Updated on 2024/10/07

写真a

 
KASUGA Kensaku
 
Organization
Brain Research Institute Center for Bioresources Assistant Professor
Title
Assistant Professor
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Degree

  • 医学博士 ( 2009.3   新潟大学 )

Research Interests

  • アルツハイマー病

  • リン酸化タウ

  • インスリンシグナル

  • βアミロイド

  • Alzheimer's disease

  • Fluid biomarker

  • バイオマーカー

Research Areas

  • Life Science / Neurology

Research History (researchmap)

  • Brain Research Institute, Niigata University   Department of Molecular Genetics   Assistant Professor

    2018.4

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  • Brain Research Institute, Niigata University   Department of Molecular Genetics   Contract Assistant Professor

    2017.4 - 2018.3

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  • Institute for Research Promotion, Niigata University   Center for Transdisciplinary Research   Assistant Professor

    2014.4 - 2017.3

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  • Niigata University Medical & Dental Hospital   Department of Neurology   Contract Assistant Professor

    2012.10 - 2014.3

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  • University of California, San Diego   Department of Neurosciences   Post doctoral fellow

    2010.4 - 2012.9

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  • Niigata University   Medical and Dental Hospital

    2010

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Research History

  • Niigata University   Brain Research Institute Center for Bioresources   Assistant Professor

    2018.4

  • Niigata University   Brain Research Institute Center for Bioresources   Specially Appointed Assistant Professor

    2017.4 - 2018.3

  • Niigata University   Institute for Research Promotion Center for Transdisciplinary Research   Assistant Professor

    2014.4 - 2017.3

  • Niigata University   University Medical and Dental Hospital Neurology   Specially Appointed Assistant Professor

    2012.10 - 2014.3

  • Niigata University   University Medical and Dental Hospital Neurology   Specially Appointed Assistant Professor

    2009.4 - 2009.9

Education

  • Niigata University   Graduate School of Medical and Dental Science

    2005.4 - 2009.3

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  • Niigata University   School of Medicine   Faculty of Medicine

    1994.4 - 2000.3

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Professional Memberships

Committee Memberships

  • 日本認知症学会   代議員  

    2018.4   

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    Committee type:Academic society

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Studying abroad experiences

  • 米国カリフォルニア大学サンディエゴ校 (University of California, San Diego)   博士研究員 (Postdoctoral fellow)

    2010.4 - 2012.9

 

Papers

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

    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   2021.12

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    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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  • An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations. Reviewed International journal

    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   2019.11

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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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  • Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Reviewed International journal

    Oliver Preische, Stephanie A Schultz, Anja Apel, Jens Kuhle, Stephan A Kaeser, Christian Barro, Susanne Gräber, Elke Kuder-Buletta, Christian LaFougere, Christoph Laske, Jonathan Vöglein, 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 and Xiong Xu

    Nature medicine   25 ( 2 )   277 - 283   2019.2

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    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-β 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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  • Serum microRNA miR-501-3p as a potential biomarker related to the progression of Alzheimer's disease. Reviewed International journal

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

    Acta neuropathologica communications   5 ( 1 )   10 - 10   2017.1

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

    DOI: 10.1186/s40478-017-0414-z

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  • Systematic review and meta-analysis of Japanese familial Alzheimer's disease and FTDP-17. Reviewed International journal

    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 - 3   2015.5

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    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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  • Hyperphosphorylation of Tau induced by naturally secreted amyloid-β at nanomolar concentrations is modulated by insulin-dependent Akt-GSK3β signaling pathway. Reviewed International journal

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

    The Journal of biological chemistry   287 ( 42 )   35222 - 33   2012.10

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    Alzheimer disease (AD) is neuropathologically characterized by the formation of senile plaques from amyloid-β (Aβ) and neurofibrillary tangles composed of phosphorylated Tau. Although there is growing evidence for the pathogenic role of soluble Aβ species in AD, the major question of how Aβ induces hyperphosphorylation of Tau remains unanswered. To address this question, we here developed a novel cell coculture system to assess the effect of extracellular Aβ 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 Aβ 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 Aβ production in donor cells. The expression of familial AD-linked PSEN1 mutants and APP ΔE693 mutant that induce the production of oligomeric Aβ in donor cells results in a similar hyperphosphorylation of Tau in recipient cells. The mechanism underlying the Aβ-induced Tau hyperphosphorylation is mediated by the impaired insulin signal transduction because we demonstrated that the phosphorylation of Akt and GSK3β upon insulin stimulation is less activated under this condition. Treating cells with the insulin-sensitizing drug rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, attenuates the Aβ-dependent hyperphosphorylation of Tau. These findings suggest that the disturbed insulin signaling cascade may be implicated in the pathways through which soluble Aβ induces Tau phosphorylation and further support the notion that correcting insulin signal dysregulation in AD may offer a potential therapeutic approach.

    DOI: 10.1074/jbc.M112.348300

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  • Differential levels of alpha-synuclein, beta-amyloid42 and tau in CSF between patients with dementia with Lewy bodies and Alzheimer's disease. Reviewed International journal

    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 - 10   2010.6

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    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 alpha-synuclein, beta-amyloid42 (Abeta42) and tau in the CSF of patients with DLB, Alzheimer'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. Abeta 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 Abeta40/42 and tau/Abeta42 ratios were significantly higher in AD patients than in patients with DLB (p<0.01) and other dementias (p<0.01). CSF alpha-synuclein levels in DLB patients were significantly lower than those in patients with AD (p<0.05) and other dementias (p<0.01). CSF alpha-synuclein level correlated with the Abeta42 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 Abeta42 and tau analysis.

    DOI: 10.1136/jnnp.2009.197483

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  • Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease. Reviewed International journal

    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 - 2   2009.9

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    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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  • Ubiquitin-Proteasome System in the Different Stages of Dominantly Inherited Alzheimer's Disease. International journal

    Eric McDade, Haiyan Liu, Quoc Bui, Jason Hassenstab, Brian Gordon, Tammie Benzinger, Yuanyuan Shen, Jigyasha Timsina, Lihua Wang, Yun Ju Sung, Celeste Karch, Alan Renton, Alisha Daniels, John Morris, Chengjie Xiong, Laura Ibanez, Richard Perrin, Jorge J Llibre-Guerra, Gregory Day, Charlene Supnet-Bell, Xiong Xu, Sarah Berman, Jasmeer Chhatwal, Takeshi Ikeuchi, Kensaku Kasuga, Yoshiki Niimi, Edward Huey, Peter Schofield, William Brooks, Natalie Ryan, Mathias Jucker, Christoph Laske, Johannes Levin, Jonathan Vöglein, Jee Hoon Roh, Francisco Lopera, Randall Bateman, Carlos Cruchaga

    Research square   2024.7

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    This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating® (CDR®). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR®. Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis.

    DOI: 10.21203/rs.3.rs-4202125/v1

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  • Combining plasma Aβ and p-tau217 improves detection of brain amyloid in non-demented elderly. Reviewed International journal

    Yoshiki Niimi, Shorena Janelidze, Kenichiro Sato, Naoki Tomita, Tadashi Tsukamoto, Takashi Kato, Kenji Yoshiyama, Hisatomo Kowa, Atsushi Iwata, Ryoko Ihara, Kazushi Suzuki, Kensaku Kasuga, Takeshi Ikeuchi, Kenji Ishii, Kengo Ito, Akinori Nakamura, Michio Senda, Theresa A Day, Samantha C Burnham, Leonardo Iaccarino, Michael J Pontecorvo, Oskar Hansson, Takeshi Iwatsubo

    Alzheimer's research & therapy   16 ( 1 )   115 - 115   2024.5

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    BACKGROUND: Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer's disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-β (Aβ)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aβ-positron emission tomography (PET) in the preclinical and prodromal AD. METHODS: We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study. J-TRC included 474 non-demented individuals (CDR 0: 331, CDR 0.5: 143). Participants underwent plasma Aβ and p-tau217 assessments, and Aβ-PET imaging. Findings in J-TRC were replicated in the BioFINDER cohort including 177 participants (cognitively unimpaired: 114, mild cognitive impairment: 63). In both cohorts, plasma Aβ(1-42) (Aβ42) and Aβ(1-40) (Aβ40) were measured using immunoprecipitation-MALDI TOF mass spectrometry (Shimadzu), and p-tau217 was measured with an immunoassay on the Meso Scale Discovery platform (Eli Lilly). RESULTS: Aβ-PET was abnormal in 81 participants from J-TRC and 71 participants from BioFINDER. Plasma Aβ42/Aβ40 ratio and p-tau217 individually showed moderate to high accuracies when detecting abnormal Aβ-PET scans, which were improved by combining plasma biomarkers and by including age, sex and APOE genotype in the models. In J-TRC, the highest AUCs were observed for the models combining p-tau217/Aβ42 ratio, APOE, age, sex in the whole cohort (AUC = 0.936), combining p-tau217, Aβ42/Aβ40 ratio, APOE, age, sex in the CDR 0 group (AUC = 0.948), and combining p-tau217/Aβ42 ratio, APOE, age, sex in the CDR 0.5 group (AUC = 0.955), respectively. Each subgroup results were replicated in BioFINDER, where the highest AUCs were seen for models combining p-tau217, Aβ42/40 ratio, APOE, age, sex in cognitively unimpaired (AUC = 0.938), and p-tau217/Aβ42 ratio, APOE, age, sex in mild cognitive impairment (AUC = 0.914). CONCLUSIONS: Combination of plasma Aβ-related biomarkers and p-tau217 exhibits high performance when predicting Aβ-PET positivity. Adding basic clinical information (i.e., age, sex, APOE ε genotype) improved the prediction in preclinical AD, but not in prodromal AD. Combination of Aβ-related biomarkers and p-tau217 could be highly useful for pre-screening of participants in clinical trials of preclinical and prodromal AD.

    DOI: 10.1186/s13195-024-01469-w

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  • Polygenic effects on the risk of Alzheimer’s disease in the Japanese population

    Masataka Kikuchi, Akinori Miyashita, Norikazu Hara, Kensaku Kasuga, Yuko Saito, Shigeo Murayama, Akiyoshi Kakita, Hiroyasu Akatsu, Kouichi Ozaki, Shumpei Niida, Ryozo Kuwano, Takeshi Iwatsubo, Akihiro Nakaya, Takeshi Ikeuchi, Michael W. Weiner, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Lon S. Schneider, Sonia Pawluczyk, Mauricio Beccera, Liberty Teodoro, Bryan M. Spann, Laurel Beckett, Robert C. Green, John Morris, Leslie M. Shaw, Beau Ances, John C. Morris, Maria Carroll, Mary L. Creech, Erin Franklin, Mark A. Mintun, Stacy Schneider, Angela Oliver, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Rachelle S. Doody, Javier Villanueva-Meyer, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, 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, Martin R. 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Kuwabara, Ryuji Nakamuta, Minoru Tanaka, Manabu Ikeda, Yuusuke Yatabe, Mamoru Hashimoto, Keiichirou Kaneda, Kazuki Honda, Naoko Ichimi, Mariko Morinaga, Miyako Noda, Fumi Akatuka, Mika Kitajima, Toshinori Hirai, Shinya Shiraishi, Naoji Amano, Shinsuke Washizuka, Tetsuya Hagiwara, Yatsuka Okada, Tomomi Ogihara, Toru Takahashi, Shin Inuzuka, Nobuhiro Sugiyama, Takehiko Yasaki, Minori Kitayama, Tomonori Owa, Akiko Ryokawa, Rie Takeuchi, Satoe Goto, Keiko Yamauchi, Mie Ito, Tomoki Kaneko, Hitoshi Ueda, Shuichi Ikeda, Ban Mihara, Hirofumi Kubo, Akiko Takano, Gou Yasui, Masami Akuzawa, Kaori Yamaguchi, Toshinari Odawara, Naomi Oota, Megumi Shimamura, Mikiko Sugiyama, Atsushi Watanabe, Shigeo Takebayashi, Yoshigazu Hayakawa, Mitsuhiro Idegawa, Noriko Toya, Kazunari Ishii

    Alzheimer's Research &amp; Therapy   16 ( 1 )   2024.2

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    Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract

    Background

    Polygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer’s disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using genome-wide association study (GWAS) statistics from Europeans.

    Methods

    In this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort (n = 565) and the North American ADNI (NA-ADNI) cohort (n = 617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD.

    Results

    The PRS using 131 SNPs had an effect independent of APOE. The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with the APOE variants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels (β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD in APOE ε4 noncarriers with a hazard rate of 2.22. In addition, we also developed a PRS model adjusted for LD and observed similar results.

    Conclusions

    We showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences.

