池内 健, 小野 賢二郎

    Dementia Japan   35 ( 4 )   644 - 644   2021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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  • 血清BDNFのアルツハイマー病のバイオマーカーの可能性

    森 友紀子, 辻 まゆみ, 小口 達敬, 春日 健作, 木村 篤史, 二村 明徳, 杉本 あずさ, 笠井 英世, 黒田 岳志, 矢野 怜, 稗田 宗太郎, 木内 祐二, 池内 健, 小野 賢二郎

    Dementia Japan   35 ( 4 )   618 - 618   2021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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  • ApoE分泌におけるプレセニリンの制御作用

    Sadequl Islam, 孫 陽, 高 原, 中村 知寿, 木村 成志, 松原 悦郎, 春日 健作, 池内 健, 富田 泰輔, 鄒 鶤, 道川 誠

    Dementia Japan   35 ( 4 )   651 - 651   2021年10月

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    記述言語:英語   出版者・発行元:(一社)日本認知症学会  

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  • 神経核内封入体病(NIID)におけるNOTCH2NLCリピート伸長と臨床的特徴の検討

    樋口 陽, 原 範和, Yusran Ady Fitrah, 種田 朝音, 徳武 孝允, 三浦 健, 岩淵 洋平, 五十嵐 修一, 林 秀樹, 石黒 敬信, 三瓶 一弘, 武田 勇人, 高橋 俊昭, 金澤 雅人, 宮下 哲典, 小野寺 理, 池内 健

    Dementia Japan   35 ( 4 )   612 - 612   2021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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  • ApoE分泌におけるプレセニリンの制御作用

    Sadequl Islam, 孫 陽, 高 原, 中村 知寿, 木村 成志, 松原 悦郎, 春日 健作, 池内 健, 富田 泰輔, 鄒 鶤, 道川 誠

    Dementia Japan   35 ( 4 )   651 - 651   2021年10月

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    記述言語:英語   出版者・発行元:(一社)日本認知症学会  

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  • A Novel Heterozygous Missense Variant in the CIAO1 Gene in a Family with Alzheimer's Disease: The Val67Ile Variant Promotes the Interaction of CIAO1 and Amyloid-β Protein Precursor. 国際誌

    Haitian Nan, Yeon-Jeong Kim, Mai Tsuchiya, Toko Fukao, Noriko Hara, Atsushi Hagihara, Kenya Nishioka, Nobutaka Hattori, Norikazu Hara, Takeshi Ikeuchi, Toshihisa Ohtsuka, Yoshihisa Takiyama

    Journal of Alzheimer's disease : JAD   84 ( 2 )   599 - 605   2021年9月

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    記述言語:英語  

    Familial dementia is a rare inherited disease involving progressive impairment of memory, thinking, and behavior. We report a novel heterozygous pathogenic variant (c.199G > A, p.Val67Ile) in the CIAO1 gene that appears to be co-segregated with Alzheimer's disease in a Japanese family. Biochemical analysis of CIAO1 protein revealed that the variant increases the interaction of CIAO1 with immature amyloid-β protein precursor (AβPP), but not mature or soluble AβPP, indicating plausible CIAO1 involvement in AβPP processing. Our study indicates that a heterozygous variant in the CIAO1 gene may be closely related to autosomal dominant familial dementia.

    DOI: 10.3233/JAD-210706

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  • Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex. 国際誌

    Yuka Koike, Akihiro Sugai, Norikazu Hara, Junko Ito, Akio Yokoseki, Tomohiko Ishihara, Takuma Yamagishi, Shintaro Tsuboguchi, Mari Tada, Takeshi Ikeuchi, Akiyoshi Kakita, Osamu Onodera

    Communications biology   4 ( 1 )   1107 - 1107   2021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)  

    In amyotrophic lateral sclerosis (ALS), TAR DNA-binding protein 43 (TDP-43), which is encoded by TARDBP, forms aggregates in the motor cortex. This aggregate formation may be triggered by an increase in the TDP-43 level with aging. However, the amount of TDP-43 is autoregulated by alternative splicing of the TARDBP 3'UTR, and how this autoregulation is affected by aging remains to be elucidated. We found that DNA demethylation in the autoregulatory region in the TARDBP 3'UTR reduced alternative splicing and increased TARDBP mRNA expression. Furthermore, in the human motor cortex, we found that this region was demethylated with aging, resulting in increased expression of TARDBP mRNA. The acceleration of DNA demethylation in the motor cortex was associated with the age of ALS onset. In summary, the dysregulation of TDP-43 autoregulation by age-related DNA demethylation in the motor cortex may explain the contribution of aging and motor system selectivity in ALS.

    DOI: 10.1038/s42003-021-02621-0

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  • An autopsied FTDP-17 case with MAPT IVS 10 + 14C > T mutation presenting with frontotemporal dementia. 国際誌

    Ryohei Watanabe, Ito Kawakami, Takeshi Ikeuchi, Shigeo Murayama, Tetsuaki Arai, Haruhiko Akiyama, Mitsumoto Onaya, Masato Hasegawa

    eNeurologicalSci   24   100363 - 100363   2021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)  

    •We report the immunohistochemical and biochemical features of an FTDP-17 case with MAPT IVS 10 + 14C > T mutation.•Postmortem examination of the patient with bvFTD revealed diffuse neuronal and glial 4-repeat tau pathology similar to CBD.•The structure of tau filaments associated with MAPT IVS 10 + 14C > T mutation was characterized by electron microscopy.

    DOI: 10.1016/j.ensci.2021.100363

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  • 多系統萎縮症における脳脊髄液中NG2と臨床症状の検討

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

    臨床神経学   61 ( Suppl. )   S304 - S304   2021年9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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  • 【疾患修飾薬開発の基盤構築:TRC(Trial-ready cohort)と国際連携】DIAN Japan研究とゲノム医療

    池内 健, 井原 涼子

    Dementia Japan   35 ( 3 )   408 - 417   2021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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  • Genetic Variations and Neuropathologic Features of Patients with PRKN Mutations. 国際誌

    Naohiko Seike, Akio Yokoseki, Ryoko Takeuchi, Kento Saito, Hiroaki Miyahara, Akinori Miyashita, Tetsuhiko Ikeda, Izumi Aida, Takashi Nakajima, Masato Kanazawa, Masatoshi Wakabayashi, Yasuko Toyoshima, Hitoshi Takahashi, Riki Matsumoto, Tatsushi Toda, Osamu Onodera, Atsushi Ishikawa, Takeshi Ikeuchi, Akiyoshi Kakita

    Movement disorders : official journal of the Movement Disorder Society   36 ( 7 )   1634 - 1643   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Mutations in PRKN are the most common cause of autosomal recessive juvenile parkinsonism. The objective of this study was to investigate the association between genotype and pathology in patients with PRKN mutations. METHODS: We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients. RESULTS: All the patients harbored biallelic PRKN mutations. Two patients were homozygous and heterozygous, respectively, for the missense mutation p.C431F. Seven patients had exon rearrangements, including 2 patients from a single family who harbored a homozygous deletion of exon 4, and 3 patients who carried a homozygous duplication of exons 6-7, a homozygous duplication of exons 10-11, and a heterozygous duplication of exons 2-4. In the other 2 patients, we found a compound heterozygous duplication of exon 2, deletion of exon 3, and a heterozygous duplication of exon 2. However, sequencing of cDNA prepared from mRNA revealed 2 different transcripts derived from triplication of exon 2 and deletion of exons 2-3 and from duplication of exons 2-4 and deletion of exons 3-4. Western blotting and immunohistochemistry revealed faint or no expression of Parkin in their brains. In the substantia nigra pars compacta, a subfield-specific pattern of neuronal loss and mild gliosis were evident. Lewy bodies were found in 3 patients. Peripheral sensory neuronopathy was a feature. CONCLUSIONS: Genomic and mRNA analysis is needed to identify the PRKN mutations. Variable mutations may result in no or little production of mature Parkin and the histopathologic features may be similar. © 2021 International Parkinson and Movement Disorder Society.

    DOI: 10.1002/mds.28521

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  • An autopsy case of corticobasal degeneration with inferior olivary hypertrophy. 国際誌

    Chiho Ishida, Yuko Kato-Motozaki, Daisuke Noto, Kiyonobu Komai, Masato Hasegawa, Takeshi Ikeuchi, Masahito Yamada

    Neuropathology : official journal of the Japanese Society of Neuropathology   41 ( 3 )   226 - 235   2021年6月

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    記述言語:英語  

    We report autopsy results of a female patient who was confirmed pathologically as having corticobasal degeneration (CBD). This patient presented with progressive gait disturbance at the age of 66 years, and subsequently showed parkinsonism with a right-sided predominance and dementia. She was clinically diagnosed as having possible corticobasal syndrome without palatal myoclonus throughout the disease course. An autopsy at 72 years of age revealed that neuronal loss with gliosis was severe in the substantia nigra and the portion from hippocampal cornu ammonis (CA1) region to the parahippocampal gyrus, and mild-to-moderate in the basal ganglia, thalamus, red nucleus, dentate nucleus, and cerebral cortices, predominantly in the frontal lobe. Myelin pallor was observed in the pyramidal tract of the brainstem and central tegmental tract. Neurodegenerative or axonal degenerative findings were observed predominantly on the left side, except for the dentate nucleus, which was more affected on the right side. The inferior olivary nucleus exhibited hypertrophic degeneration predominantly on the left side. The topography of neurodegeneration was likely to correspond to the dentate nucleus and inferior olivary nucleus. Phosphorylated tau-immunoreactive pretangles, neurofibrillary tangles, coiled bodies, and threads were diffusely observed in the whole brain. The distribution of tau deposits was prominent in the deeper affected lesions of the dentate nucleus and inferior olivary nucleus. Inferior olivary hypertrophy is unusual in patients with CBD. It is highly possible that the neurodegeneration of the inferior olivary nucleus followed that of the dentate nucleus in our patient. Moreover, these results indicate not only the severity of neurodegenerative changes, but also that of tau deposition that could be related to the topography of the projections of the dentato-olivary pathway. Tau propagation and subsequent neurodegeneration along the fiber connections may have occurred. Our results support the possibility that progression of CBD lesions can be mediated by tau propagation.

