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赤津 裕康アカツ ヒロヤス

所属部署医学研究科地域医療教育学分野
職名教授(診療担当)
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Last Updated :2020/06/02

研究者基本情報

学歴

  • 1992年 - 1996年, 名古屋市立大学, 大学院
  • 1985年 - 1991年, 名古屋市立大学, 医学部

学位

  • 医学, 名古屋市立大学医学研究科

所属学協会

  • 日本内科学会
  • 日本老年学会
  • 日本認知症学会
  • 日本静脈経腸栄養学会
  • 日本神経病理学会

研究活動情報

研究キーワード

    認知機能, 運動機能, 第12染色体短腕, 中隔核, 対角核, アポリポ蛋白E, 第21染色体, 施設入所, レビー小体型認知症, アポリポ蛋白C1, アポリポ蛋白C2, アセチルコリン, アルツハイマー病, リスク遺伝子, ダイナミン, 海馬, アルツハイマー型認知症, 歩行解析, フレイル予防

論文

  • Establishment of Method for the Determination of Aggregated α-Synuclein in DLB Patient Using RT-QuIC Assay., Seok-Joo Park, Yun-Jung Lee, Jeong-Ho Park, Hyoung-Tae Jin, Myoung-Ju Choi, Cha-Gyun Jung, Hiroyasu Akatsu, Eun-Kyoung Choi, Yong-Sun Kim, Protein and peptide letters,   2020年04月19日, 査読有り, BACKGROUND: The accumulation of aggregated α-synuclein (αSyn) is known as one of the critical reasons to exhibit their variable molecular pathologies and phenotypes in synucleinopathies. Recent studies suggested that the real-time quaking-induced conversion (RT-QuIC) assay is one of the potential methods to detect these αSyn aggregates and could detect the aggregated αSyn in the brain tissue and cerebrospinal fluid (CSF) using the propensity of the prion-like oligomerization. OBJECTIVE: We tried to optimize the αSyn RT-QuIC assay based on the aggregation of αSyn in brain samples of synucleinopathies by comparing the conditions of the recently reported αSyn RT-QuIC assays. METHODS: This study applied a highly sensitive RT-QuIC assay using recombinant αSyn (rαSyn) to detect aggregated αSyn in the brain tissue from dementia with Lewy bodies (DLB). RESULTS: This study compared αSyn RT-QuIC assays under conditions such as beads, rαSyn as substrate, reaction buffers, and fluorescence detectors. We observed that the addition of beads and the use of 6x His-tagged rαSyn as substrate help to obtain higher positive responses from αSyn RTQuIC assay seeding with brain homogenate (BH) of DLB and phosphate buffer-based reaction showed higher positive responses than HEPES buffer-based reaction on both fluorescent microplate readers. We also observed that the DLB BHs gave positive responses within ~15-25 h, which is faster high positive responses than recently reported assays. CONCLUSION: This established αSyn RT-QuIC assay will be able to apply to the early clinical diagnosis of αSyn aggregates related disease in various biofluids such as CSF.
  • Comprehensive quantification of purine and pyrimidine metabolism in Alzheimer's disease postmortem cerebrospinal fluid by LC-MS/MS with metal-free column., Yoshio Muguruma, Haruhito Tsutsui, Hiroyasu Akatsu, Koichi Inoue, Biomedical chromatography : BMC, 34, (2) ,   2020年02月, 査読有り, The metabolome presence of nucleobases, nucleosides, nucleotides and related phosphorylated metabolites has been examined for Alzheimer's disease (AD). Although reversed-phase liquid chromatography tandem mass spectrometry (LC-MS/MS) has been used for the determination of these analytes, they were limited in chromatographic signal intensity and reproducibility owing to significant peak tailing caused by complexing with metallic cations and phosphate groups. In this work, we applied LC-MS/MS analysis with a metal-free column for comprehensive quantification of 40 analytes regarding to purine and pyrimidine metabolism in postmortem cerebrospinal fluid (pCSF) from AD patients. For the analytical column, an InertSustain AQ-C18 metal-free PEEK column was used. MS detection was by electrospray positive ionization. The metal-free column allowed for sharp peak detection of highly polar metabolites within a running time of 17 min. In validation, the limits of detection (LOD), the limit of quantitation (LOQ) and recovery value using a pooled pCSF sample are 1-500  nM, 0.5-250 nM and a range of 53.1-144.0% (RSD ranged from 0.4 to 19.6%). The developed LC-MS/MS method utilizing a metal-free column provides an accurate quantification of some metabolites regarding purine and pyrimidine metabolism in pCSF samples obtained from AD patients.