    DOI: 10.1186/s13195-024-01414-x

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  • アルツハイマー型認知症での認知機能低下とミクログリア活性化 PETイメージング研究

    安野 史彦, 木村 泰之, 小縣 綾, 阿部 潤一郎, 南 博之, 南 ひかる, 二橋 尚志, 服部 沙織, 下田 信義, 春日 健作, 池内 健, 武田 章敬, 櫻井 孝, 伊藤 健吾, 加藤 隆司

    老年精神医学雑誌   34 ( 増刊II )   211 - 211   2023.10

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  • パーキンソン病における軽度認知機能障害と脳血流シンチグラムの特徴

    黒羽 泰子, 高橋 哲哉, 荒井 祐生, 吉野 美穂子, 小林 彩夏, 小野 純花, 斎藤 奈つみ, 畠野 雄也, 若杉 尚宏, 春日 健作, 長谷川 有香, 松原 奈絵, 池内 健

    臨床神経学   63 ( Suppl. )   S245 - S245   2023.9

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  • パーキンソン病における軽度認知機能障害と脳血流シンチグラムの特徴

    黒羽 泰子, 高橋 哲哉, 荒井 祐生, 吉野 美穂子, 小林 彩夏, 小野 純花, 斎藤 奈つみ, 畠野 雄也, 若杉 尚宏, 春日 健作, 長谷川 有香, 松原 奈絵, 池内 健

    臨床神経学   63 ( Suppl. )   S245 - S245   2023.9

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  • Neuroimaging biomarkers of glial activation for predicting the annual cognitive function decline in patients with Alzheimer's disease. International journal

    Fumihiko Yasuno, Yasuyuki Kimura, Aya Ogata, Hiroshi Ikenuma, Junichiro Abe, Hiroyuki Minami, Takashi Nihashi, Kastunori Yokoi, Saori Hattori, Nobuyoshi Shimoda, Atsushi Watanabe, Kensaku Kasuga, Takeshi Ikeuchi, Akinori Takeda, Takashi Sakurai, Kengo Ito, Takashi Kato

    Brain, behavior, and immunity   2023.8

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    BACKGROUND: Glial activation is central to the pathogenesis of Alzheimer's disease (AD). However, researchers have not demonstrated its relationship to longitudinal cognitive deterioration. We aimed to compare the prognostic effects of baseline positron emission tomography (PET) imaging of glial activation and amyloid/tau pathology on the successive annual cognitive decline in patients with AD. METHODS: We selected 17 patients diagnosed with mild cognitive impairment or AD. We assessed the annual changes in global cognition and memory. Furthermore, we assessed the predictive effects of baseline amyloid and tau pathology indicated by cerebrospinal fluid (CSF) concentrations and PET imaging of glial activation (11C-DPA-713-binding potential in the area of Braak 1-3 [11C-DPA-713-BPND]) on global cognition and memory using a stepwise regression analysis. RESULTS: The final multiple regression model of annual changes in global cognition and memory scores included 11C-DPA-713-BPND as the predictor. The CSF Aβ42/40 ratios and p-tau concentrations were removed from the final model. In stepwise Bayesian regression analysis, the Bayes factor-based model comparison suggested that the best model included 11C-DPA-713-BPND as the predictor of decline in global cognition and memory. CONCLUSIONS: Translocator protein-PET imaging of glial activation is a stronger predictor of AD clinical progression than the amount of amyloid/tau pathology measured using CSF concentrations. Glial activation is the primary cause of tau-induced neuronal toxicity and cognitive deterioration, thereby highlighting the potential of blocking maladaptive microglial responses as a therapeutic strategy for AD treatment.

    DOI: 10.1016/j.bbi.2023.08.027

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  • The clinical application of optimized AT(N) classification in Alzheimer’s clinical syndrome (ACS) and non-ACS conditions

    Kensaku Kasuga, Tamao Tsukie, Masataka Kikuchi, Takayoshi Tokutake, Kazuo Washiyama, Soichiro Shimizu, Hiroshi Yoshizawa, Yasuko Kuroha, Ryuji Yajima, Hiroshi Mori, Yasuaki Arakawa, Kiyoshi Onda, Akinori Miyashita, Osamu Onodera, Takeshi Iwatsubo, Takeshi Ikeuchi

    Neurobiology of Aging   127   23 - 32   2023.7

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    DOI: 10.1016/j.neurobiolaging.2023.03.007

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  • Heterogenous Genetic, Clinical, and Imaging Features in Patients with Neuronal Intranuclear Inclusion Disease Carrying NOTCH2NLC Repeat Expansion. International journal

    Yusran Ady Fitrah, Yo Higuchi, Norikazu Hara, Takayoshi Tokutake, Masato Kanazawa, Kazuhiro Sanpei, Tomone Taneda, Akihiko Nakajima, Shin Koide, Shintaro Tsuboguchi, Midori Watanabe, Junki Fukumoto, Shoichiro Ando, Tomoe Sato, Yohei Iwafuchi, Aki Sato, Hideki Hayashi, Takanobu Ishiguro, Hayato Takeda, Toshiaki Takahashi, Nobuyoshi Fukuhara, Kensaku Kasuga, Akinori Miyashita, Osamu Onodera, Takeshi Ikeuchi

    Brain sciences   13 ( 6 )   2023.6

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    Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.

    DOI: 10.3390/brainsci13060955

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  • Parkinson症候群の治療法開発の最前線 進行性核上性麻痺の新規治療法開発 どのように臨床試験を成功させるか

    金澤 雅人, 春日 健作, 島田 斉, 池内 健, 小野寺 理

    神経治療学   40 ( 3 )   259 - 265   2023.5

  • Parkinson症候群の治療法開発の最前線 進行性核上性麻痺の新規治療法開発 どのように臨床試験を成功させるか

    金澤 雅人, 春日 健作, 島田 斉, 池内 健, 小野寺 理

    神経治療学   40 ( 3 )   259 - 265   2023.5

  • 【認知症のゲノム医療】APOEの遺伝型とレアミスセンスバリアント 臨床応用への可能性

    宮下 哲典, 原 範和, 春日 健作, 菊地 正隆, 尾崎 浩一, 新飯田 俊平, 他田 真理, 柿田 明美, 池内 健

    Dementia Japan   37 ( 2 )   239 - 249   2023.4

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  • Brain p3-Alcβ peptide restores neuronal viability impaired by Alzheimer's amyloid β-peptide. International journal

    Saori Hata, Haruka Saito, Takeharu Kakiuchi, Dai Fukumoto, Shigeyuki Yamamoto, Kensaku Kasuga, Ayano Kimura, Koichi Moteki, Ruriko Abe, Shungo Adachi, Shoich Kinoshita, Kumiko Yoshizawa-Kumagaye, Hideki Nishio, Takashi Saito, Takaomi C Saido, Tohru Yamamoto, Masaki Nishimura, Hidenori Taru, Yuriko Sobu, Hiroyuki Ohba, Shingo Nishiyama, Norihiro Harada, Takeshi Ikeuchi, Hideo Tsukada, Yasuomi Ouchi, Toshiharu Suzuki

    EMBO molecular medicine   15 ( 5 )   e17052   2023.3

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    We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3-Alcβ37 is generated from the neuronal protein alcadein β through cleavage of γ-secretase, similar to the generation of amyloid β (Aβ) derived from Aβ-protein precursor/APP. Neurotoxicity by Aβ oligomers (Aβo) is the prime cause prior to the loss of brain function in AD. We found that p3-Alcβ37 and its shorter peptide p3-Alcβ9-19 enhanced the mitochondrial activity of neurons and protected neurons against Aβo-induced toxicity. This is due to the suppression of the Aβo-mediated excessive Ca2+ influx into neurons by p3-Alcβ. Successful transfer of p3-Alcβ9-19 into the brain following peripheral administration improved the mitochondrial viability in the brain of AD mice model, in which the mitochondrial activity is attenuated by increasing the neurotoxic human Aβ42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased Aβ and reduced p3-Alcβ37 levels, the administration of p3-Alcβ9-19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD.

    DOI: 10.15252/emmm.202217052

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  • Soluble form of the APP fragment, sAPPβ, positively regulates tau secretion. International journal

    Haruaki Sato, Kensaku Kasuga, Noriko Isoo, Toshihiro Hayashi, Takeshi Ikeuchi, Yukiko Hori, Taisuke Tomita

    Neuroscience research   193   63 - 70   2023.3

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    Extracellular tau has been highlighted in the pathogenesis of Alzheimer disease (AD), which is the most common neurodegenerative disease. Pathological analyses as well as model animal studies suggest that amyloid-β peptide (Aβ) deposition facilitates the spreading of tau aggregation pathology via extracellular tau. However, the precise mechanism of tau secretion remains unknown. Here, we show that the overexpression of amyloid precursor protein (APP) enhances the secretion of tau phosphorylated at threonine 181 in mouse neuroblastoma Neuro2a cells. Moreover, we found that soluble amyloid precursor protein β (sAPPβ), which is generated by β-site APP cleaving enzyme 1 (BACE1), mediates tau secretion. Our results demonstrate that BACE1-mediated cleavage of APP plays pathological roles in AD pathogenesis by not only Aβ production, but by the spreading of tau aggregation pathology via sAPPβ in AD patients.

    DOI: 10.1016/j.neures.2023.03.002

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  • Novel Partial Deletions, Frameshift and Missense Mutations of CSF1R in Patents with CSF1R-Related Leukoencephalopathy. International journal

    Takanobu Ishiguro, Takuya Konno, Norikazu Hara, Bin Zhu, Satoshi Okada, Mamoru Shibata, Reiko Saika, Takaya Kitano, Megumi Toko, Tomohisa Nezu, Yuka Hama, Tomoya Kawazoe, Ikuko Takahashi-Iwata, Ichiro Yabe, Kota Sato, Hayato Takeda, Shintaro Toda, Jin Nishimiya, Toshiyuki Teduka, Hiroaki Nozaki, Kensaku Kasuga, Akinori Miyashita, Osamu Onodera, Takeshi Ikeuchi

    European journal of neurology   30 ( 7 )   1861 - 1870   2023.3

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    BACKGROUND: CSF1R-related leukoencephalopathy is an adult-onset leukoencephalopathy caused by mutations in CSF1R. The present study aimed to explore the broader genetic spectrum of CSF1R-related leukoencephalopathy in association with clinical and imaging features. METHODS: Mutational analysis of CSF1R was performed for 100 consecutive patients with adult-onset leukoencephalopathy. Sequence and copy number variation (CNV) analyses of CSF1R were performed. The genomic ranges of the deletions were determined by long-read sequencing. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing the CSF1R mutants identified in this study. RESULTS: We identified CSF1R mutations in 15 patients, accounting for 15% of the adult-onset leukoencephalopathy cases. Seven novel and five previously reported CSF1R mutations were identified. The novel mutations, including three missense and one in-frame 3-bp deletion, were located in the tyrosine kinase domain (TKD) of CSF1R. Functional assays revealed that none of the novel mutations in the TKD showed autophosphorylation of CSF1R. We identified two partial deletions of CSF1R that resulted in the lack of the C-terminal region, including the distal TKD, in two patients. Variable clinical features including cognitive impairment, psychiatric symptoms, and gait disturbance were observed. Various degrees of the white matter lesions and corpus callosum abnormalities on MRI and characteristic calcifications on CT were observed as imaging features. CONCLUSIONS: Our results highlighted the importance of examining the CNV of CSF1R even when Sanger or exome sequencing reveal no CSF1R mutations. Genetic examination of sequences and CNV analyses of CSF1R are recommended for an accurate diagnosis of CSF1R-related leukoencephalopathy.

    DOI: 10.1111/ene.15796

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  • Urinary proteome profiles associated with cognitive decline in community elderly residents-A pilot study. International journal

    Yumi Watanabe, Yoshitoshi Hirao, Kensaku Kasuga, Kaori Kitamura, Kazutoshi Nakamura, Tadashi Yamamoto

    Frontiers in neurology   14   1134976 - 1134976   2023

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    Non-invasive and simple methods enabling easy identification of individuals at high risk of cognitive decline are needed as preventive measures against dementia. This pilot study aimed to explore protein biomarkers that can predict cognitive decline using urine, which can be collected non-invasively. Study subjects were selected from participants in a cohort study of middle-aged and older community-dwelling adults who underwent cognitive testing using the Mini-Mental State Examination and provided spot urine samples at two time points with an interval of approximately 5 years. Seven participants whose cognitive function declined 4 or more points from baseline (Group D) and 7 sex- and age-matched participants whose cognitive function remained within the normal range during the same period (Group M) were selected. Urinary proteomics using mass spectrometry was performed and discriminant models were created using orthogonal partial least squares-discriminant analysis (OPLS-DA). OPLS-DA yielded two models that significantly discriminated between the two groups at baseline and follow-up. Both models had ORM1, ORM2, and SERPINA3 in common. A further OPLS-DA model using baseline ORM1, ORM2, and SERPINA3 data showed similar predictive performance for data at follow-up as it did for baseline data (sensitivity: 0.85, specificity: 0.85), with the receiver operating characteristic curve analysis yielding an area under the curve of 0.878. This prospective study demonstrated the potential for using urine to identify biomarkers of cognitive decline.