    DOI: 10.1111/neup.12725

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  • State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease. 国際誌

    Harald Hampel, Leslie M Shaw, Paul Aisen, Christopher Chen, Alberto Lleó, Takeshi Iwatsubo, Atsushi Iwata, Masahito Yamada, Takeshi Ikeuchi, Jianping Jia, Huali Wang, Charlotte E Teunissen, Elaine Peskind, Kaj Blennow, Jeffrey Cummings, Andrea Vergallo

    Alzheimer's & dementia : the journal of the Alzheimer's Association   2021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)  

    Recent advances in developing disease-modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health-care systems toward biomarker-guided early detection, diagnosis, and therapeutic decision-making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs-once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state-of-the-art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP-associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD.

    DOI: 10.1002/alz.12372

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  • 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 psychiatry   11 ( 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 : JAD   79 ( 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 : JAD   80 ( 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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  • Toxic Amyloid-β42 Conformer May Accelerate the Onset of Alzheimer's Disease in the Preclinical Stage. 国際誌

    Akinori Futamura, Sotaro Hieda, Yukiko Mori, Kensaku Kasuga, Azusa Sugimoto, Hideyo Kasai, Takeshi Kuroda, Satoshi Yano, Mayumi Tsuji, Takeshi Ikeuchi, Kazuhiro Irie, Kenjiro Ono

    Journal of Alzheimer's disease : JAD   80 ( 2 )   639 - 646   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: Toxic amyloid-β protein (Aβ) conformers play an important role in the progression of Alzheimer's disease (AD). The ratio of toxic conformer to total Aβ42 in cerebrospinal fluid (CSF) was significantly high in AD and mild cognitive impairment (MCI) due to AD using an enzyme-linked immunosorbent assay kit with a 24B3 antibody. OBJECTIVE: We compared the toxic Aβ42, conformer at different stages of AD to identify its contribution to AD pathogenesis. METHODS: We compared 5 patients with preclinical AD, 11 patients with MCI due to AD, 21 patients with AD, and 5 healthy controls to measure CSF levels of total Aβ42, total tau, tau phosphorylated at threonine 181 (p-tau), and toxic Aβ conformers. All were classified using the Clinical Dementia Rating. Cognitive function was assessed using the Japanese version of the Mini-Mental State Examination (MMSE-J). RESULTS: Toxic Aβ conformer level was insignificant between groups, but its ratio to Aβ42 was significantly higher in AD than in preclinical AD (p < 0.05). Toxic Aβ42 conformer correlated positively with p-tau (r = 0.67, p < 0.01) and p-tau correlated negatively with MMSE-J (r = -0.38, p < 0.05). CONCLUSION: Toxic Aβ conformer triggers tau accumulation leading to neuronal impairment in AD pathogenesis.

    DOI: 10.3233/JAD-201407

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  • Cerebrospinal Fluid Amyloid-β Oligomer Levels in Patients with Idiopathic Normal Pressure Hydrocephalus. 国際誌

    Kaito Kawamura, Masakazu Miyajima, Madoka Nakajima, Mitsuyasu Kanai, Yumiko Motoi, Shuko Nojiri, Chihiro Akiba, Ikuko Ogino, Hanbing Xu, Chihiro Kamohara, Shinya Yamada, Kostadin Karagiozov, Takeshi Ikeuchi, Akihide Kondo, Hajime Arai

    Journal of Alzheimer's disease : JAD   83 ( 1 )   179 - 190   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: The amyloid-β oligomers, consisting of 10-20 monomers (AβO10-20), have strong neurotoxicity and are associated with cognitive impairment in Alzheimer's disease (AD). However, their role in patients with idiopathic normal pressure hydrocephalus (iNPH) is poorly understood. OBJECTIVE: We hypothesized that cerebrospinal fluid (CSF) AβO10-20 accumulates in patients with iNPH, and its clearance after CSF shunting contributes to neurological improvement. We measured CSF AβO10-20 levels before and after CSF shunting in iNPH patients evaluating their diagnostic and prognostic role. METHODS: We evaluated two iNPH cohorts: "evaluation" (cohort-1) with 32 patients and "validation" (cohort-2) with 13 patients. Comparison cohorts included: 27 neurologically healthy controls (HCs), and 16 AD, 15 Parkinson's disease (PD), and 14 progressive supranuclear palsy (PSP) patients. We assessed for all cohorts CSF AβO10-20 levels and their comprehensive clinical data. iNPH cohort-1 pre-shunting data were compared with those of comparison cohorts, using cohort-2 for validation. Next, we compared cohort-1's clinical and CSF data: 1) before and after CSF shunting, and 2) increased versus decreased AβO10-20 levels at baseline, 1 and 3 years after shunting. RESULTS: Cohort-1 had higher CSF AβO10-20 levels than the HCs, PD, and PSP cohorts. This result was validated with data from cohort-2. CSF AβO10-20 levels differentiated cohort-1 from the PD and PSP groups, with an area under receiver operating characteristic curve of 0.94. AβO10-20 levels in cohort-1 decreased after CSF shunting. Patients with AβO10-20 decrease showed better cognitive outcome than those without. CONCLUSION: AβO10-20 accumulates in patients with iNPH and is eliminated by CSF shunting. AβO10-20 can be an applicable diagnostic and prognostic biomarker.

    DOI: 10.3233/JAD-210226

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  • [Loss of homeostatic microglia in rare neurological disorders: implications for cell transplantation].

    Takeshi Ikeuchi, Yusran Ady Fitrah, Bin Shu

    Nihon yakurigaku zasshi. Folia pharmacologica Japonica   156 ( 4 )   225 - 229   2021年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Microglia originating from yolk sac exert various functions to maintain the homeostasis in the brain, and their functional breakdown appears to be involved in the pathophysiology of various neurological diseases. In this review article, loss of homeostatic microglia and new therapeutic approaches for rare neurological disorders are discussed. ASLP (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) known as a primary microgliopathy is an adult-onset leukoencephalopathy caused by CSF1R mutation. CSF1 receptor encoded by CSF1R plays an important role in the function of microglia. In brain of ALSP patients, homeostatic microglia are significantly reduced. The biallelic mutations for CSF1R cause childhood-onset severe phenotype and elimination of microglia from the brain parenchyma. Since microglia also almost disappear in CSF1R-deficient mice and rats, CSF1R deficiency and loss of microglia appear to be tightly associated across species. Based on the underlying mechanism of homeostatic microglia loss, novel approaches using cell transplantation of normal microglia-like cells have been attempted. Transplantation of wild-type bone marrow cells into Csf1r-/- mice results in replacement by donor-derived microglial-like cells in the recipient's brain. The concept of "microglial niche" may explain the rationale behind the microglial cell transplantation in disease condition(s). Hematopoietic stem cell transplantation (HSCT) has been attempted in 4 patients with ALSP. Beneficial effects by showing stabilization of the disease course have been observed. Although the effectiveness of HSCT for ALSP patients warrants further investigation, the approach of cell transplantation that replaces ruptured homeostatic microglia with normal microglia-like cells seems to be promising.

    DOI: 10.1254/fpj.21017

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  • Serum BDNF as a Potential Biomarker of Alzheimer's Disease: Verification Through Assessment of Serum, Cerebrospinal Fluid, and Medial Temporal Lobe Atrophy. 国際誌

    Yukiko Mori, Mayumi Tsuji, Tatsunori Oguchi, Kensaku Kasuga, Atsushi Kimura, Akinori Futamura, Azusa Sugimoto, Hideyo Kasai, Takeshi Kuroda, Satoshi Yano, Sotaro Hieda, Yuji Kiuchi, Takeshi Ikeuchi, Kenjiro Ono

    Frontiers in neurology   12   653267 - 653267   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    There is an urgent need to establish blood biomarkers for Alzheimer's disease (AD). Although it has been speculated that brain-derived neurotrophic factor (BDNF) is associated with AD, whether it can be used as a blood biomarker has yet to be determined. We used serum, cerebrospinal fluid (CSF), and medial temporal lobe atrophy from patients with AD to evaluate the association of BDNF with AD and assess its severity. For the blood analysis, 66 participants [21 normal controls (NCs) with normal cognitive function, 22 patients with mild cognitive impairment (MCI) due to AD, and 23 patients with AD] were included. For the CSF analysis, 30 participants were included. Magnetic resonance imaging, including a voxel-based specific regional analysis system for AD, and a Mini Mental State Examination were performed. Serum levels of BDNF and CSF levels of amyloid-β42, total tau, and phosphorylated tau were measured using ELISA. Serum BDNF levels were significantly lower in the MCI due to AD group than in the NC group (p = 0.037). Although there was no significant difference in the AD group, there was a downward trend compared to the NC group. Serum BDNF levels were positively correlated with CSF Aβ42 levels (r = 0.49, p = 0.005). There was a significant correlation between serum BDNF levels and medial temporal lobe atrophy. Decreased serum BDNF can potentially be used as a biomarker for early AD detection. Early detection of AD with a less invasive blood test is very beneficial, as it allows for intervention before dementia progresses.