  • Beta-Amyloid Increases the Expression Levels of Tid1 Responsible for Neuronal Cell Death and Amyloid Beta Production., Chunyu Zhou, Ferdous Taslima, Mona Abdelhamid, Sung-Woo Kim, Hiroyasu Akatsu, Makoto Michikawa, Cha-Gyun Jung, Molecular neurobiology, 57, (2) 1099 - 1114,   2020年02月, 査読有り, Mitochondrial dysfunctions and oxidative stress play important roles in the early pathogenesis of Alzheimer's disease (AD), which also involves the aberrant expression levels of mitochondrial proteins. However, the molecular mechanisms underlying the aberrant expression levels of these proteins in the pathogenesis of AD are still not completely understood. Tid1 (DnaJA3/mtHsp40), a mammalian homolog of the Drosophila tumor suppressor Tid56, is reported to induce mitochondrial fragmentation associated with an increase in reactive oxygen species (ROS) levels, resulting in cell death in some cancer cells. However, the involvement of Tid1 in AD pathogenesis is as yet unknown. In this study, we found that the Tid1 protein levels were upregulated in the hippocampus of AD patients and Tg2576 mice. Our in vitro studies showed that Aβ42 increased the expression levels of Tid1 in primary rat cortical neurons. The knockdown of Tid1 protected against neuronal cell death induced by Aβ42, and Tid1-mediated neuronal cell death, was dependent on the increased ROS generation and caspase-3 activity. The overexpression of Tid1 in HEK293-APP cells increased the BACE1 levels, resulting in increased Aβ production. Conversely, Tid1 knockdown in HEK293-APP cells and primary cultured neurons decreased Aβ production through the reduction in the BACE1 levels. We also found that the overexpression of Tid1 activated c-Jun N-terminal kinase (JNK) leading to increased Aβ production. Taken together, our results suggest that upregulated Tid1 levels in the hippocampus of patients with AD and Tg2576 mice induce apoptosis and increase Aβ production, and Tid1 may therefore be a suitable target in therapeutic interventions for AD.
  • Serum levels of proteins involved in amyloid-β clearance are related to cognitive decline and neuroimaging changes in mild cognitive impairment., Liu S, Suzuki H, Ito H, Korenaga T, Akatsu H, Meno K, Uchida K, Alzheimer's & dementia (Amsterdam, Netherlands), 11, 85 - 97,   2019年12月, 査読有り
  • Differential protein expression of DARPP-32 versus Calcineurin in the prefrontal cortex and nucleus accumbens in schizophrenia and bipolar disorder., Yasuto Kunii, Mizuki Hino, Junya Matsumoto, Atsuko Nagaoka, Hiroyuki Nawa, Akiyoshi Kakita, Hiroyasu Akatsu, Yoshio Hashizume, Hirooki Yabe, Scientific reports, 9, (1) 14877 - 14877,   2019年10月16日, 査読有り, Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) integrates dopaminergic signaling into that of several other neurotransmitters. Calcineurin (CaN), located downstream of dopaminergic pathways, inactivates DARPP-32 by dephosphorylation. Despite several studies have examined their expression levels of gene and protein in postmortem patients' brains, they rendered inconsistent results. In this study, protein expression levels of DARPP-32 and CaN were measured by enzyme-linked immunosorbent assay (ELISA) in the prefrontal cortex (PFC), and nucleus accumbens (NAc) of 49 postmortem samples from subjects with schizophrenia, bipolar disorder, and normal