    DOI: 10.3389/fneur.2023.1134976

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  • Estimation of blood-based biomarkers of glial activation related to neuroinflammation. International journal

    Fumihiko Yasuno, Atsushi Watanabe, Yasuyuki Kimura, Yumeka Yamauchi, Aya Ogata, Hiroshi Ikenuma, Junichiro Abe, Hiroyuki Minami, Takashi Nihashi, Kastunori Yokoi, Saori Hattori, Nobuyoshi Shimoda, Kensaku Kasuga, Takeshi Ikeuchi, Akinori Takeda, Takashi Sakurai, Kengo Ito, Takashi Kato

    Brain, behavior, & immunity - health   26   100549 - 100549   2022.12

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    BACKGROUND: Neuroinflammation is a well-known feature of Alzheimer's disease (AD), and a blood-based test for estimating the levels of neuroinflammation would be expected. In this study, we examined and validated a model using blood-based biomarkers to predict the level of glial activation due to neuroinflammation, as estimated by 11C-DPA-713 positron emission tomography (PET) imaging. METHODS: We included 15 patients with AD and 10 cognitively normal (CN) subjects. Stepwise backward deletion multiple regression analysis was used to determine the predictors of the TSPO-binding potential (BPND) estimated by PET imaging. The independent variables were age, sex, diagnosis, apolipoprotein E4 positivity, body mass index and the serum concentration of blood-based biomarkers, including monocyte chemotactic protein 1 (MCP-1), fractalkine, chitinase 3-like protein-1 (CHI3L1), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and clusterin. RESULTS: Sex, diagnosis, and serum concentrations of MCP1 and sTREM2 were determined as predictors of TSPO-BPND in the Braak1-3 area. The serum concentrations of MCP1 and sTREM2 correlated positively with TSPO-BPND. In a leave one out (LOO) cross-validation (CV) analysis, the model gave a LOO CV R2 of 0.424, which indicated that this model can account for approximately 42.4% of the variance of brain TSPO-BPND. CONCLUSIONS: We found that the model including serum MCP-1 and sTREM2 concentration and covariates of sex and diagnosis was the best for predicting brain TSPO-BPND. The detection of neuroinflammation in AD patients by blood-based biomarkers should be a sensitive and useful tool for making an early diagnosis and monitoring disease progression and treatment effectiveness.

    DOI: 10.1016/j.bbih.2022.100549

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  • Involvement of inflammation in the medial temporal region in the development of agitation in Alzheimer's disease: an <i>in vivo</i> positron emission tomography study

    Fumihiko Yasuno, Yasuyuki Kimura, Aya Ogata, Hiroshi Ikenuma, Junichiro Abe, Hiroyuki Minami, Takashi Nihashi, Kastunori Yokoi, Saori Hattori, Nobuyoshi Shimoda, Atsushi Watanabe, Kensaku Kasuga, Takeshi Ikeuchi, Akinori Takeda, Takashi Sakurai, Kengo Ito, Takashi Kato

    Psychogeriatrics   2022.11

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    DOI: 10.1111/psyg.12915

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  • アルツハイマー病患者尿中におけるグリセロリン脂質代謝関連代謝物の変動

    渡邊 裕美, 春日 健作, 徳武 孝允, 北村 香織, 池内 健, 中村 和利

    老年精神医学雑誌   33 ( 増刊II )   261 - 261   2022.11

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  • 治験即応コホートJ-TRCにおける血漿アミロイドβ測定の有用性に関する検討

    新美 芳樹, 佐藤 健一郎, 冨田 尚希, 岩田 淳, 塚本 忠, 加藤 隆司, 吉山 顕次, 古和 久朋, 春日 健作, 池内 健, 石井 賢二, 伊藤 健吾, 千田 道雄, 岩坪 威

    老年精神医学雑誌   33 ( 増刊II )   315 - 315   2022.11

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  • 特発性正常圧水頭症の症例で複合病理を考慮する 5症例のバイオマーカーから

    伊関 千書, 小林 良太, 春日 健作, 鈴木 佑弥, 猪狩 龍佑, 佐藤 裕康, 小山 信吾, 板垣 寛, 池内 健, 園田 順彦, 太田 康之

    老年精神医学雑誌   33 ( 増刊II )   320 - 320   2022.11

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  • APP依存的な新規タウ分泌現象の発見

    佐藤 玄謙, 春日 健作, 磯尾 紀子, 林 俊宏, 堀 由起子, 池内 健, 富田 泰輔

    日本生化学会大会プログラム・講演要旨集   95回   1P - 358   2022.11

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  • 神経炎症と認知症アジテーション症状との関係 生体内PETイメージング研究

    安野 史彦, 木村 泰之, 小縣 綾, 阿部 潤一郎, 南 博之, 二橋 尚志, 横井 克典, 服部 沙織, 下田 信義, 渡邉 淳, 春日 健作, 池内 健, 武田 章敬, 櫻井 孝, 伊藤 健吾, 加藤 隆司

    老年精神医学雑誌   33 ( 増刊II )   342 - 343   2022.11

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  • Biallelic <i>COX10</i> Mutations and <i>PMP22</i> Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy

    Yasuko Kuroha, Takanobu Ishiguro, Mari Tada, Norikazu Hara, Kei Murayama, Izumi Kawachi, Kensaku Kasuga, Akinori Miyashita, Arika Hasegawa, Tetsuya Takahashi, Nae Matsubara, Osamu Onodera, Akiyoshi Kakita, Ryoko Koike, Takeshi Ikeuchi

    Neurology Genetics   8 ( 5 )   e200030 - e200030   2022.10

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    Objectives

    Leigh syndrome is a progressive encephalopathy characterized by symmetrical lesions in brain. This study aimed to investigate the clinicopathologic and genetic characteristics of a family with Leigh syndrome and hereditary neuropathy with liability to pressure palsy (HNPP).

    Methods

    Data from a Japanese family's clinical features, MRIs, muscle biopsy, and an autopsy were analyzed. A whole-exome sequence was performed, as well as real-time PCR analysis to determine copy number variations and Western blot analyses.

    Results

    The proband and her 2 siblings developed spastic paraplegia and mental retardation during childhood. The proband and her sister had peripheral neuropathy, whereas their father developed compression neuropathy. Leigh encephalopathy was diagnosed neuropathologically. Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum. Muscle biopsy revealed type 2 fiber uniformity and decreased staining of cytochrome c oxidase. The COX10 missense mutation was identified through whole-exome sequence. A 1.4-Mb genomic deletion extending from intron 5 of COX10 to PMP22 was detected.

    Discussion

    These findings suggest that in this family, Leigh syndrome is associated with a mitochondrial respiratory chain complex IV deficiency caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion.

    DOI: 10.1212/nxg.0000000000200030

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  • アルツハイマー病患者尿中におけるグリセロリン脂質代謝関連代謝物の変動

    渡邊 裕美, 春日 健作, 徳武 孝允, 北村 香織, 池内 健, 中村 和利

    Dementia Japan   36 ( 4 )   760 - 760   2022.10

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  • パーキンソン症候群の治療法開発の最前線 PSPの新規治療法開発 どのように臨床試験を成功させるか

    金澤 雅人, 春日 健作, 島田 斉, 池内 健, 小野寺 理

    神経治療学   39 ( 6 )   S118 - S118   2022.10

  • 特発性正常圧水頭症の症例で複合病理を考慮する 5症例のバイオマーカーから

    伊関 千書, 小林 良太, 春日 健作, 鈴木 佑弥, 猪狩 龍佑, 佐藤 裕康, 小山 信吾, 板垣 寛, 池内 健, 園田 順彦, 太田 康之

    Dementia Japan   36 ( 4 )   786 - 786   2022.10

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  • 神経炎症と認知症アジテーション症状との関係 生体内PETイメージング研究

    安野 史彦, 木村 泰之, 小縣 綾, 阿部 潤一郎, 南 博之, 二橋 尚志, 横井 克典, 服部 沙織, 下田 信義, 渡邉 淳, 春日 健作, 池内 健, 武田 章敬, 櫻井 孝, 伊藤 健吾, 加藤 隆司

    Dementia Japan   36 ( 4 )   796 - 796   2022.10

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  • 治験即応コホートJ-TRCにおける血漿アミロイドβ測定の有用性に関する検討

    新美 芳樹, 佐藤 健一郎, 冨田 尚希, 岩田 淳, 塚本 忠, 加藤 隆司, 吉山 顕次, 古和 久朋, 春日 健作, 池内 健, 石井 賢二, 伊藤 健吾, 千田 道雄, 岩坪 威

    Dementia Japan   36 ( 4 )   783 - 783   2022.10

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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   20   5296 - 5308   2022.8

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    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. International journal

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

    Parkinsonism & related disorders   102   30 - 35   2022.7

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    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.

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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   2022.7

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    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.

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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. International journal

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

    Foods (Basel, Switzerland)   11 ( 6 )   2022.3

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    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 &lt; 0.05). Moreover, subjects who consumed the WFBSK rice had lower insulin secretion levels than those who consumed the control polished rice (p &lt; 0.05).

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  • アルツハイマー病患者尿中代謝産物の網羅的解析

    渡邊 裕美, 春日 健作, 徳武 孝允, 北村 香織, 池内 健, 中村 和利

    日本衛生学雑誌   77 ( Suppl. )   S204 - S204   2022.3

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  • アルツハイマー病患者尿中代謝産物の網羅的解析

    渡邊 裕美, 春日 健作, 徳武 孝允, 北村 香織, 池内 健, 中村 和利

    日本衛生学雑誌   77 ( Suppl. )   S204 - S204   2022.3

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

    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 )   2022.2

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    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.

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  • Presenilin is essential for ApoE secretion, a novel role of presenilin involved in Alzheimer's disease pathogenesis. Reviewed International journal

    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   2022.1

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    Alzheimer disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β-protein (Aβ) into amyloid plaques in patient brain. 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 (NCT) 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, expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal controls. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENTFAD typically results from mutations in the genes encoding amyloid precursor protein (APP), PS1 or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased Aβ42/Aβ40 ratio, which induce early amyloid deposition and FAD. On the other hand, ApoE4 is the major genetic risk factor for 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.

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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. International journal

    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

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    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.

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  • White Matter Lesions May Aid in Differentiating Idiopathic Normal Pressure Hydrocephalus and Alzheimer's Disease. Reviewed International journal

    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   2021.12

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    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, Aβ 40, Aβ 38, 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 Aβ 38 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.

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  • Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Reviewed International journal

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

    Translational psychiatry   11 ( 1 )   558 - 558   2021.11

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    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.

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  • 認知症のゲノム医療 APOEの遺伝型とミスセンスレアバリアント:臨床応用への可能性

    宮下 哲典, 原 範和, 春日 健作, 菊地 正隆, 尾崎 浩一, 新飯田 俊平, 他田 真理, 柿田 明美, 池内 健

    Dementia Japan   35 ( 4 )   585 - 585   2021.10

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  • ヒト剖検脳による神経疾患横断的なレアバリアント解析 APOE

    宮下 哲典, 他田 真理, 原 範和, 長谷川 舞衣, 月江 珠緒, Lixin Liu, Bin Zhu, Yusran Ady Fitrah, 春日 健作, 菊地 正隆, 柿田 明美, 池内 健

    Dementia Japan   35 ( 4 )   650 - 650   2021.10

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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   2021.10

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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   2021.10

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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   2021.10

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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   2021.10

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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   2021.10

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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   2021.10

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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   2021.9

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  • Follow-up study of a patient with early onset cerebral amyloid angiopathy following childhood cadaveric dural graft. Reviewed International journal

    Kenji Yoshiki, Genjiro Hirose, Kazuhiko Kumahashi, Yukihiko Kohda, Kazunori Ido, Akihiro Shioya, Kouichi Misaki, Kensaku Kasuga

    Acta neurochirurgica   163 ( 5 )   1451 - 1455   2021.5

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    We retrospectively studied the T2 star (T2*)-weighted magnetic resonance imaging (MRI) of a 40-year-old patient diagnosed with symptomatic early-onset cerebral amyloid angiopathy (CAA), occurring 34 years following childhood neurosurgery using a cadaveric dural patch. Our findings revealed that CAA associated with cadaveric dural transplantation could progress rapidly, sometimes with bilateral bleeding. This microbleed evolution is suggestive of water-soluble amyloid-β transmission via cerebrospinal fluid alongside perivascular drainage pathways with deposition in the cerebral artery walls due to clearance disturbances. Multiple intracerebral hemorrhages associated with CAA with a childhood cadaveric dural graft should be considered a life-threatening medical complication.