    DOI: 10.3389/fneur.2021.653267

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  • Potential Novel Genes for Late-Onset Alzheimer's Disease in East-Asian Descent Identified by APOE-Stratified Genome-Wide Association Study. 国際誌

    Sarang Kang, Jungsoo Gim, Jiwoon Lee, Tamil Iniyan Gunasekaran, Kyu Yeong Choi, Jang Jae Lee, Eun Hyun Seo, Pan-Woo Ko, Ji Yeon Chung, Seong-Min Choi, Young Min Lee, Jee Hyang Jeong, Kyung Won Park, Min Kyung Song, Ho-Won Lee, Ki Woong Kim, Seong Hye Choi, Dong Young Lee, Sang Yun Kim, Hoowon Kim, Byeong C Kim, Takeshi Ikeuchi, Kun Ho Lee

    Journal of Alzheimer's disease : JAD   82 ( 4 )   1451 - 1460   2021年

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    記述言語:英語  

    The present study reports two novel genome-wide significant loci for late-onset Alzheimer's disease (LOAD) identified from APOE ε4 non-carrier subjects of East Asian origin. A genome-wide association study of Alzheimer's disease was performed in 2,291 Korean seniors in the discovery phase, from the Gwangju Alzheimer' and Related Dementias (GARD) cohort study. The study was replicated in a Japanese cohort of 1,956 subjects that suggested two novel susceptible SNPs in two genes: LRIG1 and CACNA1A. This study demonstrates that the discovery of AD-associated variants is feasible in non-European ethnic groups using samples comprising fewer subjects from the more homogeneous genetic background.

    DOI: 10.3233/JAD-210145

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  • Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development. 国際誌

    Spyros Papapetropoulos, Angela Pontius, Elizabeth Finger, Virginija Karrenbauer, David S Lynch, Matthew Brennan, Samantha Zappia, Wolfgang Koehler, Ludger Schoels, Stefanie N Hayer, Takuya Konno, Takeshi Ikeuchi, Troy Lund, Jennifer Orthmann-Murphy, Florian Eichler, Zbigniew K Wszolek

    Frontiers in neurology   12   788168 - 788168   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.

    DOI: 10.3389/fneur.2021.788168

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  • Alterations in Glycerolipid and Fatty Acid Metabolic Pathways in Alzheimer's Disease Identified by Urinary Metabolic Profiling: A Pilot Study. 国際誌

    Yumi Watanabe, Kensaku Kasuga, Takayoshi Tokutake, Kaori Kitamura, Takeshi Ikeuchi, Kazutoshi Nakamura

    Frontiers in neurology   12   719159 - 719159   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    An easily accessible and non-invasive biomarker for the early detection of Alzheimer's disease (AD) is needed. Evidence suggests that metabolic dysfunction underlies the pathophysiology of AD. While urine is a non-invasively collectable biofluid and a good source for metabolomics analysis, it is not yet widely used for this purpose. This small-scale pilot study aimed to examine whether the metabolic profile of urine from AD patients reflects the metabolic dysfunction reported to underlie AD pathology, and to identify metabolites that could distinguish AD patients from cognitively healthy controls. Spot urine of 18 AD patients (AD group) and 18 age- and sex-matched, cognitively normal controls (control group) were analyzed by mass spectrometry (MS). Capillary electrophoresis time-of-flight MS and liquid chromatography-Fourier transform MS were used to cover a larger range of molecules with ionic as well as lipid characteristics. A total of 304 ionic molecules and 81 lipid compounds of 12 lipid classes were identified. Of these, 26 molecules showed significantly different relative concentrations between the AD and control groups (Wilcoxon's rank-sum test). Moreover, orthogonal partial least-squares discriminant analysis revealed significant discrimination between the two groups. Pathway searches using the KEGG database, and pathway enrichment and topology analysis using Metaboanalyst software, suggested alterations in molecules relevant to pathways of glycerolipid and glycerophospholipid metabolism, thermogenesis, and caffeine metabolism in AD patients. Further studies of urinary metabolites will contribute to the early detection of AD and understanding of its pathogenesis.

    DOI: 10.3389/fneur.2021.719159

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  • A Japanese Multicenter Study on PET and Other Biomarkers for Subjects with Potential Preclinical and Prodromal Alzheimer’s Disease

    M. Senda, K. Ishii, K. Ito, T. Ikeuchi, H. Matsuda, T. Iwatsubo, A. Iwata, R. Ihara, K. Suzuki, K. Kasuga, Y. Ikari, Y. Niimi, H. Arai, A. Tamaoka, Y. Arahata, Y. Itoh, H. Tachibana, Y. Ichimiya, S. Washizuka, T. Odawara, K. Ishii, K. Ono, T. Yokota, A. Nakanishi, E. Matsubara, H. Mori, H. Shimada

    The Journal Of Prevention of Alzheimer's Disease   1 - 8   2021年

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:SERDI  

    BACKGROUND: PET (positron emission tomography) and CSF (cerebrospinal fluid) provide the “ATN” (Amyloid, Tau, Neurodegeneration) classification and play an essential role in early and differential diagnosis of Alzheimer’s disease (AD). OBJECTIVE: Biomarkers were evaluated in a Japanese multicenter study on cognitively unimpaired subjects (CU) and early (E) and late (L) mild cognitive impairment (MCI) patients. MEASUREMENTS: A total of 38 (26 CU, 7 EMCI, 5 LMCI) subjects with the age of 65-84 were enrolled. Amyloid-PET and FDG-PET as well as structural MRI were acquired on all of them, with an additional tau-PET with 18F-flortaucipir on 15 and CSF measurement of Aβ1-42, P-tau, and T-tau on 18 subjects. Positivity of amyloid and tau was determined based on the positive result of either PET or CSF. RESULTS: The amyloid positivity was 13/38, with discordance between PET and CSF in 6/18. Cortical tau deposition quantified with PET was significantly correlated with CSF P-tau, in spite of discordance in the binary positivity between visual PET interpretation and CSF P-tau in 5/8 (PET-/CSF+). Tau was positive in 7/9 amyloid positive and 8/16 amyloid negative subjects who underwent tau measurement, respectively. Overall, a large number of subjects presented quantitative measures and/or visual read that are close to the borderline of binary positivity, which caused, at least partly, the discordance between PET and CSF in amyloid and/or tau. Nine subjects presented either tau or FDG-PET positive while amyloid was negative, suggesting the possibility of non-AD disorders. CONCLUSION: Positivity rate of amyloid and tau, together with their relationship, was consistent with previous reports. Multicenter study on subjects with very mild or no cognitive impairment may need refining the positivity criteria and cutoff level as well as strict quality control of the measurements.

    DOI: 10.14283/jpad.2021.37

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  • Peripheral Blood BRCA1 Methylation Positively Correlates with Major Alzheimer’s Disease Risk Factors

    T. Mano, K. Sato, T. Ikeuchi, T. Toda, T. Iwatsubo, A. Iwata

    The Journal of Prevention of Alzheimer's Disease   1 - 6   2021年

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:SERDI  

    BACKGROUND: Recent biomarker studies demonstrated that the central nervous system (CNS) environment can be observed from peripherally-derived samples. In a previous study, we demonstrated significant hypomethylation of the BRCA1 promoter region in neuronal cells from post-mortem brains of Alzheimer’s disease patients through neuron-specific methylome analysis. Thus, we investigate the methylation changes in the BRCA1 promoter region in the blood samples. OBJECTIVES: To analyze the methylation level of the BRCA1 promoter in peripheral blood from AD patients and normal controls. DESIGN, SETTING, PARTICIPANTS: Genomic DNA samples from peripheral blood were obtained from the J-ADNI repository, and their biomarker data were obtained J-ADNI from the National Bioscience Database Center. Genomic DNA samples from an independent cohort for validation was obtained from Niigata University Hospital (Niigata, Japan). Amyloid positivity was defied by visual inspection of amyloid PET or a CSF Aβ42 value ≤ 333 pg/mL at the baseline. MEASUREMENTS: Methylation level of the BRCA1 promoter was analyzed by pyrosequencing. RESULTS: Compared to normal controls, methylation of the BRCA1 promoter in AD patients was not significantly changed; however, in AD patients, it showed a positive correlation with AD risk factors. CONCLUSIONS: Our data confirmed the importance of cell-type specific methylome analysis and also suggested that environmental changes in the CNS can be detected by observing the peripheral blood, implying that the peripheral BRCA1 methylation level can be a surrogate for AD.