controls. We also examined the association between this expression and genetic variants of 8 dopaminergic system-associated molecules for 55 SNPs in the same postmortem samples. In the PFC of patients with schizophrenia, levels of DARPP-32 were significantly decreased, while those of CaN tended to increase. In the NAc, both of DARPP-32 and CaN showed no significant alternations in patients with schizophrenia or bipolar disorder. Further analysis of the correlation of DARPP-32 and CaN expressions, we found that positive correlations in controls and schizophrenia in PFC, and schizophrenia in NAc. In PFC, the expression ratio of DARPP-32/CaN were significantly lower in schizophrenia than controls. We also found that several of the aforementioned SNPs may predict protein expression, one of which was confirmed in a second independent sample set. This differential expression of DARPP-32 and CaN may reflect potential molecular mechanisms underlying the pathogenesis of schizophrenia and bipolar disorder, or differences between these two major psychiatric diseases.
  • Factors influencing hospital admission among patients with autopsy-confirmed dementia., Tamami Matsuoka, Toshie Manabe, Hiroyasu Akatsu, Yoshio Hashizume, Sakon Yamamoto, Norihiro Ogawa, Takeshi Kanesaka, Chie Taniguchi, Takayuki Yamamoto, Katsuyoshi Mizukami, Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society, 19, (3) 255 - 263,   2019年05月, 査読有り, BACKGROUND: The symptoms of geriatric syndromes and the behavioural and psychological symptoms of dementia (BPSD), in addition to clinical conditions, are associated with hospital admission among dementia patients. However, the principal factors that necessitate hospital admission among dementia patients have not been fully elucidated. METHODS: We retrospectively reviewed the data in the medical and autopsy reports of patients who had been treated at a hospital in Toyohashi, Japan. Each patient had been hospitalized sometime between 2012 and 2016 and underwent a brain autopsy. Dementia and the subtypes of dementia were diagnosed neuropathologically. Information about patients' general backgrounds, clinical conditions at the time of admission, and the geriatric syndrome symptoms and BPSD before admission was collected; comparisons were then made between patients with and without dementia and among those with the different major subtypes of dementia. Then, the factors relating to hospital admission of dementia patients were comprehensively evaluated by using principle component analysis. RESULTS: Of the 128 eligible patients, 100 (78.1%) had dementia. In the comparison of patients with and without dementia, patients without dementia were younger at both admission (P = 0.034) and death (P = 0.003). Among the patients with dementia with Lewy bodies, delusions had a significantly high prevalence (P = 0.014). Principal component analysis identified nine components (disinhibition, irritability/lability, agitation/aggression, anxiety, delusions, sleep/night-time behaviour disorders, hallucinations, aberrant motor behaviour, and speech impairment) as the principal factors related to hospital admission among dementia patients. Thus, BPSD were identified as principal factors. CONCLUSIONS: Compared to other factors, BPSD are more likely to cause dementia patients to be admitted to hospital. The present results indicate that measures should be taken to ameliorate the difficulties associated with caring for patients with BPSD at home.