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  • アルツハイマー病患者における尿中ApoC3、Igfbp3、ApoDタンパク質濃度の検討

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

    日本衛生学雑誌   76 ( Suppl. )   S173 - S173   2021.3

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

    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

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    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.

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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. Reviewed International journal

    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

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    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.

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  • Toxic Amyloid-β42 Conformer May Accelerate the Onset of Alzheimer's Disease in the Preclinical Stage. Reviewed International journal

    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

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    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.

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

    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

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    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.

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

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

    Frontiers in neurology   12   719159 - 719159   2021

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    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.

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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

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    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.

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  • Urinary Apolipoprotein C3 Is a Potential Biomarker for Alzheimer’s Disease Reviewed

    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   2020.9

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    &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.

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  • Refractory Myositis Affecting the Intrinsic Muscles of the Hand. Reviewed

    Kosei Nakamura, Akihiro Sugai, Etsuji Saji, Kensaku Kasuga, Osamu Onodera

    Internal medicine (Tokyo, Japan)   59 ( 9 )   1211 - 1214   2020.5

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    Myositis generally affects the proximal muscles. However, we herein report a case of a 48-year-old woman with intractable myositis affecting the intrinsic muscles of the hands. Her myositis, which developed in childhood, was refractory to treatment with steroids and several immunosuppressants, causing walking disability. After experiencing pain and swelling in the hands for six months, she was diagnosed with myositis of the intrinsic muscles of the hands and tested positive for the anti-signal recognition particle antibody. Intravenous immunoglobulin therapy improved the myositis of the hands. This case suggests that inflammation caused by intractable myositis can extend to the hands.

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  • A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease

    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 M. McDade, Ricardo Allegri, Jacob Bechara, Tammie Benzinger, Sarah Berman, Courtney Bodge, Susan Brandon, William (Bill) Brooks, Jill Buck, Sochenda Chea, Patricio Chrem Mendez, Helena Chui, Jake Cinco, Jack Clifford, Carlos Cruchaga, Tamara Donahue, Jane Douglas, Noelia Edigo, Nilufer Erekin-Taner, Anne Fagan, Martin Farlow, Colleen Fitzpatrick, Gigi Flynn, Erin Franklin, Hisako Fujii, Cortaiga Gant, Samantha Gardener, Bernardino Ghetti, Alison Goate, Jill Goldman, Neill Graff-Radford, Julia Gray, Alexander Groves, Jason Hassenstab, Laura Hoechst-Swisher, David Holtzman, Russ Hornbeck, Siri Houeland DiBari, Snezana Ikonomovic, Gina Jerome, Celeste Karch, Kensaku Kasuga, Takeshi Kawarabayashi, William (Bill) Klunk, Robert Koeppe, Elke Kuder-Buletta, Christoph Laske, Jae-Hong Lee, Johannes Levin, Ralph Martins, Neal Scott Mason, Denise Maue-Dreyfus, Hiroshi Mori, Akem Nagamatsu, Katie Neimeyer, Joanne Norton, Richard Perrin, Marc Raichle, Alan Renton, John Ringman, Jee Hoon Roh, Peter Schofield, Hiroyuki Shimada, Wendy Sigurdson, Hamid Sohrabi, Paige Sparks, Kazushi Suzuki, Kevin Taddei, Peter Wang, Xiong Xu, the Dominantly Inherited Alzheimer Network

    Nature Medicine   26 ( 3 )   398 - 407   2020.3

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    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.

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

    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   2019.1

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    DOI: 10.1159/000496100

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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. Reviewed International journal

    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

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    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.

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  • Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy. Reviewed International journal

    Naomi Mezaki, Takeshi Miura, Kotaro Ogaki, Makoto Eriguchi, Yuri Mizuno, Kenichi Komatsu, Hiroki Yamazaki, Natsuki Suetsugi, Sumihiro Kawajiri, Ryo Yamasaki, Takanobu Ishiguro, Takuya Konno, Hiroaki Nozaki, Kensaku Kasuga, Yasuyuki Okuma, Jun-Ichi Kira, Hideo Hara, Osamu Onodera, Takeshi Ikeuchi

    Neurology. Genetics   4 ( 6 )   e292   2018.12

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    Objective: To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). Methods: Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. Results: We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. Conclusions: We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.

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  • 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. Reviewed International journal

    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   2018.10

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    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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  • Case Report: A patient with spinocerebellar ataxia type 31 and sporadic Creutzfeldt-Jakob disease. Reviewed International journal

    Natsumi Saito, Tomohiko Ishihara, Kensaku Kasuga, Mana Nishida, Takanobu Ishiguro, Hiroaki Nozaki, Takayoshi Shimohata, Osamu Onodera, Masatoyo Nishizawa

    Prion   12 ( 2 )   147 - 149   2018.3

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    We report a Japanese patient with spinocerebellar ataxia type 31 (SCA31) and sporadic Creutzfeldt-Jakob disease (sCJD). A 52-year-old man developed progressive cognitive impairment after the appearance of cerebellar symptoms. Brain MR diffusion-weighted imaging (DWI) demonstrated a slowly expanding hyperintense lesion in the cerebral cortex. The patient was finally diagnosed as having both SCA31 and sCJD by identification of genetic mutations and by real-time quaking-induced conversion (RT-QUIC) analysis of the cerebrospinal fluid (CSF), respectively. Here, we report the clinical details of this rare combined case, with particular reference to the association between prion protein and the early onset of SCA31.

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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. Reviewed International journal

    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

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

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

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

    BMC neurology   17 ( 1 )   182 - 182   2017.9

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    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.

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

    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   2017.2

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    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 β-secretase and acetylcholinesterase even after heating. Black rice bran showed greater β-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 β 40 peptide in the blood than mice fed a commercial diet (p < 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 β production, but also abrupt increases in postprandial BGLs.

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

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

    a literature review. BMC Neurology   2017

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  • Multifunctional roles of APOE in Alzheimer's disease pathogenesis

    Tokutake, T., Kasuga, K., Hara, N., Ikeuchi, T.

    Brain and Nerve   68 ( 7 )   2016

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  • Multifocal hits for propagation of prion protein in sporadic Creutzfeldt-Jakob disease. Reviewed International journal

    Kensaku Kasuga, Ryoko Takeuchi, Toshiaki Takahashi, Nae Matsubara, Ryoko Koike, Akio Yokoseki, Masatoyo Nishizawa

    Neurology(R) neuroimmunology & neuroinflammation   2 ( 1 )   e53   2015.2

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  • ApoE-isoform-dependent cellular uptake of amyloid-β is mediated by lipoprotein receptor LR11/SorLA. Reviewed International journal

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

    Biochemical and biophysical research communications   456 ( 1 )   482 - 8   2015.1

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    The formation of senile plaques composed of β-amyloid (Aβ) in the brain is likely the initial event in Alzheimer's disease (AD). Possession of the APOE ε4 allele, the strong genetic factor for AD, facilitates the Aβ 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-β (Aβ) through the binding of Aβ 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 Aβ 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>apoE3>apoE2). ApoE-isoform-dependent differences in cellular uptake of FAM-labeled Aβ 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 Aβ into the recipient cells was most prominently accentuated when cocultured 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 Aβ mediated by LR11/SorLA.

    DOI: 10.1016/j.bbrc.2014.11.111

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  • Reduced CSF Water Influx in Alzheimer's Disease Supporting the β-Amyloid Clearance Hypothesis. Reviewed International journal

    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 )   e0123708   2015

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    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 ≥ 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 [15O]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 < 0.001) and also compared to normal senior controls (0.981 ± 0.253, p < 0.05). Influx ratio in normal senior controls was significantly reduced compared to young controls (p < 0.01). CONCLUSION: Water influx into the CSF is significantly reduced in AD patients. β-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 β-amyloid, and therefore be linked to the pathogenesis of AD. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000011939.

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  • リポ蛋白受容体LR11によるApoE isoform依存性のApoE-Aβ複合体代謝調節機構の解析

    矢島 隆二, 徳武 孝允, 小山 哲秀, 手塚 敏之, 春日 健作, 西澤 正豊, 池内 健

    臨床神経学   54 ( Suppl. )   S183 - S183   2014.12

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  • 構音障害と上位運動ニューロン徴候で発症し、後に特異な失語を呈した81歳の女性例

    宇津見 宏太, 春日 健作, 眞島 卓弥, 大槻 美佳, 下畑 享良, 西澤 正豊

    臨床神経学   54 ( 5 )   449 - 449   2014.5

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  • A Japanese family with idiopathic basal ganglia calcification with novel SLC20A2 mutation presenting with late-onset hallucination and delusion. Reviewed International journal

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

    Journal of neurology   261 ( 1 )   242 - 4   2014.1

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  • Brain insulin signaling and cognition

    Tokutake, T., Kasuga, K., Ikeuchi, T.

    Journal of the Japan Diabetes Society   57 ( 9 )   2014

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  • Parkinsonian features in a patient with diffuse neurofibrillary tangles with calcification (DNTC). Reviewed International journal

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

    Parkinsonism & related disorders   18 ( 5 )   649 - 50   2012.6

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

    Kensaku Kasuga, Takeshi Ikeuchi

    Brain and nerve = Shinkei kenkyu no shinpo   64 ( 5 )   505 - 13   2012.5

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    Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in the elderly. DLB is clinically characterized by fluctuating cognitive dysfunction, visual hallucinations, and parkinsonism. It is sometimes difficult to clinically diagnose patients with DLB because of the overlap of the clinical and pathological findings of this disease with those of Alzheimer's disease. Precise clinical diagnosis is important for determining the drug therapy appropriate for improving DLB symptoms. Biomarkers that enable more accurate diagnosis of DLB and reflect its complex clinical progression are highly desired. Cognitive impairment frequently occurs in patients with Parkinson's disease (PD). The common pathological features of DLB and PD are Lewy bodies and Lewy neurites, both of which are composed of α-synuclein. DLB and PD are now considered to belong to a common spectrum of disorders designated as Lewy body disease (LBD). We have previously reported that the α-synuclein levels in cerebrospinal fluid (CSF) are significantly lower in patients with DLB than in patients with other types of dementia. However, the significance of quantifying the CSF α-synuclein levels as a biomarker for DLB has been a matter of debate because the results for these levels have been inconsistent among different studies. Similar inconsistency has been observed in studies on the plasma α-synuclein levels in patients with LBD. Here, we review the recent progress on biomarkers of LBD, especially in DLB, and discuss their application to clinical diagnosis.

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  • α-Synuclein as CSF and Blood Biomarker of Dementia with Lewy Bodies. Reviewed International journal

    Kensaku Kasuga, Masatoyo Nishizawa, Takeshi Ikeuchi

    International journal of Alzheimer's disease   2012   437025 - 437025   2012

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    Dementia with Lewy bodies (DLB) is a common subtype of dementia in the elderly. DLB is neuropathologically characterized by the presence of Lewy bodies and Lewy neurites, both of which are composed of α-synuclein. Although α-synuclein was initially considered to be an exclusively intracellular protein, it has been found to be secreted into biological fluids. α-Synuclein in biological fluids such as cerebrospinal fluid (CSF) and blood has been discussed as a potential biomarker of DLB and α-synuclein-related disorders, because α-synuclein is characteristically accumulated in the brain of patients with these disorders. The α-synuclein level in CSF has been examined by several investigators, and the majority of studies have shown a reduction in CSF α-synuclein level in DLB and α-synuclein-related disorders. Discrepant findings of studies of plasma α-synuclein level in patients with DLB have been reported. Because the level of α-synuclein stored in red blood cells is considerably high, blood contamination and haemolysis during sample collection and processing should be considered as a confounding factor for quantification of α-synuclein. Here, the recent progress in the studies of α-synuclein as a biomarker of DLB and their potential clinical applications are reviewed.