    DOI: 10.14283/jpad.2021.31

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  • Frequent Germline and Somatic Single Nucleotide Variants in the Promoter Region of the Ribosomal RNA Gene in Japanese Lung Adenocarcinoma Patients. 国際誌

    Riuko Ohashi, Hajime Umezu, Ayako Sato, Tatsuya Abé, Shuhei Kondo, Kenji Daigo, Seijiro Sato, Norikazu Hara, Akinori Miyashita, Takeshi Ikeuchi, Teiichi Motoyama, Masashi Kishi, Tadahiro Nagaoka, Keiko Horiuchi, Atsushi Shiga, Shujiro Okuda, Tomoki Sekiya, Aya Ohtsubo, Kosuke Ichikawa, Hiroshi Kagamu, Toshiaki Kikuchi, Satoshi Watanabe, Jun-Ichi Tanuma, Peter Schraml, Takao Hamakubo, Masanori Tsuchida, Yoichi Ajioka

    Cells   9 ( 11 )   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)  

    Ribosomal RNA (rRNA), the most abundant non-coding RNA species, is a major component of the ribosome. Impaired ribosome biogenesis causes the dysfunction of protein synthesis and diseases called "ribosomopathies," including genetic disorders with cancer risk. However, the potential role of rRNA gene (rDNA) alterations in cancer is unknown. We investigated germline and somatic single-nucleotide variants (SNVs) in the rDNA promoter region (positions -248 to +100, relative to the transcription start site) in 82 lung adenocarcinomas (LUAC). Twenty-nine tumors (35.4%) carried germline SNVs, and eight tumors (9.8%) harbored somatic SNVs. Interestingly, the presence of germline SNVs between positions +1 and +100 (n = 12; 14.6%) was associated with significantly shorter recurrence-free survival (RFS) and overall survival (OS) by univariate analysis (p < 0.05, respectively), and was an independent prognostic factor for RFS and OS by multivariate analysis. LUAC cell line PC9, carrying rDNA promoter SNV at position +49, showed significantly higher ribosome biogenesis than H1650 cells without SNV. Upon nucleolar stress induced by actinomycin D, PC9 retained significantly higher ribosome biogenesis than H1650. These results highlight the possible functional role of SNVs at specific sites of the rDNA promoter region in ribosome biogenesis, the progression of LUAC, and their potential prognostic value.

    DOI: 10.3390/cells9112409

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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 Society   20 ( 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 medicine   12 ( 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 Neuropathology   40 ( 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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  • 残存する認知機能を活用し就労継続に効果が得られた意味性認知症の1例

    荒木 亜希, 春日 健作, 樋口 陽, 徳武 孝允, 小野寺 理, 池内 健

    Dementia Japan   34 ( 4 )   489 - 489   2020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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  • 認知症と精神疾患の鑑別における血液バイオマーカーの有用性の検討

    樋口 陽, 春日 健作, 徳武 孝允, 宮下 哲典, 茂木 崇治, 横山 裕一, 福井 直樹, 染矢 俊幸, 小野寺 理, 池内 健

    Dementia Japan   34 ( 4 )   527 - 527   2020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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  • 多系統萎縮症における脳脊髄液中NG2と認知機能の検討

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

    Dementia Japan   34 ( 4 )   490 - 490   2020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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  • ヒト死後脳に由来するDNA、RNAの品質管理

    長谷川 舞衣, 宮下 哲典, 春日 健作, 原 範和, 月江 珠緒, 齋藤 祐子, 赤津 裕康, 橋詰 良夫, 柿田 明美, 吉田 眞理, 村山 繁雄, 池内 健

    Dementia Japan   34 ( 4 )   525 - 525   2020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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  • アルツハイマー病と正常圧水頭症の鑑別における脳脊髄液バイオマーカーの有用性

    黒田 岳志, 森 友紀子, 二村 明徳, 杉本 あずさ, 矢野 怜, 笠井 英世, 稗田 宗太郎, 春日 健作, 池内 健, 小野 賢二郎

    Dementia Japan   34 ( 4 )   495 - 495   2020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とDLBの脳血流SPECTの有用性

    二村 明徳, 森 友紀子, 杉本 あずさ, 笠井 英世, 黒田 岳志, 矢野 怜, 稗田 宗太郎, 春日 健作, 池内 健, 小野 賢二郎

    Dementia Japan   34 ( 4 )   486 - 486   2020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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  • Urinary Apolipoprotein C3 Is a Potential Biomarker for Alzheimer’s Disease

    Yumi Watanabe, Yoshitoshi Hirao, Kensaku Kasuga, Takayoshi Tokutake, Kaori Kitamura, Shumpei Niida, Takeshi Ikeuchi, Kazutoshi Nakamura, Tadashi Yamamoto

    Dementia and Geriatric Cognitive Disorders Extra   10 ( 3 )   94 - 104   2020年9月

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

    &lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Biomarkers of Alzheimer’s disease (AD) that can easily be measured in routine health checkups are desirable. Urine is a source of biomarkers that can be collected easily and noninvasively. We previously reported on the comprehensive profile of the urinary proteome of AD patients and identified proteins estimated to be significantly increased or decreased in AD patients by a label-free quantification method. The present study aimed to validate urinary levels of proteins that significantly differed between AD and control samples from our proteomics study (i.e., apolipoprotein C3 [ApoC3], insulin-like growth factor-binding protein 3 [Igfbp3], and apolipoprotein D [ApoD]). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Enzyme-linked immunosorbent assays (ELISAs) were performed using urine samples from the same patient and control groups analyzed in the previous proteomics study (18 AD and 18 controls, set 1) and urine samples from an independent group of AD patients and controls (13 AD, 5 mild cognitive impairment [MCI], and 32 controls) from the National Center for Geriatrics and Gerontology Biobank (set 2). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; In set 1, the crude urinary levels of ApoD, Igfbp3, and creatinine-adjusted ApoD were significantly higher in the AD group relative to the control group (&lt;i&gt;p&lt;/i&gt; = 0.003, &lt;i&gt;p&lt;/i&gt; = 0.002, and &lt;i&gt;p&lt;/i&gt; = 0.019, respectively), consistent with our previous proteomics results. In set 2, however, the crude urinary levels of Igfbp3 were significantly lower in the AD+MCI group than in the control group (&lt;i&gt;p&lt;/i&gt; = 0.028), and the levels of ApoD and ApoC3 did not differ significantly compared to the control group. Combined analysis of all samples revealed creatinine-adjusted ApoC3 levels to be significantly higher in the AD+MCI group (&lt;i&gt;p&lt;/i&gt; = 0.015) and the AD-only group (&lt;i&gt;p&lt;/i&gt; = 0.011) relative to the control group. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; ApoC3 may be a potential biomarker for AD, as validated by ELISA. Further analysis of ApoC3 as a urinary biomarker for AD is warranted.

    DOI: 10.1159/000509561

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

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

    Nature medicine   26 ( 1 )   131 - 142   2020年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 communications   8 ( 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

    Neuropediatrics   51 ( 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 communications   8 ( 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 medicine   26 ( 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 Biology   34 ( 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

    Nature   580 ( 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 genetics   29 ( 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 medicine   26 ( 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 Society   35 ( 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 Australasia   72   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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  • 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事情

    宮下 哲典, 原 範和, 春日 健作, 池内 健

    新潟医学会雑誌   134 ( 1 )   13 - 18   2020年1月

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    記述言語:日本語   出版者・発行元:新潟医学会  

    認知症の半数以上を占めるアルツハイマー病(Alzheimer's Disease:AD)はガン、糖尿病、高血圧などと同じく「ありふれた疾患」である。個々人の遺伝的素因を背景に環境要因(ライフスタイル、食生活、運動など)が加わって潜行性に発症し、緩徐に不可逆的に進行する。遺伝要因、環境要因の寄与率はそれぞれおよそ6割、4割を占めることがこれまでに明らかにされている。マイクロサテライトマーカーを用いた連鎖解析、ジーンチップによるゲノムワイド関連解析(Genome-Wide Association Study:GWAS)、次世代シーケンサーを駆使したターゲットリシーケンシング、全エクソーム解析、全ゲノム解析によって、家族性AD、孤発性ADに関与する遺伝子や病的・保護的バリアントが続々と見出されている。1990年代に若年性の家族性ADの原因遺伝子として報告されたAPP、PSEN1、PSEN2のバリアント解析は、今では臨床診断を確定する際に極めて有効である。同じく1990年代に孤発性ADの感受性遺伝子として初めて報告されたAPOEは、その周辺領域を含めゲノムワイドなレベルで非常に強力にADと関連することが2000年代のGWASで確証された。認知機能、脳画像、液性バイオマーカー(アミロイドベータタンパクやタウタンパク)などの量的形質とも強い関連を示す。そのため孤発性ADの病態を解明し、その治療戦略を考える上で無視できない重要な感受性遺伝子としての地位が確立した。これまでのところ、APOEのインパクトを凌ぐAD感受性遺伝子やバリアントは報告されていない。本稿では講演内容の一部を抜粋し、ADの原因遺伝子、感受性遺伝子にフォーカスして論を進める。この機会にADの遺伝要因に関する理解を深め、今後の更なる研究展開に向けた糧としたい。(著者抄録)

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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 neurology   11   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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  • 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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  • 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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  • APP処理に対し時間・程度依存性の神経細胞活性化が及ぼす影響(Time- and extent- dependent effect of neuronal activation on APP processing)

    Ishiguro Takanobu, Kasuga Kensaku, Saito Kento, Mezaki Naomi, Miura Takeshi, Tokutake Takayoshi, Onodera Osamu, Ikeuchi Takeshi