  • Isotope Corrected Chiral and Achiral Nontargeted Metabolomics: An Approach for High Accuracy and Precision Metabolomics Based on Derivatization and Its Application to Cerebrospinal Fluid of Patients with Alzheimer's Disease., Takahiro Takayama, Hajime Mizuno, Toshimasa Toyo'oka, Hiroyasu Akatsu, Koichi Inoue, Kenichiro Todoroki, Analytical chemistry, 91, (7) 4396 - 4404,   2019年04月02日, 査読有り, We propose a chiral metabolomics approach based on a data-dependent MS/MS analysis (DDA) using high-resolution quadrupole-time-of-flight mass spectrometry (Q-TOFMS) and 13C-isotope coded derivatization (ICD) reagents, i.e., iDMT-( S)-A and iDMT-( S)-PO. The advantage of the method is the correction of all detected derivatives by parallel derivatization of the isotope-coded and noncoded reagents. The automatic data analysis platform using an MSDIAL and ICD discrimination program, called DINA, was also developed and used for the data analysis process. As a result, a 0.5-2.0% (d-/l-isomer) variation of the isomers was correctly recognized in the automatic data analysis step. Both the semiquantitative comparison and identification efficiency were improved as a result of the high resolution/accuracy of the MS and MS/MS spectra derived from the DDA analysis. This method was used for biomarker discovery in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). Twenty-four biomarker candidates were successfully determined, including 8 chiral ones.
  • Flotillin is a Novel Diagnostic Blood Marker of Alzheimer's Disease., Mohammad Abdullah, Noriyuki Kimura, Hiroyasu Akatsu, Yoshio Hashizume, Taslima Ferdous, Takuto Tachita, Shinsuke Iida, Kun Zou, Etsuro Matsubara, Makoto Michikawa, Journal of Alzheimer's disease : JAD, 72, (4) 1165 - 1176,   2019年, 査読有り, Currently, best-characterized indicators for Alzheimer's disease (AD) diagnosis are the decreased levels of amyloid-β protein 42 and increased levels of phosphorylated tau in cerebrospinal fluid (CSF). The positron emission tomography (PET) imaging with Pittsburgh compound B (PiB) is also used in AD diagnosis by visualizing amyloid deposition in the brain. These methods are invasive or expensive; therefore, less invasive and easily detectable blood biomarkers are required. Because our previous study showed that flotillin release, a marker of exosomes, was attenuated by Aβ, we designed the present study to determine whether flotillin level could be reduced in CSF and/or serum of patients with AD. In this study, we analyzed flotillin levels in CSF and serum of non-AD controls, patients with AD and mild cognitive impairment (MCI) by western blotting. Flotillin levels in cerebroventricular fluid (CVF) and serum of AD, vascular dementia (VaD), and non-AD autopsy cases were also analyzed. Flotillin levels significantly decreased in the CSF and serum of AD patients compared with those of non-AD controls, respectively. Moreover, in patients with MCI due to AD determined by PiB-PET, CSF and serum flotillin levels significantly decreased compared with those of patients with MCI due to non-AD. Flotillin levels remained unchanged in CVF and serum of autopsy cases diagnosed as VaD. Serum flotillin level is negatively associated with brain amyloid deposition indicated as PiB uptake. These results demonstrate that serum flotillin level can serve as one of the blood markers for estimation of brain amyloid deposition and early diagnosis of AD.