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  • A patient with fragile x-associated tremor/ataxia syndrome presenting with executive cognitive deficits and cerebral white matter lesions. Reviewed International journal

    Kensaku Kasuga, Takeshi Ikeuchi, Keiko Arakawa, Ryuji Yajima, Takayoshi Tokutake, Masatoyo Nishizawa

    Case reports in neurology   3 ( 2 )   118 - 23   2011.5

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    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that primarily affects males who are carriers of a premutation of a CGG expansion in the FMR1 gene. In Asian populations, FXTAS has rarely been reported. Here, we report the case of a Japanese FXTAS patient who showed predominant executive cognitive deficits as the main feature of his disease. In contrast, the patient exhibited only very mild symptoms of intention tremor and ataxia, which did not interfere with daily activities. A gene analysis revealed that the patient carried a premutation of a CGG expansion (111 CGG repeats) in the FMR1 gene. The mRNA expression level of FMR1 in the patient was 1.5-fold higher than in controls. On brain MRI scans, fluid-attenuated inversion recovery images showed high-intensity lesions in the middle cerebellar peduncles and the cerebral white matter, with a frontal predominance. The present case extends previous notions regarding the cognitive impairment in FXTAS patients. Recognizing FXTAS patients with predominant cognitive impairment from various ethnic backgrounds would contribute to our understanding of the phenotypic variation of this disease.

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  • Evidence for a Common Founder and Clinical Characteristics of Japanese Families with the MAPT R406W Mutation. Reviewed International journal

    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   2011.1

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

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  • Increased levels of soluble LR11 in cerebrospinal fluid of patients with Alzheimer disease. Reviewed International journal

    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

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    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 (Abeta42) were determined by sandwich ELISA. RESULTS: The CSF tau level and tau/Abeta42 ratio were significantly increased (p < 0.01) in the AD patients. The CSF sLR11 level in the AD patients was significantly higher (p < 0.01) than that of the frontotemporal lobar degeneration patients and the controls. The APOE-epsilon4-positive AD patients have higher sLR11 levels than the APOE-epsilon4-negative patients (p < 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.

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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. Reviewed International journal

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

    Journal of neurology   256 ( 8 )   1351 - 3   2009.8

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  • The 28-amino acid form of an APLP1-derived Abeta-like peptide is a surrogate marker for Abeta42 production in the central nervous system. Reviewed International journal

    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 - 35   2009.7

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    Surrogate markers for the Alzheimer disease (AD)-associated 42-amino acid form of amyloid-beta (Abeta42) 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 Abeta-like peptides (APL1beta) that are generated by beta- and gamma-cleavages at a concentration of approximately 4.5 nM. These novel peptides, APL1beta25, APL1beta27 and APL1beta28, were not deposited in AD brains. Interestingly, most gamma-secretase modulators (GSMs) and familial AD-associated presenilin1 mutants that up-regulate the relative production of Abeta42 cause a parallel increase in the production of APL1beta28 in cultured cells. Moreover, in CSF from patients with pathological mutations in presenilin1 gene, the relative APL1beta28 levels are higher than in non-AD controls, while the relative Abeta42 levels are unchanged or lower. Most strikingly, the relative APL1beta28 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 APL1beta28 in the CSF as a candidate surrogate marker for the relative level of Abeta42 production in the brain.

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

    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   2008.10

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    DOI: 10.1212/01.wnl.0000327607.28928.e6

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  • Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia. Reviewed International journal

    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 - 9   2008.4

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    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.

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  • Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Reviewed International journal

    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 - 9   2008

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    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.

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

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

    NEUROSCIENCE RESEARCH   61   S264 - S264   2008

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  • Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 deltaT440 mutant associated with familial Lewy body disease and variant Alzheimer's disease. Reviewed International journal

    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

    The Journal of neuroscience : the official journal of the Society for Neuroscience   27 ( 48 )   13092 - 7   2007.11

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    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 (deltaT440) 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 deltaT440 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, deltaE9, and PS1 deltaT440 mutants and now demonstrate that the expression of the PS1 deltaT440 mutant led to a marked elevation in the ratio of beta-amyloid (Abeta) 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 deltaT440 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 deltaT440 mutation. These observations raise the intriguing suggestion that the mechanism(s) by which the PS1 deltaT440 mutant causes DLB and variant AD are by enhancing the phosphorylation of alpha-synuclein and the ratio of Abeta(42/40) peptides, respectively, in the brain.

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  • Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3. Reviewed International journal

    Takayoshi Shimohata, Kenju Hara, Kazuhiro Sanpei, Jin-ichi Nunomura, Tetsuya Maeda, Izumi Kawachi, Masato Kanazawa, Kensaku Kasuga, Akinori Miyashita, Ryozo Kuwano, Koichi Hirota, Shoji Tsuji, Osamu Onodera, Masatoyo Nishizawa, Yoshiaki Honma

    Brain : a journal of neurology   130 ( Pt 9 )   2302 - 9   2007.9

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    Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 (average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called 'senile chorea'. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3-q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (theta = 0.00). Haplotype analysis of both the families defined the candidate region as 21.5 Mb interval flanked by M9267 and D8S1139. We named this adult-onset dominant inherited chorea 'benign hereditary chorea type 2 (BHC2)'.

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  • Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3. Reviewed

    Shimohata Takayoshi, Hara Kenju, Sanpei Kazuhiro, Nunomura Jin-ichi, Maeda Tetsuya, Kawachi Izumi, Kanazawa Masato, Kasuga Kensaku, Miyashita Akinori, Kuwano Ryozo, Hirota Koichi, Tsuji Shoji, Onodera Osamu, Nishizawa Masatoyo, Honma Yoshiaki

    Brain   130 ( Pt 9 )   2302 - 2309   2007.9

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    Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 (average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called &#039;senile chorea&#039;. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3-q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (theta = 0.00). H

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

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

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   360 ( 1 )   90 - 96   2007.8

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    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.

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  • SPECTでposterior circulationの可逆的血流低下を認めた高血圧性脳症の2例

    春日 健作, 三浦 智史, 梅田 能生, 成瀬 聡, 藤田 信也

    神経内科   66 ( 6 )   593 - 597   2007.6

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    SPECTでposterior circulation(PC)の可逆的血流低下を認めた高血圧性脳症の2例を経験した。症例1は52歳女性であった。5年前から高血圧を放置していたが、目のかすみで近医にて眼底に乳頭浮腫を認め紹介入院した。血圧は219/146mmHg、腎機能障害及び頭部MRIで後頭葉白質から脳幹・小脳を主体としたPCの病変を認めた。降圧療法で目のかすみ、MRI上の異常所見は消失し、入院5日目の99mTc-HMPAO SPECTで認めたPCの血流低下も改善した。症例2は50歳女性であった。30歳代から高血圧を放置していたが、嘔気、嘔吐で他院に搬送され、血圧300mmHG以上、全身痙攣を来し、CTで右後頭側頭葉に出血を認め紹介入院した。意識障害、眼底に乳頭浮腫、左下肢に不全麻痺、左心不全及び頭部MRIで脳幹・小脳・両側前頭葉白質に及ぶ広範なPCの病変を認めた。降圧療法で意識障害、心不全は改善し、MRI上の異常所見は消失した。また、入院2週の99mTc-HMPAO SPECTで認めた脳出血部位とPCの血流低下は著明に改善した。

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  • New locus for benign hereditary chorea with adult-onset maps to chromosome 8q22.2-q23.3 Reviewed

    Kenju Hara, Takayoshi Shimohata, Sanpei Kazuhiro, Jin-ichi Nunomura, Izumi Kawachi, Masato Kanazawa, Kensaku Kasuga, Akinori Miyashita, Ryozo Kuwano, Koichi Hirota, Shoji Tsuji, Osamu Onodera, Masatoyo Nishizawa, Yoshiaki Honma

    NEUROLOGY   68 ( 12 )   A326 - A327   2007.3

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  • [Case of cerebral venous thrombosis due to graves' disease with increased factor VIII activity]. Reviewed

    Kensaku Kasuga, Satoshi Naruse, Maiko Umeda, Midori Tanaka, Nobuya Fujita

    Rinsho shinkeigaku = Clinical neurology   46 ( 4 )   270 - 3   2006.4

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    A 39 year-old man was admitted to our hospital because of severe headache with fever continuing over two weeks. Three days after admission he developed aphasia and right hemiparesis, when his CT revealed subarachnoid hemorrhage at the left sylvian fissure. He was diagnosed as suffering from cerebral venous thrombosis because empty delta sign was positive on the enhanced brain CT. Suprasagittal sinus and bilateral transverse sinuses were not detected on the cerebral angiography. He was also diagnosed as having Graves' disease for the first time on the basis of free T3 13.56 pg/ml, free T4 4.65 ng/dl, TSH < 0.01 IU/ml, anti-TSH receptor antibody 4.3 IU/l, and thyroid stimulating antibody 224%. On the examination, homocystine and activities of antithrombin III, protein C, and protein S were normal. Antinculear, anti-DNA, anti-Sm, anticardiolipin beta2GP-I antibodies, and PR3ANCA were negative. Factor VIII activity, however, markedly increased over 300%, which has been known to increase in the cases of hyperthyroidism. He recovered well after the treatment with thiamazole in addition to warfarin followed by intravenous heparin. There are only six cases of cerebral venous thrombosis due to hyperthyroidism with increased factor VIII level. All of those cases were female, and 5 of them were taking oral contraceptives. This is a first Japanese male case.

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  • Recurrent hypertensive brainstem encephalopathy Reviewed

    M Kanazawa, K Sanpei, K Kasuga

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY   76 ( 6 )   888 - 890   2005.6

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    DOI: 10.1136/jnnp.2004.059543

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    Other Link: http://orcid.org/0000-0001-6337-8156

  • [Recent progress in genetic study of hereditary spastic paraplegia]. Reviewed

    Hiroki Takano, Kensaku Kasuga, Hisa Kobayashi, Masatoyo Nishizawa

    No to shinkei = Brain and nerve   55 ( 9 )   757 - 63   2003.9

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  • [Hereditary spastic paraplegia associated with thin corpus callosum]. Reviewed

    Kensaku Kasuga, Masatoyo Nishizawa

    No to shinkei = Brain and nerve   55 ( 9 )   765 - 70   2003.9

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  • Delayed onset acute renal failure associated with Amanita pseudoporphyria Hongo ingestion. Reviewed

    Yoichi Iwafuchi, Takashi Morita, Hideyuki Kobayashi, Kensaku Kasuga, Kazuhisa Ito, Osamu Nakagawa, Kaoru Kunisada, Shigeru Miyazaki, Akira Kamimura

    Internal medicine (Tokyo, Japan)   42 ( 1 )   78 - 81   2003.1

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    A 66-year-old man with diabetes developed acute renal failure after ingestion of Amanita pseudoporphyria Hongo. Laboratory data showed acute nonoliguric renal failure. A renal biopsy showed acute tubular necrosis with glomerular minor abnormalities. He received hemodialysis treatment for 3 weeks and his renal function normalized 2 months after admission. We discuss the differences in acute renal failure caused by possible toxins of Amanita pseudoporphyria Hongo from that caused by other poisonous mushrooms.

    DOI: 10.2169/internalmedicine.42.78

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Books

  • 非定型パーキンソニズム : 基礎と臨床

    下畑, 享良

    文光堂  2019  ( ISBN:9784830615474

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    Total pages:xxvii, 242p   Language:Japanese

    CiNii Books

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MISC

  • この症例をどう診るか-今,診断バイオマーカーの意義を再考する-症例検討

    竹野下尚仁, 春日健作, 春日健作, 池内健, 石井賢二, 清水聰一郎, 小林良太, 川勝忍, 金田大太, 松田実

    老年精神医学雑誌   35   2024

  • 血漿ニューロフィラメント軽鎖と脳脊髄液バイオマーカーの臨床的有用性の検討

    春日健作, 月江珠緒, 五十嵐一也, 五十嵐一也, 石黒敬信, 徳武孝允, 小野寺理, 池内健

    日本神経学会学術大会プログラム・抄録集   64th   2023

  • CSF1R関連白質脳症:部分欠失を含む新規CSF1R変異の同定と臨床・画像的特徴

    石黒敬信, 今野卓哉, 原範和, 朱斌, 岡田聡, 柴田護, 雑賀玲子, 北野貴也, 祢津智久, 浜由香, 川添僚也, 岩田育子, 佐藤恒太, 春日健作, 宮下哲典, 小野寺理, 池内健

    日本神経学会学術大会プログラム・抄録集   64th   2023

  • Development of novel disease-modifying therapies against progressive supranuclear palsy -How to conduct successful clinical trials-

    金澤雅人, 春日健作, 島田斉, 池内健, 小野寺理

    神経治療学(Web)   40 ( 3 )   2023

  • APP依存的な新規タウ分泌現象の発見

    佐藤 玄謙, 春日 健作, 磯尾 紀子, 林 俊宏, 堀 由起子, 池内 健, 富田 泰輔

    日本生化学会大会プログラム・講演要旨集   95回   1P - 358   2022.11

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  • 認知症に対する全国規模のレジストリ研究・多施設共同研究・調査Up to Date DIAN-Japan研究-観察研究と治療介入研究-