    臨床神経学   59 ( Suppl. )   S411 - S411   2019年11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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  • 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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  • 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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  • An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations. 査読 国際誌

    Umber Dube, Jorge L Del-Aguila, Zeran Li, John P Budde, Shan Jiang, Simon Hsu, Laura Ibanez, Maria Victoria Fernandez, Fabiana Farias, Joanne Norton, Jen Gentsch, Fengxian Wang, Stephen Salloway, Colin L Masters, Jae-Hong Lee, Neill R Graff-Radford, Jasmeer P Chhatwal, Randall J Bateman, John C Morris, Celeste M Karch, Oscar Harari, Carlos Cruchaga, Ricardo Allegri, Fatima Amtashar, Tammie Benzinger, Sarah Berman, Courtney Bodge, Susan Brandon, William Brooks, Jill Buck, Virginia Buckles, Sochenda Chea, Patricio Chrem, Helena Chui, Jake Cinco, Jack Clifford, Mirelle D’Mello, Tamara Donahue, Jane Douglas, Noelia Edigo, Nilufer Erekin-Taner, Anne Fagan, Marty Farlow, Angela Farrar, Howard Feldman, Gigi Flynn, Nick Fox, Erin Franklin, Hisako Fujii, Cortaiga Gant, Samantha Gardener, Bernardino Ghetti, Alison Goate, Jill Goldman, Brian Gordon, Julia Gray, Jenny Gurney, Jason Hassenstab, Mie Hirohara, David Holtzman, Russ Hornbeck, Siri Houeland DiBari, Takeshi Ikeuchi, Snezana Ikonomovic, Gina Jerome, Mathias Jucker, Kensaku Kasuga, Takeshi Kawarabayashi, William Klunk, Robert Koeppe, Elke Kuder-Buletta, Christoph Laske, Johannes Levin, Daniel Marcus, Ralph Martins, Neal Scott Mason, Denise Maue-Dreyfus, Eric McDade, Lucy Montoya, Hiroshi Mori, Akem Nagamatsu, Katie Neimeyer, James Noble, Joanne Norton, Richard Perrin, Marc Raichle, John Ringman, Jee Hoon Roh, Peter Schofield, Hiroyuki Shimada, Tomoyo Shiroto, Mikio Shoji, Wendy Sigurdson, Hamid Sohrabi, Paige Sparks, Kazushi Suzuki, Laura Swisher, Kevin Taddei, Jen Wang, Peter Wang, Mike Weiner, Mary Wolfsberger, Chengjie Xiong and Xiong Xu

    Nature neuroscience   22 ( 11 )   1903 - 1912   2019年11月

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    Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; ncontrol = 13; nAD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA-AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis.

    DOI: 10.1038/s41593-019-0501-5

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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 reports   13 ( 4 )   684 - 699   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)  

    DOI: 10.1016/j.stemcr.2019.08.011

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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 shinpo   71 ( 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 Japan   33 ( 4 )   519 - 519   2019年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • 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 Japan   33 ( 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  

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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 Japan   33 ( 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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  • 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 genomics   12 ( 1 )   128 - 128   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/s12920-019-0574-8

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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 medicine   8 ( 8 )   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3390/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 reports   9 ( 1 )   10591 - 10591   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41598-019-47033-7

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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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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/s10020-019-0090-5

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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 neurology   19 ( 1 )   113 - 113   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/s12883-019-1346-y

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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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  • 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 sciences   399   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 Neuropathology   39 ( 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 metabolism   37 ( 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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  • 本年の動向 成人発症遺伝性白質脳症の医療基盤

    今野 卓哉, 野崎 洋明, 池内 健, 小野寺 理

    Annual Review神経   2019   82 - 88   2019年3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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  • 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 communications   7 ( 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 国際誌

    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 chemistry   489   29 - 34   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.cca.2018.11.024

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  • 非標識プロテオミクスによる尿を用いたアルツハイマー病バイオマーカーの可能性

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

    日本衛生学雑誌   74 ( Suppl. )   S147 - S147   2019年2月

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    記述言語:日本語   出版者・発行元:(一社)日本衛生学会  

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  • Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

    Oliver Preische, Stephanie A. Schultz, Anja Apel, Jens Kuhle, Stephan A. Kaeser, Christian Barro, Susanne Graeber, Elke Kuder-Buletta, Christian LaFougere, Christoph Laske, Jonathan Voeglein, Johannes Levin, Colin L. Masters, Ralph Martins, Peter R. Schofield, Martin N. Rossor, Neill R. Graff-Radford, Stephen Salloway, Bernardino Ghetti, John M. Ringman, James M. Noble, Jasmeer Chhatwal, Alison M. Goate, Tammie L. S. Benzinger, John C. Morris, Randall J. Bateman, Guoqiao Wang, Anne M. Fagan, Eric M. McDade, Brian A. Gordon, Mathias Jucker, Ricardo Allegri, Fatima Amtashar, Randall Bateman, Tammie Benzinger, Sarah Berman, Courtney Bodge, Susan Brandon, William Brooks, Jill Buck, Virginia Buckles, Sochenda Chea, Jasmeer Chhatwal, Patricio Chrem, Helena Chui, Jake Cinco, Jack Clifford, Carlos Cruchaga, Mirelle D'Mello, Tamara Donahue, Jane Douglas, Noelia Edigo, Nilufer Erekin-Taner, Anne Fagan, Marty Farlow, Angela Farrar, Howard Feldman, Gigi Flynn, Nick Fox, Erin Franklin, Hisako Fujii, Cortaiga Gant, Samantha Gardener, Bernardino Ghetti, Alison Goate, Jill Goldman, Brian Gordon, Neill Graff-Radford, Julia Gray, Jenny Gurney, Jason Hassenstab, Mie Hirohara, David Holtzman, Russ Hornbeck, Siri Houeland DiBari, Takeshi Ikeuchi, Snezana Ikonomovic, Gina Jerome, Mathias Jucker, Celeste Karch, Kensaku Kasuga, Takeshi Kawarabayashi, William Klunk, Robert Koeppe, Elke Kuder-Buletta, Christoph Laske, Jae-Hong Lee, Johannes Levin, Daniel Marcus, Ralph Martins, Neal Scott Mason, Colin Masters, Denise Maue-Dreyfus, Eric McDade, Lucy Montoya, Hiroshi Mori, John Morris, Akem Nagamatsu, Katie Neimeyer, James Noble, Joanne Norton, Richard Perrin, Marc Raichle, John Ringman, Jee Hoon Roh, Stephen Salloway, Peter Schofield, Hiroyuki Shimada, Tomoyo Shiroto, Mikio Shoji, Wendy Sigurdson, Hamid Sohrabi, Paige Sparks, Kazushi Suzuki, Laura Swisher, Kevin Taddei, Jen Wang, Peter Wang, Mike Weiner, Mary Wolfsberger, Chengjie Xiong, Xiong Xu

    NATURE MEDICINE   25 ( 2 )   277 - +   2019年2月

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

    Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-beta deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.

    DOI: 10.1038/s41591-018-0304-3

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  • 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 extra   9 ( 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. Clinical   24   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 : JAD   68 ( 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.

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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

    Neurology   91 ( 24 )   1092 - 1104   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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 ( Suppl. )   S207 - S207   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)   出版者・発行元:(一社)日本神経学会  

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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. Genetics   4 ( 6 )   e292   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1212/NXG.0000000000000292

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  • 進行性核上性麻痺における臨床型別臨床経過の検討 多施設共同前向きコホート研究

    饗場 郁子, 池内 健, 瀧川 洋史, 徳田 隆彦, 下畑 享良, 森田 光哉, 村山 繁雄, 小野寺 理, 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. )   S211 - S211   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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  • 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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  • 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 neurology   265 ( 10 )   2415 - 2424   2018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)  

    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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  • 多系統萎縮症における認知症関連・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, 三浦 健, 目崎 直実, 下畑 享良, 小野寺 理, 池内 健

    Dementia Japan   32 ( 3 )   465 - 465   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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  • 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 Japan   32 ( 3 )   423 - 423   2018年9月

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  • 佐渡市における和太鼓を用いた認知症予防事業 認知機能トレーニングとの比較

    三浦 健, 目崎 直実, 濱田 香津恵, 森本 芳典, 石黒 敬信, 春日 健作, 小野寺 理, 池内 健

    Dementia Japan   32 ( 3 )   487 - 487   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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  • 血漿中アミノ酸およびアミン類のプロファイルを用いた認知症早期診断の可能性

    矢野 由紀, 神通 寛子, 村松 孝彦, 河合 信宏, 嵐田 直子, 西本 瑠美, 新保 和高, 遠藤 直人, 佐久間 真由美, 田中 弘, 手塚 敏之, 徳武 孝允, 春日 健作, 池内 健

    Dementia Japan   32 ( 3 )   448 - 448   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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  • AARS2変異による成人発症大脳白質脳症の分子臨床遺伝学的解析

    目崎 直実, 原 範和, 月江 珠緒, 馬場 徹, 緒方 利安, 三浦 健, 樋口 陽, 石黒 敬信, 野崎 洋明, 春日 健作, 森 悦朗, 坪井 義夫, 小野寺 理, 池内 健

    Dementia Japan   32 ( 3 )   455 - 455   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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  • 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 Association   14 ( 8 )   1077 - 1087   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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 Neurology   25 ( 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.