  • Pneumonia-associated death in patients with dementia: A systematic review and meta-analysis., Toshie Manabe, Yuji Fujikura, Katsuyoshi Mizukami, Hiroyasu Akatsu, Koichiro Kudo, PloS one, 14, (3) ,   2019年, 査読有り, BACKGROUND: Pneumonia is a serious disease associated with mortality among patients with dementia. However, the reported frequency of pneumonia as a cause of death in patients with dementia varies, the reason for which has not been fully elucidated. METHODS: We conducted a systematic search in PubMed and the Cochrane Database of Systematic Reviews (inception to December 2016). Two authors independently determined the suitability of studies and potential bias and extracted the data. The primary outcome was frequency of pneumonia-associated death in patients with dementia. Stratified subgroup analysis was conducted among studies grouped according to type of mortality cause (immediate or underlying), information source of mortality cause (autopsy or death certificate), and study setting (clinic, hospital, or nursing home). RESULTS: We included 7 studies reporting the cause of death among patients with dementia and 12 studies comparing the cause of death among patients with and without dementia. The frequency of pneumonia-associated death among 19 eligible studies was 29.69% (95% confidence interval [CI], 25.86-33.53). Those frequencies differed according to whether the source for information about cause of death was an autopsy confirmation (49.98%; 95% CI, 43.75-56.71) or death certificate (19.65%; 95% CI, 15.48-23.83) and according to whether the type of mortality cause was an indirect cause of death (13.96%; 95% CI, 9.42-18.51) or direct cause of death (44.45%; 95% CI, 29.81-50.10). The risk of pneumonia-associated death in patients with dementia was twice as high as among those without dementia (odds ratio, 2.15; 95% CI, 1.63-2.83; p < 0.001). CONCLUSION: The various frequencies of pneumonia-associated death in patients with dementia were associated with the information source, type of mortality cause, and study setting. Patients with dementia in the terminal stages urgently require careful clinical management of pneumonia, to maximize patient life expectancy and quality.
  • 認知症患者への薬物治療が生命予後に及ぼす影響についての検討, 間辺 利江, 水上 勝義, 松岡 珠実, 小川 倫弘, 兼坂 岳志, 谷口 知恵, 山本 左近, 橋詰 良夫, 大原 弘隆, 山本 孝之, 赤津 裕康, 日本老年医学会雑誌, 56, (2) 171 - 180,   2019年, 査読有り, 目的:高齢者の薬物治療は多剤併用による有害事象の出現など課題が多い.しかし認知症高齢者の薬物治療の影響についての詳細な報告は未だ乏しい.方法:愛知県豊橋市の病院に,2012年1月〜2016年12月に入院,死亡退院し,剖検により臨床神経病理学的に認知症と確定診断された患者を対象に後ろ向き観察研究を行った.基本属性,入院時臨床症状,入院前一年間のBPSD・老年症候群等を収集,対象患者を入院時持参の薬剤数で二群間に分け(≧5剤/多剤併用vs. ≦4剤/非多剤併用)比較した.多剤併用及び慎重に投与すべき薬剤の生命予後期間への影響をKaplan-Meier法及びCox回帰分析にて推定した.薬効分類は薬価基準収載医薬品コードに,慎重に投与すべき薬剤は「高齢者の安全な薬物療法ガイドライン2015(日本老年医学会編集)」に従った.結果:対象者76名の平均持参薬剤数は4剤であった.内,39.5%が多剤併用であった.観察項目の二群間比較では老年症候群の歩行障害が多剤併用群(93.3%)に有意に多かった.慎重投与薬剤の処方は多剤併用群に有意に多かった(p<0.001).Kaplan-Meier法による生存期間の二群間比較では≧5剤群が≦4剤群より短い傾向が示された(p=0.067).生命予後期間への影響は,多剤併用で短縮リスクが高い傾向にあり,これは性別及び入院時年齢での調整でより顕著であった(調整ハザード比,1.631;95%CI,0.991〜2.683;p=0.054).慎重投与薬剤の有無及び,睡眠鎮静剤,抗不安剤,精神神経用剤,その他の中枢神経用薬,ベンゾジアゼピン系薬剤は,生命予後への影響は観察されなかった.結論:本研究により人生の終末期にある認知症高齢者への多剤併用は,生命予後短縮のリスクとなる傾向が示唆された.(著者抄録)
  • Effect of coffee or coffee components on gut microbiome and short-chain fatty acids in a mouse model of metabolic syndrome., Kazuchika Nishitsuji, Syunsuke Watanabe, Jinzhong Xiao, Ryosuke Nagatomo, Hirohisa Ogawa, Takaaki Tsunematsu, Hitomi Umemoto, Yuki Morimoto, Hiroyasu Akatsu, Koichi Inoue, Koichi Tsuneyama, Scientific reports, 8, (1) 16173 - 16173,   2018年11月01日, 査読有り, We previously showed that male Tsumura Suzuki obese diabetes (TSOD) mice, a spontaneous mouse model of metabolic syndrome, manifested gut dysbiosis and subsequent disruption of the type and quantity of plasma short-chain fatty acids (SCFAs), and daily coffee intake prevented nonalcoholic steatohepatitis in this mouse model. Here, we present a preliminary study on whether coffee and its major components, caffeine and chlorogenic acid, would affect the gut dysbiosis and the disrupted plasma SCFA profile of TSOD mice, which could lead to improvement in the liver pathology of these mice. Three mice per group were used. Daily intake of coffee or its components for 16 wk prevented liver lobular inflammation without improving obesity in TSOD mice. Coffee and its components did not repair the altered levels of Gram-positive and Gram-negative bacteria and an increased abundance of Firmicutes in TSOD mice but rather caused additional changes in bacteria in six genera. However, caffeine and chlorogenic acid partially improved the disrupted plasma SCFA profile in TSOD mice, although coffee had no effects. Whether these alterations in the gut microbiome and the plasma SCFA profile might affect the liver pathology of TSOD mice may deserve further investigation.