    池内健, 春日健作, 新美芳樹, 井原涼子, 千田道雄, 石井賢二

    老年精神医学雑誌   33 ( 2 )   2022

  • プレセニリンはApoEの分泌に必須である

    イスラム サデクル, 孫陽, 高原, 中村知寿, ARSHAD Ali Noorani, 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   36 ( 4 )   2022

  • 脳脊髄液バイオマーカーがアルツハイマー病型を呈した大脳皮質基底核症候群の特徴

    石黒敬信, 春日健作, 徳武孝允, 五十嵐一也, 月江珠緒, 今野卓哉, 小野寺理, 池内健

    Dementia Japan   36 ( 4 )   2022

  • 多系統萎縮症における脳脊髄液神経変性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, 下畑享良, 小野寺理, 池内健

    Dementia Japan   36 ( 4 )   2022

  • 非アルツハイマー型認知症における脳脊髄液アミロイドマーカーの挙動

    春日健作, 月江珠緒, 五十嵐一也, 石黒敬信, 徳武孝允, 宮下哲典, 池内健

    Dementia Japan   36 ( 4 )   2022

  • 多系統萎縮症での脳脊髄液バイオマーカーと臨床症状との関連

    徳武孝允, 春日健作, 月江珠緒, 石黒敬信, 下畑享良, 小野寺理, 池内健

    日本神経学会学術大会プログラム・抄録集   63rd   2022

  • 脳脊髄液リン酸化タウ測定およびPiB-PETを施行したiNPHの5症例

    伊関千書, 小林良太, 春日健作, 鈴木佑弥, 猪狩龍佑, 佐藤裕康, 小山信吾, 大谷浩一, 池内健, 板垣寛, 園田順彦, 太田康之

    日本正常圧水頭症学会プログラム・抄録集   23rd   2022

  • 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 )   2020

  • 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 )   2020

  • 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   2019.11

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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   2019.11

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    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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  • 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, 樋口陽, 石黒敬信, 石黒敬信, 徳武孝允, 宮下哲典, 小野寺理, 池内健

    日本神経学会学術大会プログラム・抄録集   59 ( Suppl. )   S217 - S217   2019.11

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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   2019.11

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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   2019.11

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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   2019.11

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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   2019.10

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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   2019.10

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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   2019.10

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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   2019.10

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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   2019.10

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  • 認知症は告知すべき?すべきではない? 認知症は告知「すべき」の立場から

    春日 健作

    Dementia Japan   33 ( 4 )   507 - 507   2019.10

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  • PARTとSNAPの最新知見 CSFバイオマーカーによるSNAPの再考

    春日 健作

    Dementia Japan   33 ( 4 )   495 - 495   2019.10

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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, 樋口陽, 春日健作, ZHU Bin, LIU Lixin, 石黒敬信, 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   2019.10

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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   2019.10

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  • ヒト死後脳におけるAPP・APOEの遺伝子発現解析

    LIU Lixin, 宮下哲典, 村上涼太, ZHU Bin, 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   2019.10

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  • 手内筋にまで炎症が波及し免疫グロブリン大量静注療法が奏功した難治性筋炎の51歳女性例

    中村 航世, 須貝 章弘, 春日 健作, 徳武 孝允, 小野寺 理

    臨床神経学   59 ( 9 )   615 - 615   2019.9

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  • 【認知症の今と未来を捉える-超早期診断時代を迎える前に-】診断 アルツハイマー病のCSFバイオマーカー

    春日 健作

    クリニシアン   66 ( 7 )   578 - 583   2019.7

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  • 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

    日本神経学会学術大会プログラム・抄録集   60th   2019

  • 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   2018.12

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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   2018.9

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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   2018.9

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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   2018.9

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  • 家族性アルツハイマー病で同定された新規PSEN1変異の病的意義の検討

    ZHU Bin, 村上涼太, LIU Lixin, 樋口陽, 石黒敬信, 三浦健, 目崎直美, 月江珠緒, 原範和, 春日健作, 宮下哲典

    Dementia Japan   32 ( 3 )   448 - 448   2018.9

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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   2018.9

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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   2018.9

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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   2018.8

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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   2018.4

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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   2018.2

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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   2018.2

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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   2017.10

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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   2017.10

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  • パーキンソン病患者の認知機能およびADL低下と脳血流SPECT変化

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

    Dementia Japan   31 ( 4 )   582 - 582   2017.10

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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   2017.10

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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   2017.10

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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   2017.10

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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   31 ( 4 )   560 - 560   2017.10

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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   2017.10

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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   2017.10

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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   2017.10

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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   2017.10

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  • 糖尿病および認知症の複合予防効果の期待される米飯開発の試み

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

    応用糖質科学   7 ( 3 )   34 - 34   2017.8

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  • Genetic risk factors for Alzheimer disease

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

    老年精神医学雑誌   28 ( 7 )   754 - 765   2017.7

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  • 【アルツハイマー病の次世代診断・治療に向けた新知見】アルツハイマー病の新しい脳脊髄液バイオマーカーとその臨床的意義 Reviewed

    春日 健作

    分子精神医学   17 ( 2 )   92 - 103   2017.4

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    アルツハイマー病の病態を反映した脳脊髄液バイオマーカーとしてAβ1-42、総タウ蛋白、リン酸化タウ蛋白は、老人斑や神経原線維変化といった病理所見と相関し、その有用性はほぼ確立している。しかしアルツハイマー病の病態では早期からシナプスが障害されることや、炎症が深くかかわることが知られており、これらを反映する新規の脳脊髄液バイオマーカーとしてVILIP-1、neurogranin、YKL-40、sTREM2に関する知見が蓄積されつつある。いずれも早期からの病態検出を可能にし、予後予測における有用性が報告されているが、既存のバイオマーカーと比較し優越性を示せたものはない。(著者抄録)

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  • アルツハイマー病の新しい脳脊髄液バイオマーカーとその臨床的意義 (特集 アルツハイマー病の次世代診断・治療に向けた新知見)

    春日 健作

    分子精神医学   17 ( 2 )   92 - 103   2017.4

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  • 成人発症白質脳症におけるLaminB1関連常染色体優性白質脳症 遺伝子変異と臨床的特徴

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

    臨床神経学   56 ( Suppl. )   S444 - S444   2016.12

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  • 意味性認知症の臨床症状・画像的特徴・脳脊髄液バイオマーカーの検討

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

    Dementia Japan   30 ( 4 )   583 - 583   2016.10

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

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

    Dementia Japan   30 ( 4 )   599 - 599   2016.10

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  • 若年性アルツハイマー病の臨床早期にみられた非典型的進行性失語について

    横山 裕一, 春日 健作, 池内 健, 吉田 悠里, 染矢 俊幸

    Dementia Japan   30 ( 4 )   537 - 537   2016.10

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  • 意味性認知症の臨床症状・画像的特徴・脳脊髄液バイオマーカーの検討

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

    Dementia Japan   30 ( 4 )   583 - 583   2016.10

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

    徳武 孝允, 春日 健作, 原 範和, 池内 健

    BRAIN and NERVE: 神経研究の進歩   68 ( 7 )   703 - 712   2016.7

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

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  • Preclinical and early clinical stages of Alzheimer's disease Reviewed

    春日 健作

    日本早期認知症学会誌 = The journal of Japan Society for Early Stage of Dementia   9 ( 1 )   5 - 9   2016.6

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

    原 範和, 春日 健作, 宮下 哲典, 池内 健

    臨床精神医学   45 ( 4 )   395 - 403   2016.4

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  • 【アルツハイマー病UPDATE】画像・バイオマーカー・病理 アルツハイマー病の脳脊髄液バイオマーカー Reviewed

    春日 健作, 池内 健

    医学のあゆみ   257 ( 5 )   511 - 518   2016.4

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    脳脊髄液(CSF)中のAβ1-42の低下、総タウ蛋白およびリン酸化タウの上昇は、脳内の老人斑および神経原線維変化といったアルツハイマー病(AD)に特徴的な病理変化を反映する。そのため認知症患者および軽度認知障害(MCI)者におけるAD群の診断のみならず、認知機能正常者のなかからAD病態を有する症例の検出を可能にした。またこれらAD関連CSFバイオマーカーは、MCI者あるいは認知機能正常者のその後の認知機能低下を予測する。しかしその測定値には施設間でのばらつきが大きく、いまだ確立されたカットオフ値が存在しない点が重要な課題である。(著者抄録)

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  • 脳アミロイドアンギオパチー関連炎症の多様性 臨床症状、バイオマーカー

    徳武 孝允, 石井 賢二, 本間 篤, 荒川 博之, 赤岩 靖久, 石黒 敬信, 春日 健作, 笠原 壮, 小池 佑佳, 藤田 信也, 大野 司, 田中 晋, 豊原 潤, 石渡 喜一, 西澤 正豊, 池内 健

    臨床神経学   55 ( Suppl. )   S422 - S422   2015.12

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  • 日本人アルツハイマー病に関連するコピー数変異のゲノム配列中での構造と分布

    中谷 明弘, 菊地 正隆, 宮下 哲典, 原 範和, 春日 健作, 西田 奈央, 徳永 勝士, 桑野 良三, 池内 健

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [2P1263] - [2P1263]   2015.12

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  • 本邦における家族性アルツハイマー病データベース(JFADdb)の構築

    春日 健作, 菊地 正隆, 徳武 孝允, 手塚 敏之, 月江 珠緒, 原 範和, 宮下 哲典, 中谷 明弘, 桑野 良三, 池内 健

    臨床神経学   55 ( Suppl. )   S424 - S424   2015.12

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  • 脳アミロイドアンギオパチー関連炎症の臨床・画像の検討

    徳武 孝允, 石井 賢二, 赤岩 靖久, 春日 健作, 藤田 信也, 田中 晋, 豊原 潤, 石渡 喜一, 西澤 正豊, 池内 健

    Dementia Japan   29 ( 3 )   358 - 358   2015.9

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  • アルツハイマー病の血清バイオマーカーとしてのマイクロRNA解析

    原 範和, 菊地 正隆, 宮下 哲典, 初田 裕幸, 齊藤 祐子, 村山 繁雄, 春日 健作, 池内 健, 桑野 良三

    Dementia Japan   29 ( 3 )   338 - 338   2015.9

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  • APP遺伝子重複による家族性アルツハイマー病および脳アミロイド血管症の1剖検例

    横山 裕一, 豊島 靖子, 鈴木 正博, 春日 健作, 橋立 英樹, 染矢 俊幸, 高橋 均, 池内 健, 柿田 明美

    Dementia Japan   29 ( 3 )   388 - 388   2015.9

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  • Clinical/scientific notes

    Kensaku Kasuga, Ryoko Takeuchi, Toshiaki Takahashi, Nae Matsubara, Ryoko Koike, Akio Yokoseki, Masatoyo Nishizawa

    Neurology: Neuroimmunology and NeuroInflammation   2 ( 1 )   2015.2

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    DOI: 10.1212/NXI.0000000000000053

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  • 本邦・家族性アルツハイマー病のデータベース(JFADdb)の構築

    春日 健作, 菊地 正隆, 徳武 孝允, 手塚 敏之, 月江 珠緒, 原 範和, 宮下 哲典, 中谷 明弘, 桑野 良三, 池内 健

    Dementia Japan   28 ( 4 )   485 - 485   2014.10

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  • 【高齢者の糖尿病】中枢神経におけるインスリンシグナルと認知機能 Reviewed

    徳武 孝允, 春日 健作, 池内 健

    糖尿病   57 ( 9 )   682 - 684   2014.9

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    DOI: 10.11213/tonyobyo.57.682

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  • 【高齢者脆弱性骨折の予防と治療】高齢者の特徴と周術期管理 認知症への対応 Reviewed

    春日 健作, 池内 健

    整形外科   65 ( 8 )   895 - 901   2014.7

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  • 12 原発性胆汁性肝硬変の経過中に筋炎・II型呼吸不全・不整脈を呈した1例(一般演題, 第54回下越内科集談会)

    128 ( 6 )   281 - 281   2014.6

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  • 【神経症候群(第2版)-その他の神経疾患を含めて-】 変性疾患 認知症症状を主とする疾患 アルツハイマー病 家族性アルツハイマー病

    池内 健, 春日 健作, 宮下 哲典

    日本臨床   別冊 ( 神経症候群II )   7 - 11   2014.3

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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一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

    日本神経学会学術大会プログラム・抄録集   55th   2014

  • アルツハイマー病における内側側頭葉の萎縮 VSRAD advanceを用いた左右差の検討

    手塚 敏之, 横関 明男, 徳武 孝允, 矢島 隆二, 関根 有美, 春日 健作, 西澤 正豊, 池内 健

    臨床神経学   53 ( 12 )   1550 - 1550   2013.12

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  • アルツハイマー病における内側側頭葉の萎縮 VSRAD advanceを用いた左右差の検討