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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 sciences   387   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 sciences   387   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

    NEUROLOGY   90 ( 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 Neuropathology   38 ( 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 medicine   10 ( 3 )   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

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  • 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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  • 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 Neurology   25 ( 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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  • 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 Neurology   25 ( 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 Disorders   46   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.

    DOI: 10.1016/j.parkreldis.2017.08.018

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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

  • 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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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.trci.2018.06.008

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  • 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 : JAD   66 ( 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.

    DOI: 10.3233/JAD-180557

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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 AMERICA   114 ( 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.

    DOI: 10.1073/pnas.1707151114

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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 NEUROLOGY   82   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 reports   21 ( 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)  

    DOI: 10.1016/j.celrep.2017.09.032

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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 INTERNATIONAL   17 ( 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..

    DOI: 10.1111/ggi.129.7

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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

    eNeurologicalSci   8   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.

    DOI: 10.1016/j.ensci.2017.07.003

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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 NEUROLOGY   17   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 Nerve   69 ( 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 NEUROLOGY   76 ( 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 BIOCHEMISTRY   81 ( 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 Neurology   24 ( 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 SCIENCES   372   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 NEUROLOGY   24 ( 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 NEURORADIOLOGY   38 ( 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 COMMUNICATIONS   5   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.

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  • 【白質変性と非アルツハイマー型認知症】神経軸索スフェロイドを伴う遺伝性びまん性白質脳症(HDLS)の臨床症状と画像所見の特徴

    今野 卓哉, 池内 健

    Dementia Japan   31 ( 1 )   3 - 9   2017年1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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  • 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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  • 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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  • 抗Aβ抗体療法関連脳浮腫の自然発症ヒト病態モデルとしてのCAA関連炎症

    石黒 敬信, 春日 健作, 小池 佑佳, 徳武 孝允, 西澤 正豊, 池内 健

    臨床神経学   56 ( Suppl. )   S397 - S397   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 NEUROLOGY   80 ( 4 )   554 - 565   2016年10月

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

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

    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 NEUROLOGY   80   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

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

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

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

    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 shinpo   68 ( 7 )   703 - 12   2016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)  

    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 Technology   53 ( 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

    NEUROLOGY   86   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

    NEUROLOGY   86   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 PATHOLOGY   26 ( 2 )   155 - 166   2016年3月

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

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

    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 DISORDERS   31   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 PATHOLOGY   26 ( 1 )   82 - 94   2016年1月

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

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

    DOI: 10.1111/bpa.12262

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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 Extra   6 ( 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.

    DOI: 10.1159/000442585

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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 Extra   6 ( 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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  • 脳アミロイド血管症関連炎症9例における出血性病変および海馬萎縮とAPOE多型の検討

    石黒 敬信, 春日 健作, 徳武 孝允, 西澤 正豊, 池内 健

    臨床神経学   55 ( Suppl. )   S421 - S421   2015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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  • 世代間で著しい臨床的多様性を認めたHDLS一家系の臨床分子遺伝学的解析

    目崎 直実, 徳武 孝允, 勇 亜衣子, 石川 正典, 三浦 健, 今野 卓哉, 三瓶 一弘, 西澤 正豊, 池内 健

    臨床神経学   55 ( Suppl. )   S426 - S426   2015年12月

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

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

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

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

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

    DOI: 10.1007/s10048-015-0451-3

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  • 世代間で著しい臨床的多様性を認めたHDLS一家系の臨床分子遺伝学的解析

    目崎 直実, 徳武 孝允, 勇 亜衣子, 石川 正典, 三浦 健, 今野 卓哉, 三瓶 一弘, 西澤 正豊, 池内 健

    Dementia Japan   29 ( 3 )   354 - 354   2015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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  • 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 ONE   10 ( 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 GENETICS   60 ( 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/.

    DOI: 10.1038/jhg.2015.15

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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 COMMUNICATIONS   456 ( 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 MEDICINE   54 ( 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 Monitoring   1 ( 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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  • 脳アミロイドアンギオパチー関連炎症の臨床症状、画像、バイオマーカーの多様性の検討

    笠原 壮, 徳武 孝允, 春日 健作, 須貝 章弘, 赤岩 靖久, 本間 篤, 小池 佑佳, 藤田 信也, 大野 司, 田中 晋, 西澤 正豊, 池内 健

    臨床神経学   54 ( Suppl. )   S13 - S13   2014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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  • 新規SLC20A2変異を認めた特発性大脳基底核石灰化症 家系の臨床分子遺伝学的検討

    春日 健作, 今野 卓哉, 斎藤 健智, 西澤 正豊, 池内 健

    臨床神経学   54 ( Suppl. )   S244 - S244   2014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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  • Genes associated with the progression of neurofibrillary tangles in Alzheimer's disease 査読

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

    TRANSLATIONAL PSYCHIATRY   4   e396   2014年6月

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

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

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  • 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 DISORDERS   20 ( 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

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

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

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

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  • 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 NEUROLOGY   261 ( 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 : JAD   41 ( 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 DISEASES   13 ( 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 Nerve   66 ( 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 Neurology   54 ( 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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  • 脳アミロイドアンギオパチー関連炎症のバイオマーカー、血中抗Aβ抗体の検討

    徳武 孝允, 関根 有美, 須貝 章弘, 赤岩 靖久, 本間 篤, 藤田 信也, 大野 司, 田中 晋, 西澤 正豊, 池内 健

    臨床神経学   53 ( 12 )   1574 - 1574   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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  • 脳アミロイドアンギオパチー関連炎症の画像、臨床症状、バイオマーカーの検討

    徳武 孝允, 春日 健作, 須貝 章弘, 赤岩 靖久, 本間 篤, 藤田 信也, 大野 司, 田中 晋, 西澤 正豊, 池内 健

    Dementia Japan   27 ( 4 )   500 - 500   2013年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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

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

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

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

    DOI: 10.1007/s00401-013-1150-5

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  • 若年発症の認知症と脳梁菲薄化を伴うびまん性白質脳症を呈し、CSF1R遺伝子に変異を認めた45歳男性例

    宇津見 宏太, 他田 正義, 今野 卓哉, 池内 健, 西澤 正豊

    臨床神経学   53 ( 3 )   257 - 257   2013年3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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  • Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS): Clinical Characteristics and Molecular Analyses of CSF-1R 査読

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

    NEUROLOGY   80   2013年2月

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  • 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 one   8 ( 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 COMMUNICATIONS   1   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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  • アミロイドアンギオパチーに伴う頭蓋内出血の特徴の検討

    荒川 博之, 関根 有美, 赤岩 靖久, 池内 健, 西澤 正豊

    臨床神経学   52 ( 12 )   1570 - 1570   2012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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  • 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 CHEMISTRY   287 ( 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 SCLEROSIS   13 ( 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 DISORDERS   18 ( 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 shinpo   64 ( 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 AMERICA   109 ( 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 NEURODEGENERATION   7   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.

    DOI: 10.1186/1750-1326-7-16

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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 MEDICINE   4 ( 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

    Neurology   78 ( 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 disease   2012   437025 - 437025   2012年

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    記述言語:英語  

    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 Neurology   52 ( 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.

    DOI: 10.5692/clinicalneurol.52.1386

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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 NEURODEGENERATION   6   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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  • Cerebral amyloid angiopathyの関与が疑われた非対称性皮質下白質病変の1例

    荒川 博之, 赤岩 靖久, 池内 健, 西澤 正豊

    神経治療学   28 ( 5 )   561 - 561   2011年9月

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    記述言語:日本語   出版者・発行元:(一社)日本神経治療学会  

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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 neurology   3 ( 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 GENETICS   20 ( 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

    BRAIN   134   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 extra   1 ( 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.

    DOI: 10.1159/000331243

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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 NEUROPATHOLOGICA   120 ( 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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  • 開眼失行を呈した筋萎縮性側索硬化症/前頭側頭葉変性症の1例

    矢島 隆二, 春日 健作, 佐藤 朋江, 池内 健, 西澤 正豊

    臨床神経学   50 ( 9 )   645 - 650   2010年9月

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    記述言語:日本語   出版者・発行元:Societas Neurologica Japonica  

    症例は76歳の男性である.両眼の開眼失行で発症し,脳幹,頸髄,腰仙髄の各レベルで上位・下位運動ニューロン障害を呈し,針筋電図検査では神経原性変化をみとめた.さらに前頭葉機能低下が前景に立つ認知機能低下と,特徴的な失語症をともなっていた.頭部MRIで両側前頭側頭葉の萎縮をみとめ,<sup>99m</sup>Tc ECD SPECTでも同部の血流が低下していた.筋萎縮性側索硬化症/前頭側頭葉変性症に開眼失行をともなう比較的均一な病像を呈する一群がまれながら存在すると考えられた.<br>

    DOI: 10.5692/clinicalneurol.50.645

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    その他リンク: https://jlc.jst.go.jp/DN/JALC/00356674344?from=CiNii

  • 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 DISORDERS   25 ( 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 NEUROPATHOLOGICA   120 ( 1 )   21 - 32   2010年7月

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

    Tau is the pathological protein in several neurodegenerative disorders classified as frontotemporal lobar degeneration (FTLD), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). We report an unusual tauopathy in three Japanese patients presenting with Parkinsonism and motor neuron disease (neuroimaging revealed frontotemporal cerebral atrophy in two patients who were examined). At autopsy, all cases showed FTLD with the most severe neuronal loss and gliosis evident in the premotor and precentral gyri. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. In the spinal cord, loss of anterior horn cells and degeneration of the corticospinal tract were evident. In addition, the affected regions exhibited neuronal cytoplasmic inclusions resembling neurofibrillary tangles. Immunostaining using antibodies against hyperphosphorylated tau and 4-repeat tau revealed widespread occurrence of neuronal and glial cytoplasmic inclusions in the central nervous system; the astrocytic tau lesions were unique, and different in morphology from astrocytic plaques in CBD, or tufted astrocytes in PSP. However, immunoblotting of frozen brain samples available in two cases revealed predominantly 4R tau, with the approximately 37-kDa and 33-kDa low-molecular mass tau fragments characteristic of CBD and PSP, respectively. No mutations were found in the tau gene in either of the two cases. Based on these clinicopathological, biochemical, and genetic findings, we consider that the present three patients form a distinct 4R tauopathy associated with sporadic FTLD.