  • TAR DNA-Binding Protein 43 and Disrupted in Schizophrenia 1 Coaggregation Disrupts Dendritic Local Translation and Mental Function in Frontotemporal Lobar Degeneration., Ryo Endo, Noriko Takashima, Yoko Nekooki-Machida, Yusuke Komi, Kelvin Kai-Wan Hui, Masaki Takao, Hiroyasu Akatsu, Shigeo Murayama, Akira Sawa, Motomasa Tanaka, Biological psychiatry, 84, (7) 509 - 521,   2018年10月01日, 査読有り, BACKGROUND: Neurodegenerative diseases involving protein aggregation often accompany psychiatric symptoms. Frontotemporal lobar degeneration (FTLD) associated with TAR DNA-binding protein 43 (TDP-43) aggregation is characterized by progressive neuronal atrophy in frontal and temporal lobes of cerebral cortex. Furthermore, patients with FTLD display mental dysfunction in multiple behavioral dimensions. Nevertheless, their molecular origin for psychiatric symptoms remains unclear. METHODS: In FTLD neurons and mouse models with TDP-43 aggregates, we examined coaggregation between TDP-43 and disrupted in schizophrenia 1 (DISC1), a key player in the pathology of mental conditions and its effects on local translation in dendrites and psychiatric behaviors. The protein coaggregation and the expression level of synaptic proteins were also investigated with postmortem brains from patients with FTLD (n = 6). RESULTS: We found cytosolic TDP-43/DISC1 coaggregates in brains of both FTLD mouse model and patients with FTLD. At the mechanistic levels, the TDP-43/DISC1 coaggregates disrupted the activity-dependent dendritic local translation through impairment of translation initiation and, in turn, reduced synaptic protein expression. Behavioral deficits detected in FTLD model mice were ameliorated by exogenous DISC1 expression. CONCLUSIONS: Our findings reveal a novel role of the aggregate-prone TDP-43/DISC1 protein complex in regulating local translation, which affects aberrant behaviors relevant to multiple psychiatric dimensions.
  • Widely targeted metabolomics of Alzheimer's disease postmortem cerebrospinal fluid based on 9-fluorenylmethyl chloroformate derivatized ultra-high performance liquid chromatography tandem mass spectrometry., Yoshio Muguruma, Haruhito Tsutsui, Takumi Noda, Hiroyasu Akatsu, Koichi Inoue, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 1091, 53 - 66,   2018年08月01日, 査読有り, Confirmed biomarkers of postmortem cerebrospinal fluid (pCSF) are used to differentiate between Alzheimer's disease (AD) patients and healthy seniors with high diagnostic accuracy. However, the extent to which the performance of specific metabolic profiling facilitates reliable estimations of the concentrations of the different pCSF biomarkers and their ratios remains unclear. The interpretation of the lower levels of molecules of metabolic profiling and their concentration ratios in pCSF related to brain disorders could facilitate an unchallenging detection of peripheral biomarkers of AD stages and other dementia types. In this study, we proposed the use of widely targeted metabolomics for pCSF metabolic profiling using 9-fluorenylmethyl chloroformate- (FMOC) derivatized ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to evaluate the