    手塚 敏之, 横関 明男, 矢島 隆二, 徳武 孝允, 関根 有美, 春日 健作, 西澤 正豊, 池内 健

    Dementia Japan   27 ( 4 )   510 - 510   2013.10

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  • 家族性および早発型アルツハイマー病症例におけるAPP重複変異の探索

    池内 健, 温 雅南, 針谷 康夫, 宮下 哲典, 中谷 明弘, 月江 珠緒, 春日 健作, 田中 晋, 西澤 正豊, 桑野 良三

    Dementia Japan   27 ( 4 )   487 - 487   2013.10

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  • 【神経疾患のバイオマーカー】レヴィ小体型認知症の脳脊髄液・血液バイオマーカー Reviewed

    春日 健作, 池内 健

    BRAIN and NERVE: 神経研究の進歩   64 ( 5 )   505 - 513   2012.5

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    Lewy小体型認知症において臨床上有用なバイオマーカーの開発が望まれている。その候補として、血液や脳脊髄液を用いた体液マーカー、神経心理検査や自律神経機能検査、脳形態画像や脳機能画像といった画像検査が挙げられる。体液マーカー、特に脳脊髄液中・血液中・唾液中α-シヌクレインと脳脊髄液中・血漿中DJ-1について最近の知見を概説した。現段階ではα-シヌクレインおよびDJ-1のLewy小体病におけるバイオマーカーとしての有用性を結論づけることは難しい。

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  • 脳内インスリン抵抗性に着目したアルツハイマー病の新規病態解析

    池内 健, 春日 健作, 徳武 孝允

    研究結果報告書集 : 交通安全等・高齢者福祉   18   61 - 63   2012

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  • アルツハイマー病患者・髄液中における可溶性LR11の増加

    池内 健, 平山 哲, 三井田 孝, 深町 勇, 矢島 隆二, 徳武 孝允, 春日 健作, 海老沼 宏幸, 田久保 耕平, 武城 英明, 西澤 正豊

    臨床神経学   51 ( 12 )   1397 - 1397   2011.12

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  • βアミロイド依存性タウリン酸化カスケードにおけるインスリンシグナル障害の関与

    徳武 孝允, 池内 健, 春日 健作, 篠崎 真, 小野寺 理, 西澤 正豊

    臨床神経学   50 ( 12 )   1106 - 1106   2010.12

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  • 健忘主体の臨床型を呈するタウ遺伝子R406W変異を伴う家族性認知症の臨床遺伝学的解析

    池内 健, 春日 健作, 宮下 哲典, 川瀬 康裕, 杉下 守弘, 桑野 良三, 西澤 正豊

    臨床神経学   50 ( 12 )   1080 - 1080   2010.12

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  • [A case of amyotrophic lateral sclerosis/frontotemporal lobar degeneration with apraxia of eyelid opening]. Reviewed

    Ryuji Yajima, Kensaku Kasuga, Tomoe Sato, Takeshi Ikeuchi, Masatoyo Nishizawa

    Rinsho shinkeigaku = Clinical neurology   50 ( 9 )   645 - 50   2010.9

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    We report the case of a 76-year-old man with apraxia of eyelid opening (AEO) and amyotrophic lateral sclerosis with dementia (ALS-D)/frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). The initial symptom was AEO. Neurological examination revealed mainly bulbar symptoms with a neurogenic pattern on needle electromyograms of the tongue muscles and the biceps muscles. Furthermore, he developed severe dementia with frontal lobe dysfunction and progressive non-fluent aphasia. Brain magnetic resonance imaging revealed severe cerebral atrophy and leukoaraiosis in the bilateral frontal lobes and the anterior part of the bilateral temporal lobes; brain 99mTc ethyl cysteinate dimer single photon emission computed tomography (ECD SPECT) showed hypoperfusion in the same areas. The patient showed improvement in stereotyped behavior and AEO after treatment with 50 mg/day of fluvoxamine maleate (the initial dose was 25 mg/day). Because serotonin receptors are markedly reduced in the frontal and temporal cortexes of patients with FTLD, we considered that dysfunction of the serotonergic system in the frontotemporal lobe caused AEO. Considering the findings of this case along with those of previous reports, we propose that there is a relatively homogeneous development of ALS-D/FTLD-MND with AEO.

    DOI: 10.5692/clinicalneurol.50.645

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  • アルツハイマー病患者・髄液中では可溶性LR11が増加する

    池内 健, 平山 哲, 三井田 孝, 深町 勇, 矢島 隆二, 徳武 孝允, 春日 健作, 金子 博之, 田久保 耕平, 海老沼 宏幸, 武城 英明, 西澤 正豊

    Dementia Japan   24 ( 3 )   311 - 311   2010.9

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  • 遺伝子変異を伴った家族性アルツハイマー病の表現型の比較

    池内 健, 春日 健作, 野崎 洋明, 石原 智彦, 金子 博之, 篠崎 真, 桑野 良三, 小野寺 理, 西澤 正豊

    臨床神経学   49 ( 12 )   984 - 984   2009.12

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  • 認知症性疾患の髄液バイオマーカーとしてのαシヌクレインの検討

    春日 健作, 池内 健, 石川 厚, 徳田 隆彦, 中川 正法, 小野寺 理, 西澤 正豊

    臨床神経学   49 ( 12 )   1141 - 1141   2009.12

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  • Impaired insulin signal transduction promotes alzheimer's disease pathology

    Niigata medical journal   123 ( 12 )   618 - 630   2009.12

  • Aβはインスリンシグナルを障害することでタウの過剰リン酸化を引き起こすか?

    春日 健作, 徳武 孝允, 篠崎 眞, 西澤 正豊, 小野寺 理, 池内 健

    Dementia Japan   23 ( 2 )   202 - 202   2009.8

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  • 健忘を主体とする特異な臨床型を呈するタウ遺伝子(MAPT)R406W変異を伴う家族性認知症の臨床分子遺伝学的解析

    池内 健, 春日 健作, 宮下 哲典, 川瀬 康裕, 小野寺 理, 杉下 守弘, 桑野 良三, 西澤 正豊

    Dementia Japan   23 ( 2 )   175 - 175   2009.8

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  • プレセニリン1変異による難溶性αシヌクレイン蓄積の分子機序

    池内 健, 金子 博之, 柿田 明美, 春日 健作, 野崎 洋明, 石川 厚, 高橋 均, 小野寺 理, 西澤 正豊

    臨床神経学   48 ( 12 )   1244 - 1244   2008.12

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  • 家族性および早発型アルツハイマー病におけるAPP遺伝子重複 2家系の臨床遺伝学的検討

    春日 健作, 池内 健, 志賀 篤, 徳永 純, 下畑 享良, 桑野 良三, 小野寺 理, 西澤 正豊

    臨床神経学   48 ( 12 )   1243 - 1243   2008.12

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  • 認知症を伴う遺伝性パーキンソニズムにおけるα-synuclein遺伝子(SNCA)重複

    池内 健, 春日 健作, 志賀 篤, 金子 博之, 柿田 明美, 内山 剛, 大橋 寿彦, 石川 厚, 高橋 均, 西澤 正豊, 小野寺 理

    臨床神経学   47 ( 12 )   1125 - 1125   2007.12

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  • γセクレターゼによるインスリン受容体の膜内切断および細胞内局在の検討

    春日 健作, 池内 健, 金子 博之, 小山 哲秀, 他田 正義, 西澤 正豊, 小野寺 理

    臨床神経学   47 ( 12 )   1011 - 1011   2007.12

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  • Chronic myositis with cardiomyopathy and respiratory failure associated with mild form of organ-specific autoimmune diseases

    K. Tanaka, A. Sato, K. Kasuga, M. Kanazawa, K. Yanagawa, M. Umeda, M. Tada, M. Tanaka, M. Nishizawa

    CLINICAL RHEUMATOLOGY   26 ( 11 )   1917 - 1919   2007.11

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    We report the four patients with chronic myositis characterized by a very slow progression with cardiomyopathy and frequently with marked respiratory muscle weakness associated with other organ-specific autoimmune diseases such as primary biliary cirrhosis. The histopathology of the muscle showed many degenerative and regenerative fibers, but inflammatory-cell infiltration were minimal. The patients showed favorable response to high-dose corticosteroid treatment. Because of these clinical features, these patients are sometimes misdiagnosed as muscular dystrophy and not treated properly. It is important to distinguish this type of treatable myositis.

    DOI: 10.1007/s10067-007-0698-7

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  • 10 認知症のみで経過し,頭部MRI拡散強調画像が診断に有用であった高齢発症のプリオン病の1例(第47回下越内科集談会)

    松原 奈絵, 長谷川 有香, 福島 隆男, 小池 亮子, 春日 健作, 藤田 信也

    新潟医学会雑誌   121 ( 9 )   539 - 539   2007.9

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    Other Link: http://search.jamas.or.jp/link/ui/2008088806

  • 筋ジストロフィーの治療とケア(12)筋強直性ジストロフィーの治療の展望

    春日 健作

    難病と在宅ケア   13 ( 1 )   47 - 51   2007.4

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    Other Link: http://search.jamas.or.jp/link/ui/2007167425

  • 第8番染色体長腕に連鎖する成人発症良性遺伝性舞踏病

    原 賢寿, 下畑 享良, 三瓶 一弘, 河内 泉, 金澤 雅人, 春日 健作, 宮下 哲典, 桑野 良三, 辻 省次, 小野寺 理, 西澤 正豊, 本間 義章

    臨床神経学   46 ( 12 )   1119 - 1119   2006.12

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  • Presenilin/γ-secretaseによるインスリン受容体の切断および細胞内局在に及ぼす影響

    春日 健作, 池内 健, 金子 博之, 小山 哲秀, 西澤 正豊, 小野寺 理

    Dementia Japan   20 ( 2 )   172 - 172   2006.8

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  • α-Synuclein遺伝子重複を認めた遺伝性Lewy小体病の分子遺伝学および生化学的解析

    志賀 篤, 池内 健, 春日 健作, 金子 博之, 譚 春鳳, 柿田 明美, 高橋 均, 西澤 正豊, 小野寺 理, 石川 厚

    Dementia Japan   20 ( 2 )   169 - 169   2006.8

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  • バセドウ病にともなう第VIII因子活性亢進により脳静脈洞血栓症をきたした若年男性の1例

    春日 健作, 成瀬 聡, 梅田 麻衣子, 田中 みどり, 藤田 信也

    臨床神経学   46 ( 4 )   270 - 273   2006.4

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    症例は38歳男性である.くりかえす頭痛の後,意識障害,失語,右片麻痺をきたし,上矢状静脈洞から両側横静脈洞にいたる脳静脈洞血栓症(cerebral venous thrombosis;CVT)と診断された.入院時にはじめてバセドウ病に気づかれ,第VIII因子活性が著明に亢進しており,発症の原因と考えられた.抗凝固療法に加えバセドウ病に対する治療をおこない,甲状腺機能の改善にともない第VIII因子活性も改善し,良好な経過がえられた.原因不明のCVTにおいて,第VIII因子の上昇をともなった甲状腺機能亢進症を念頭におくことが重要と考えられた(著者抄録)

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  • 眼で見る神経内科 筋強直性ジストロフィーにおける側頭葉前部白質病変

    春日 健作, 成瀬 聡, 梅田 能生, 藤田 信也

    神経内科   64 ( 3 )   309 - 310   2006.3

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  • 大脳白質病変の重症度とMRAによる頭蓋内血管病変との相関

    金澤 雅人, 三瓶 一弘, 赤岩 靖久, 小野寺 理, 他田 正義, 川村 邦雄, 春日 健作, 高野 弘基, 西澤 正豊

    臨床神経学   45 ( 12 )   1155 - 1155   2005.12

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  • 全身性筋萎縮に呼吸筋・心筋障害を伴い,慢性に経過する筋炎の3例

    谷 卓, 春日 健作, 金澤 雅人, 茨木 麻衣子, 他田 正義, 佐藤 晶, 田中 惠子, 西澤 正豊, 田中 正美

    神経治療学   21 ( 3 )   300 - 300   2004.5

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  • A case with severe respiratory muscle weakness due to chronic myositis associated with PBC

    Kensaku Kasuga, Aki Sato, Masato Kanazawa, Hisashi Kobayashi, Keiko Tanaka, Masatoyo Nishizawa

    Clinical Neurology   44 ( 4-5 )   280 - 285   2004.4

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    We report a 37-year-old woman with slowly developing muscular weakness for 2 years following insidious stiffness of calf muscle. Serum CK was elevated up to 4,207 IU/l. She presented sleepiness, weakness of proximal and truncal muscles and systemic muscular atrophy. While she had not experienced dyspnea, her arterial blood gas analysis revealed extreme hypoxia and hypercapnea due to weakness of respiratory muscles. Echocardiogram showed thinness and hypokinesis of left ventricular wall, and arrhythmia was pointed out by holter ECG. Needle elctromyogram of the proximal muscles exhibited polyphasic units with low amplitude. Muscle biopsy showed degeneration and necrosis of muscle fibers as well as regeneration. Mild infiltration of inflammatory cells was shown. Serological examination showed positive antimitochondrial M2 antibody, especially specific for primary biliary chirrhosis (PBC). She was diagnosed as chronic myositis associated with PBC. Four cases of idiopathic myositis with severe weakness of respiratory muscle, associated with PBC had been reported. These cases and our present case share the similar feature in respect of insidious or chronic course and resistance to therapy. In our present patient, respiration had been supported by BiPAP and she has been successfully improving slowly by oral steroid following 4 courses of methylprednisolone pulse therapy.