    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 PSYCHIATRY   81 ( 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

    NEUROPATHOLOGY   30 ( 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

    NEUROLOGY   74 ( 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 DISORDERS   30 ( 1 )   28 - 32   2010年

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

    Background: Recent genetic and pathological studies have suggested that a lipoprotein receptor, LR11, is intricately implicated in the pathogenesis of Alzheimer disease (AD). We have recently established a novel sandwich ELISA, which enabled the sensitive quantification of a soluble LR11 (sLR11). By this ELISA, we attempted to determine the difference in the levels of CSF sLR11 in AD patients. Methods: We examined CSF from 29 AD patients, 20 frontotemporal lobar degeneration patients and 27 age-matched control subjects. The CSF sLR11 level as well as the levels of tau and beta-amyloid42 (A beta 42) were determined by sandwich ELISA. Results: The CSF tau level and tau/A beta 42 ratio were significantly increased (p &lt; 0.01) in the AD patients. The CSF sLR11 level in the AD patients was significantly higher (p &lt; 0.01) than that of the frontotemporal lobar degeneration patients and the controls. The APOE-epsilon 4-positive AD patients have higher sLR11 levels than the APOE-epsilon 4-negative patients (p &lt; 0.01). Conclusions: These results suggest that the quantification of CSF sLR11 may serve as a biomarker of AD, although the diagnostic value for individual patients is limited. An elevated CSF sLR11 level in AD patients may be relevant to AD pathogenesis. Copyright (C) 2010 S. Karger AG, Basel

    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 NEUROPATHOLOGICA   118 ( 4 )   553 - 560   2009年10月

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

    Pathological transactivation-responsive DNA-binding protein 43 (TDP-43) has been identified as a component of ubiquitinated inclusions in frontotemporal lobar degeneration with motor neuron disease, as well as in sporadic and some forms of familial amyotrophic lateral sclerosis. To clarify whether pathological TDP-43 is present in other neurodegenerative diseases involving the motor neuron system, we immunohistochemically examined the brain and spinal cord affected by two CAG repeat (polyglutamine) diseases, Machado-Joseph disease (MJD) and spinal and bulbar muscular atrophy (SBMA), using polyclonal antibody against TDP-43. In all the MJD cases, TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs), although few in number, were found only in the lower motor neurons in the brainstem and spinal cord. TDP-43-ir NCIs appeared as linear wisp-like, skein-like, or thick, somewhat rod-like bodies. These inclusions were also visualized with antibodies against phosphoserines 409 and 410 of TDP-43, and ubiquitin, but were not recognized by antibody against expanded polyglutamine stretches or ataxin-3. The ultrastructure of the TDP-43-ir NCIs was similar to that of the inclusions seen in sporadic ALS, consisting of bundles of parallel filaments. None of the SBMA cases showed abnormal TDP-43 immunoreactivity in any of the regions examined. Immunoblot analysis failed to recognize hyperphosphorylated TDP-43 at similar to 23 kDa in two MJD cases examined. However, the immunohistochemical findings strongly suggested that in MJD, in addition to the polyglutamine-dependent disease process, TDP-43-related pathogenesis is associated with degeneration and death of the lower motor neurons.

    DOI: 10.1007/s00401-009-0552-x

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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 PSYCHIATRY   80 ( 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.

    DOI: 10.1136/jnnp.2008.161703

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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 NEUROLOGY   256 ( 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 DISORDERS   24 ( 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 MEDICINE   1 ( 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 MEDICINE   360 ( 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 RESEARCH   65   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 NEUROPATHOLOGICA   116 ( 5 )   575 - 577   2008年11月

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    記述言語:英語   出版者・発行元:SPRINGER  

    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

    NEUROLOGY   71 ( 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 KAGAKU   57 ( 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.

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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

    NEUROLOGY   71 ( 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 NEUROLOGY   63 ( 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 NEUROLOGY   65 ( 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 KORSAKOVA   108 ( 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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  • 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 RESEARCH   61   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 RESEARCH   61   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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  • 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 RESEARCH   61   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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  • 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 DISORDERS   26 ( 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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  • 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 GENETICS   44 ( 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 NEUROSCIENCE   27 ( 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 COMMUNICATIONS   360 ( 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 DISORDERS   22 ( 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 & THERAPEUTICS   113 ( 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 INTERNATIONAL   27 ( 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 LIPIDOLOGY   16 ( 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 Neurology   45 ( 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 Neurology   45 ( 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 NEUROLOGY   59 ( 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.

    DOI: 10.1001/archneur.59.11.1804

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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

    NEUROGENETICS   4 ( 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 NEUROLOGY   52 ( 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 Neuropathologica   102 ( 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 Neurosciences   13 ( 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 GENETICS   26 ( 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.

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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 & DEVELOPMENT   22   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 NEUROLOGY   48 ( 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 Research   94 ( 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 NEUROLOGY   246 ( 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 DISORDERS   9 ( 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

    NEUROGENETICS   2 ( 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 LETTERS   270 ( 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 NEUROPATHOLOGICA   96 ( 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.

    DOI: 10.1007/s004010050933

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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

    Genomics   52 ( 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

    GENOMICS   49 ( 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 SCIENCES   156 ( 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 GENETICS   18 ( 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

    NEUROLOGY   49 ( 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

    GENOMICS   40 ( 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 GENETICS   14 ( 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 nerve   48 ( 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 Genetics   58 ( 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 GENETICS   57 ( 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 NEUROLOGY   37 ( 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 BIOLOGY   6 ( 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 Neurology   35 ( 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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  • 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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  • 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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  • 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 NEUROSCIENCE   3 ( 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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  • 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 Neurology   35 ( 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 GENETICS   6 ( 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

MISC

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    Medical Technology   50 ( 3 )   210 - 211   2022年3月

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    日本医事新報   ( 5107 )   46 - 46   2022年3月

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    医学のあゆみ   278 ( 5 )   451 - 455   2021年7月

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    記述言語:日本語   出版者・発行元:医歯薬出版(株)  

    前頭側頭型認知症(FTD)とレビー小体型認知症(DLB)は、代表的な非アルツハイマー型認知症である。FTDは前頭葉および側頭葉に神経変性が生じ、行動異常や失語など多彩な臨床症状を呈する。DLBは変動する認知障害、幻視、レム睡眠行動異常、パーキンソニズムを中核症状とする。病型により脳内に蓄積するタンパク質が異なっており、FTD患者脳ではタウ陽性あるいはTDP-43陽性の封入体が認められる。DLBではαシヌクレイン陽性のレビー小体が認められる。こうした病理像の違いが生じる一因として、発症に関連する遺伝子が異なることがあげられる。本稿では、FTDとDLBのゲノム解析に関する最近の知見を紹介し、この領域のゲノム医療を展望する。(著者抄録)

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  • アルツハイマー病と正常圧水頭症の鑑別 脳脊髄液Aβ1-42/1-40、Aβ1-42/1-38比の有用性

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    臨床神経学   60 ( Suppl. )   S377 - S377   2020年11月

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    春日 健作, 月江 珠緒, 菊地 正隆, 原 範和, 宮下 哲典, 桑野 良三, 岩坪 威, 池内 健

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

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    黒羽 泰子, 荒井 祐生, 吉野 美穂子, 中村 航世, 五十嵐 一也, 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   60 ( Suppl. )   S408 - S408   2020年11月

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  • ALSP/HDLSの臨床画像と病理

    池内 健

    臨床神経学   60 ( Suppl. )   S245 - S245   2020年11月

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    臨床神経学   60 ( Suppl. )   S31 - S31   2020年11月

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    春日 健作, 月江 珠緒, 菊地 正隆, 原 範和, 宮下 哲典, 桑野 良三, 岩坪 威, 池内 健

    臨床神経学   60 ( Suppl. )   S338 - S338   2020年11月

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  • パーキンソン病における軽度認知障害(PD-MCI)の多様性について

    黒羽 泰子, 荒井 祐生, 吉野 美穂子, 中村 航世, 五十嵐 一也, 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   60 ( Suppl. )   S408 - S408   2020年11月

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  • アルツハイマー病と正常圧水頭症の鑑別 脳脊髄液Aβ1-42/1-40、Aβ1-42/1-38比の有用性

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    臨床神経学   60 ( Suppl. )   S403 - S403   2020年11月