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  • 虚血性白質病変の感受性遺伝子同定に向けたMRIによる白質病変パターン分類の試み

    赤岩 靖久, 他田 正義, 川村 邦雄, 春日 健作, 三瓶 一弘, 高野 弘基, 小野寺 理, 西澤 正豊

    脳卒中   26 ( 1 )   255 - 255   2004.3

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  • 【遺伝性痙性対麻痺】 脳梁菲薄化を伴う遺伝性痙性対麻痺

    春日 健作, 西澤 正豊

    脳と神経   55 ( 9 )   765 - 770   2003.9

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  • 【遺伝性痙性対麻痺】 遺伝性痙性対麻痺の遺伝子的研究

    高野 弘基, 春日 健作, 小林 央, 西澤 正豊

    脳と神経   55 ( 9 )   757 - 763   2003.9

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  • Hereditary Spastic Paraplegia Associated with Thin Corpus Callosum

    55 ( 9 )   765 - 770   2003.9

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  • Recent Progress in Genetic Study of Hereditary Spastic Paraplegia

    55 ( 9 )   757 - 763   2003.9

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Presentations

  • CSF and blood biomarkers for PSP Invited

    Kensaku Kasuga

    62nd Annual Meeting of the Japanese Society of Neurology  2021.5 

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  • CSFバイオマーカーによるSNAPの再考 Invited

    Kasuga Kensaku

    The 38th Annual Meeting of Japan Society for Dementia Research  2019.11 

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  • The Need and Pitfalls of Alzheimer’s disease-related Biomarkers for Preemptive Medicine Invited

    Kensaku Kasuga

    2018.9 

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  • CSF Biomarkers for Diagnosis of PSP Invited

    Kensaku Kasuga

    59th Annual Meeting of the Japanese Society of Neurology  2018.5 

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  • Progress pattern of Alzheimer’s disease based on longitudinal changes of CSF biomarkers

    62nd Annual Meeting of the Japanese Society of Neurology  2021.5 

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  • 脳脊髄液バイオマーカーの縦断的変化から考察するアルツハイマー病態の進展

    The 39th Annual Meeting of Japan Society for Dementia Research  2020.11 

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  • ディベートセッション:認知症は告知すべき Invited

    Kensaku Kasuga

    The 38th Annual Meeting of Japan Society for Dementia Research  2019.11 

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    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

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  • CSF biomarkers of Alzheimer’s clinical syndrome

    Kensaku KASUGA, Tamao TSUKIE, Takayoshi TOKUTAKE, Yo HIGUCHI, Takanobu ISHIGURO, Akinori MIYASHITA, Osamu ONODERA, Takeshi IKEUCHI

    Alzheimer's Association International Conference 2019  2019.7 

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    Language:English   Presentation type:Poster presentation  

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  • Cerebrospinal fluid analysis of Alzheimer’s clinical syndrome

    2019.5 

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    Language:Japanese   Presentation type:Oral presentation (general)  

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  • The AT(N) system provides an insight into differential diagnosis of cognitive disorders

    Kensaku KASUGA, Tamao TSUKIE, Yo Higuchi, Takanobu ISHIGURO, Takayoshi TOKUTAKE, Akinori MIYASHITA, Osamu ONODERA, Takeshi IKEUCHI

    The 14th International Conference on Alzheimer's & Parkinson's Diseases (AD/PD 2019)  2019.3 

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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, 三浦健, 目﨑直実, 徳武孝允, 宮下哲典, 小野寺理, 池内健

    The 37th Annual Meeting of Japan Society for Dementia Research  2018.10 

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  • Non-Alzheimer’s disease subjects occasionally mimic CSF pattern of preclinical Alzheimer’s disease

    Tamao TSUKIE, Takayoshi TOKUTAKE, Takeshi MIURA, Naomi MEZAKI, Takanobu ISHIGURO, Akinori MIYASHITA, Osamu ONODERA, Takeshi IKEUCHI

    Alzheimer's Association International Conference 2018  2018.7 

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Awards

  • 学会奨励賞(臨床経過部門)

    2018.10   Japan Society for Dementia Research  

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Research Projects

  • Alzheimer's disease related biomarkers in progressive supranuclear palsy

    Grant number:19K07991

    2019.4 - 2022.3

    System name:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    Kasuga Kensaku

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    Grant amount:\3770000 ( Direct Cost: \2900000 、 Indirect Cost:\870000 )

    In the cerebrospinal fluid (CSF) of patients with progressive supranuclear palsy (PSP), β-amyloid (Aβ), which is an Alzheimer's disease-related molecule, is lower than that of healthy elderly. In Alzheimer's disease, only Aβ42 consisting of 42 amino acids is decreased, whereas in PSP, in addition to Aβ42, Aβ38 and Aβ40, which reflect the production of Aβ in the brain and the transfer to CSF, are also decreased. In the PSP model in which mutant tau is expressed in cultured cells, Aβ production (processing) is reduced. Taken together, because the expression of pathogenic tau in PSP reduces Aβ production, the finding that all Aβ species are reduced in CSF could be an useful diagnostic biomarker for PSP.

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  • プリオン病の早期診断基準の作成を目指した新たなエビデンス創出とその検証に用いる遺伝性プリオン病未発症例の臨床調査と画像・生体材料の収集

    2018 - 2020

    System name:日本医療研究開発機構研究費 難治性疾患実用化研究事業

    佐藤克也

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    Grant type:Competitive

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  • 血液バイオマーカーを用いた認知症と精神・神経疾患の簡易鑑別診断システムの構築

    2017 - 2019

    System name:日本医療研究開発機構研究費 認知症研究開発事業

    池内健

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    Grant type:Competitive

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  • Neuronal activity affects AD pathophysiology

    Grant number:16K09669

    2016.4 - 2019.3

    System name:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    Kasuga Kensaku

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

    To clarify the association between Alzheimer's pathophysiology and neuronal activity, we analyzed the processing of amyloid precursor protein (APP) under various conditions of glutamatergic activation using primary culture of rat cortical neurons. At 100 μM glutamate, the expression of full-length APP transiently decreased after 2 hours of activation, with decreased APP C-terminal fragment β (CTFβ). In contrast, at 0.1 μM glutamate, the expression of CTFβ increased after 2 hours activation, and levels of Aβ elevated after 24 hours activation. Furthermore, this elevation of Aβ was suppressed by inhibiting the NMDA receptor. These results suggest that suppression of sustained neural activation would be a novel therapeutic target for Alzheimer's disease.

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  • Validation study on insulin resistance occuring in brain of Alzheimer disease

    Grant number:15H04839

    2015.4 - 2018.3

    System name:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    Ikeuchi Takeshi, SATO Naoyuki, TEZUKA Toshiyuki, SAITO Kento, MIYASHITA Akinori, HARA Norikazu, TSUKIE Tamao

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    Grant type:Competitive

    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

    Neumerous epidemiological studies have suggested that type 2 diabetes is a risk factor of Alzheimer's diesase. However, the detailed underlying mechanism has been largely unclear. We previously showed that insulin resistance in central nervous system plays an important role of the pathogenesis of Alzheimer's diesase. In this study, we attempted to validate impaired insulin signal network occuring in brain of Alzheimer's disease by analyzing autopsied samples. By this analysis, we demonstrated that expressions of molecules associated with insulin signal were significantly altered, supporting the notion that insulin resistance is present in human brain of Alzheimer's disease.

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  • Amino acid profile in plasma of Alzheimer's disease

    Grant number:15K15335

    2015.4 - 2018.3

    System name:Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Research category:Grant-in-Aid for Challenging Exploratory Research

    Awarding organization:Japan Society for the Promotion of Science

    Ikeuchi Takeshi, KASUGA Kensaku, TOKUTAKE Takayoshi, KAWAI Nobuhiro

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    Grant amount:\3510000 ( Direct Cost: \2700000 、 Indirect Cost:\810000 )

    There is a strong need for blood-based biomarker for the diagnosis of dementia including Alzheimer’s disease (AD). Plasma free amino acids and amines are potent metabolites, and different patterns of plasma free amino acid have shown to be associated with various disease conditions in previous studies. We here determine the plasma free amino acids in patients with AD (n=36) and cognitively normal controls (n=34). Five metabolites showed significant changes in AD patients. Among them, the level of the amino acid was significantly correlated with the MMSE scores. These results suggest that measurement of the plasma free amino acids and amines may offer a potential blood-based diagnostic tool for AD.

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  • Neuronal activity promotes tau phosphorylation via enhancement of APP processing

    Grant number:26870209

    2014.4 - 2016.3

    System name:Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Research category:Grant-in-Aid for Young Scientists (B)

    Awarding organization:Japan Society for the Promotion of Science

    Kasuga Kensaku

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

    Alzheimer’s disease (AD) is the most common cause of dementia, which is pathologically characterized by extracellular deposits of β-amyloid (Aβ) and intracellular accumulation of hyperphosphorylated tau. Hippocampal neurons showing hyperactivity early in the disease course send those axons to the default-mode network where Aβ accumulates remarkably in the brain. Aβ is derived from amyloid precursor protein (APP) by sequential cleavages.
    Here we performed in vitro assay with murine neuroblastoma cells and rat cortical neuron primary cultures. After glutamatergic stimulation, we found that full length APP was reduced in a neuronal activity dependent manner. In addition, C-terminal fragments of APP increased after the stimulation, suggesting that the stimulation enhanced β-cleavage. We previously showed Aβ-dependent tau phosphorylation by using the coculture system. Taken together, neuronal activity may affect APP processing and tau phosphorylation in neuronal network.

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  • アルツハイマー病・異常リン酸化タウ蓄積におけるインスリンシグナル伝達障害の関与

    Grant number:21890078

    2009

    System name:科学研究費助成事業 研究活動スタート支援

    Research category:研究活動スタート支援

    Awarding organization:日本学術振興会

    春日 健作

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2600000 ( Direct Cost: \2000000 、 Indirect Cost:\600000 )

    アルツハイマー病の病態仮説として広く認められている「アミロイドカスケード」仮説において,βアミロイド(Aβ)産生亢進がタウ異常リン酸化を引き起こすメカニズムについてはいまだ不明な点が多い.近年,国内外の疫学研究により2型糖尿病の病態として重要なインスリン抵抗性がアルツハイマー病の発病リスクを高めるという知見が明らかにされたことから,研究代表者はAβ産生亢進がインスリンシグナル障害を介しタウ異常リン酸化を引き起こす可能性を考え,本研究課題を立案した.Aβがタウ異常リン酸化を引き起こす際のインスリンシグナルの役割を解析するため,研究代表者は新しいアッセイ系を確立した.ドナー細胞にAPPを過剰発現する細胞を,レシピエント細胞にタウを過剰発現する細胞を用いてこれらを共培養することにより,細胞外Aβがレシピエント細胞のタウのリン酸化に及ぼす影響を検討可能とした.この共培養システムにおいてAβ産生亢進が生じる培養細胞(APPswe)をドナー細胞した場合,野生型APPを発現する培養細胞(APP WT)をドナー細胞とした場合に比べ,レシピエント細胞のタウのリン酸化が上昇することをリン酸化特異抗体により確認した.さらに,このリン酸化タウの蓄積がインスリンシグナル障害に起因することを示すため,レシピエント細胞のインスリンシグナル関連蛋白(インスリン受容体,Akt,GSK 3β)の発現レベルおよびそのリン酸化の程度をウエスタンブロット法により確認した.これによりAPP sweをドナー細胞とした場合,インスリンシグナル関連蛋白は定常状態で既にリン酸化していることを確認した.研究代表者は,定常状態でのインスリンシグナル関連蛋白のリン酸化が増加した場合,インスリン抵抗性をきたすことを確認しており,Aβ産生亢進がインスリンシグナル障害を介しタウ異常リン酸化を引き起こす可能性が考えられた.

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