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  • 多系統萎縮症における脳脊髄液中NG2とα-シヌクレインの検討

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

    臨床神経学   60 ( Suppl. )   S433 - S433   2020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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  • ALSP/HDLSの臨床画像と病理

    池内 健

    臨床神経学   60 ( Suppl. )   S245 - S245   2020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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  • 神経疾患・精神疾患の鑑別における血漿炎症性サイトカインの有用性

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    臨床神経学   60 ( Suppl. )   S377 - S377   2020年11月

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  • ABCA7、SORL1、TREM2におけるアルツハイマー病関連レアバリアントの探索

    原 範和, 宮下 哲典, 尾崎 浩一, 新飯田 俊平, 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 Japan   34 ( 4 )   526 - 526   2020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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  • データドリブンな軽度認知障害のサブタイピングおよびアルツハイマー病発症予測

    菊地 正隆, 小林 香織, 春日 健作, 宮下 哲典, 池内 健, 湯本 英二, 伏見 泰人, 武田 理宏, 真鍋 史朗, 上條 憲一, 松村 泰志

    Dementia Japan   34 ( 4 )   501 - 501   2020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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  • ヒト死後脳に由来するDNA、RNAの品質管理

    長谷川 舞衣, 宮下 哲典, 春日 健作, 原 範和, 月江 珠緒, 齋藤 祐子, 赤津 裕康, 橋詰 良夫, 柿田 明美, 吉田 眞理, 村山 繁雄, 池内 健

    Dementia Japan   34 ( 4 )   525 - 525   2020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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  • APP依存的な新規タウ分泌現象の発見

    佐藤 玄謙, 堀 由起子, 春日 健作, 池内 健, 富田 泰輔

    Dementia Japan   34 ( 4 )   522 - 522   2020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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  • 日本人コホートJGSCAD、J-ADNI、NCGG、ToMMoにおけるバリアント解析 APOE

    宮下 哲典, 原 範和, 春日 健作, Lixin Liu, 樋口 陽, Bin Zhu, 月江 珠緒, 長谷川 舞衣, Yusran Adyfitrah, 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, 岩坪 威, 池内 健

    Dementia Japan   34 ( 4 )   521 - 521   2020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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  • ヒト死後脳、ヒト培養細胞におけるAPOEの遺伝子発現解析

    Lixin Liu, 宮下 哲典, 村上 涼太, 原 範和, 菊地 正隆, Bin Zhu, 樋口 陽, Yusran Adyfitrah, 月江 珠緒, 長谷川 舞衣, 春日 健作, 赤津 裕康, 橋詰 良夫, 柿田 明美, 村山 繁雄, 池内 健

    Dementia Japan   34 ( 4 )   521 - 521   2020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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  • 認知症と精神疾患の鑑別における血液バイオマーカーの有用性の検討

    樋口 陽, 春日 健作, 徳武 孝允, 宮下 哲典, 茂木 崇治, 横山 裕一, 福井 直樹, 染矢 俊幸, 小野寺 理, 池内 健

    Dementia Japan   34 ( 4 )   527 - 527   2020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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  • CSF1RバリアントのキナーゼアッセイによるCSF1R関連脳症の発症機序解析

    朱 斌, Liu Lixin, 樋口 陽, Yusran Adyfitrah, 三浦 健, 目崎 直美, 原 範和, 月江 珠緒, 今野 卓哉, 春日 健作, 宮下 哲典, 池内 健

    Dementia Japan   34 ( 4 )   526 - 526   2020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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  • アンチエイジングに活かすゲノムサイエンス ゲノム情報を活用した認知症予防とアンチエイジング医療

    池内 健

    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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  • アンチエイジングに活かすゲノムサイエンス ゲノム情報を活用した認知症予防とアンチエイジング医療

    池内 健

    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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  • 進行性核上性麻痺(PSP)診療ガイドライン2020

    中島 健二, 饗場 郁子, 足立 正, 新井 哲明, 粟田 主一, 池内 健, 大崎 康史, 古和 久典, 榊原 隆次, 篠遠 仁, 下畑 享良, 瀧川 洋史, 徳田 隆彦, 中野 俊也, 長谷川 一子, 平野 成樹, 山本 敏之, 横田 修, 冨本 秀和, 伊井 裕一郎, 飯嶋 睦, 和泉 唯信, 伊藤 瑞規, 仙石 錬平, 村井 弘之, 村松 和浩, 森田 昭彦, 進行性核上性麻痺(PSP)診療ガイドライン2020作成委員会, 厚生労働科学研究費補助金(難治性疾患政策研究事業)「神経変性疾患領域の基盤的調査研究」一般社団法人日本神経治療学会, 日本神経治療学会外部ガイドライン対応ワーキング部会

    神経治療学   37 ( 3 )   435 - 493   2020年5月

  • Frequencies of Hereditary Cerebral Small Vessel Diseases Among Patients With Adult-Onset Leukoencephalopathy

    Masahiro Uemura, Hiroaki Nozaki, Naoko Sakai, Shouichirou Ando, Masato Kanazawa, Hajime Kondo, Akira Iwanaga, Hiroyuki Murota, Takeshi Ikeuchi, Ikuko Mizuta, Toshiki Mizuno, Osamu Onodera

    STROKE   51   2020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:LIPPINCOTT WILLIAMS & WILKINS  

    Web of Science

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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

  • アルツハイマー病マルチオミックスデータを用いたシステム生物学的研究

    菊地正隆, 関谷倫子, 関谷倫子, 原範和, 宮下哲典, 桑野良三, 池内健, 飯島浩一, 飯島浩一, 中谷明弘

    日本生化学会大会(Web)   93rd   2020年

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  • 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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  • 【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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  • 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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  • 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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  • 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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  • 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 Japan   33 ( 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 Japan   33 ( 4 )   519 - 519   2019年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

    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 Japan   33 ( 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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    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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    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 psychiatry   61 ( 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  

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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  

    J-GLOBAL

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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  

    J-GLOBAL

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    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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  • APPプロセシングに対するニューロン活性化の時間および範囲依存的影響

    ISHIGURO Takanobu, KASUGA Kensaku, SAITO Kento, MEZAKI Naomi, MIURA Takeshi, TOKUTAKE Takayoshi, ONODERA Osamu, IKEUCHI Takeshi

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

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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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  • 「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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  • 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 Japan   32 ( 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 Japan   32 ( 3 )   417 - 417   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  

    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 Japan   32 ( 3 )   450   2018年9月

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    記述言語:日本語  

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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 Japan   32 ( 3 )   429   2018年9月

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    記述言語:日本語  

    J-GLOBAL

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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 Japan   32 ( 3 )   433   2018年9月

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    記述言語:日本語  

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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 Japan   32 ( 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 Technology   46 ( 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 Japan   32 ( 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 Japan   32 ( 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  

    J-GLOBAL

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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 Japan   32 ( 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 Japan   32 ( 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  

    J-GLOBAL

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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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  • Identification and Functional Assay of Novel CSF1R Mutations in Patients with Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia

    Takeshi Miura, Naomi Mezaki, Takanobu Ishiguro, Takayoshi Tokutake, Kensaku Kasuga, Takuya Konno, Hiroaki Nozaki, Osamu Onodera, Takeshi Ikeuchi

    NEUROLOGY   90   2018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  

    Web of Science

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  • Genetic Screening of CSF1R in Familial Ischemic Stroke

    Takuya Konno, Takeshi Miura, Andrea Harriott, Naomi Mezaki, Emily Edwards, Rosa Rademakers, Owen Ross, James Meschia, Takeshi Ikeuchi, Zbigniew Wszolek

    NEUROLOGY   90   2018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  

    Web of Science

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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  

    J-GLOBAL

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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 Neuroscience   36 ( 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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    記述言語:日本語  

    J-GLOBAL

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  • 大脳皮質基底核変性症剖検例における臨床像の解明および臨床診断基準の妥当性検証~多施設共同研究~Japanese validation study of consensus criteria for the diagnosis of corticobasal degeneration~multicenter study~(J-VAC study)

    饗場郁子, 下畑享良, 小野寺理, 池内健, 豊島靖子, 柿田明美, 高橋均, 吉田眞理, 村山繁雄, 中野雄太, 徳丸阿耶, 横田隆徳, 大久保卓哉, 内原俊記, 秋山治彦, 長谷川成人, 矢部一郎, 青木正志, 長谷川隆文, 長谷川一子, 新井哲明, 大島健一, 新里和弘, 横田修, 小森隆司, 若林孝一, 齋藤祐子, 櫻井圭太, 足立正, 瀧川洋史, 中島健二

    神経変性疾患領域における基盤的調査研究 平成29年度 総括・分担研究報告書(Web)   2018年

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  • 染色体高次構造を介したアルツハイマー病リスクバリアントの影響

    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

    日本分子生物学会年会プログラム・要旨集(Web)   41st   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  

    J-GLOBAL

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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 Neuroscience   35 ( 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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  • 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 Japan   31 ( 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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  • 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 Japan   31 ( 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 Japan   31 ( 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 Japan   31 ( 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 Japan   31 ( 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 Japan   31 ( 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  

    J-GLOBAL

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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 Japan   31 ( 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 Japan   31 ( 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 Japan   31 ( 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 Japan   31 ( 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 Japan   31 ( 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 Japan   31 ( 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  

    J-GLOBAL

    <