diversity of 97 amine-mediated metabolic patterns and pathways from confirmed diagnosis based on AD brain pathology. Our results identified the metabolites that contributed toward and mutually influenced the principal component analysis plot with integrated analytes. Furthermore, the AD group showed a significant variation in several analyte concentration levels compared to those of control subjects. These trends of the concentration levels expressed by the amine metabolic pathways indicated the decreased activity of polyamine and tryptophan-kynurenine (Trp-Kyn) metabolisms. Moreover, increased metabolites such as methionine sulfoxide, 3-methoxy-anthranilate, cadaverine, guanine, and histamine were observed by widely targeted metabolomics of pCSF from the AD subjects. According to their metabolic pathway analysis using FMOC-derivatized UHPLC-MS/MS assay, we supposed that the involvement of polyamine and Trp-Kyn metabolisms was observed in the pCSF samples.
  • Integrated analysis of human genetic association study and mouse transcriptome suggests LBH and SHF genes as novel susceptible genes for amyloid-β accumulation in Alzheimer's disease., Yamaguchi-Kabata Y, Morihara T, Ohara T, Ninomiya T, Takahashi A, Akatsu H, Hashizume Y, Hayashi N, Shigemizu D, Boroevich KA, Ikeda M, Kubo M, Takeda M, Tsunoda T, Human genetics, 137, (6-7) 521 - 533,   2018年07月, 査読有り
  • Targeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology., Kyota Fujita, Xigui Chen, Hidenori Homma, Kazuhiko Tagawa, Mutsuki Amano, Ayumu Saito, Seiya Imoto, Hiroyasu Akatsu, Yoshio Hashizume, Kozo Kaibuchi, Satoru Miyano, Hitoshi Okazawa, Nature communications, 9, (1) 433 - 433,   2018年01月30日, 査読有り, Mutations in the progranulin (PGRN) gene cause a tau pathology-negative and TDP43 pathology-positive form of frontotemporal lobar degeneration (FTLD-TDP). We generated a knock-in mouse harboring the R504X mutation (PGRN-KI). Phosphoproteomic analysis of this model revealed activation of signaling pathways connecting PKC and MAPK to tau prior to TDP43 aggregation and cognitive impairments, and identified PKCα as the kinase responsible for the early-stage tau phosphorylation at Ser203. Disinhibition of Gas6 binding to Tyro3 due to PGRN reduction results in activation of PKCα via PLCγ, inducing tau phosphorylation at Ser203, mislocalization of tau to dendritic spines, and spine loss. Administration of a PKC inhibitor, B-Raf inhibitor, or knockdown of molecules in the Gas6-Tyro3-tau axis rescues spine loss and cognitive impairment of PGRN-KI mice. Collectively, these results suggest that targeting of early-stage and aggregation-independent tau signaling represents a promising therapeutic strategy for this disease.
  • 大都市旧ニュータウン在住高齢者への死後を含めた事前指示に関する意識調査と啓発介入効果, 赤津 裕康, 間辺 利江, 竹尾 淳, 川出 義浩, 木村 雄子, 近藤 麻央, 伊藤 禎芳, 長野 弘季, 野崎 耀志郎, 土井 愛美, 正木 克由規, 田中 創始, 兼松 孝好, 小嶋 雅代, 明石 惠子, 岩田 彰, 鈴木 匡, 木村 和哲, 浅井 清文, 大原 隆弘, 日本老年医学会雑誌, 55, (3) 358 - 366,   2018年, 査読有り, 目的:今後の超高齢社会を乗り切っていく重要な1つの方策は意識改革である。その要になるのはヘルスケア・メディケーションを行いつつ自らの最終ゴールを見つめる、即ちアドバンスケアプランニング(Advance care planning:以下ACPと略す)と事前指示(Advance directive:以下Adと略す)を行うことである。また、パーソナルヘルスレコード(Personal Health Record:以下PHRと略す)の匿名開示、病理解剖はあまり言及されていない。しかし、死後のことも事前に考え、意向を聞いておく環境整備も必要である。この死後対応を含めたAd/ACPの啓発・浸透が国民の意識改革にもなっていく。本研究は地域住民の意識をアンケート形式で把握し、講演(啓発活動)での変容を捉えることを目的とした。方法:高齢化の進む大都市旧ニュータウン住民へAd/ACP啓発講演を行い、その前後での意識調査を行った。意識調査はアンケートでの自記式4択を主体に末期認知症になった状況を主に想定した6大項目、38問を設けた。結果:参加者は35名(男7名、女22名)で40歳代〜80代以上で70歳代が25名であった。途中退出者が数名発生したため、前後変容に関しては、統計的解析は不可能であったが意識変容の傾向は得られた。特に死後の対応(献体)に関しては有意差をもった意識変化を認めた。また蘇生・延命の希望者数と救急搬送希望者数に乖離を認めた。結論:医療行為への希望・不安はその情報量に加え、置かれた状況でも変容する。今回の意識調査で、死後の社会貢献意識に講演前後で変化が観られた。また蘇生・延命と救急搬送は別物と捉える地域住民が多い点も明らかとなった。今後のAd/ACPの普及、意識改革では、この点を念頭においた地道な活動と医療・介護者、地域の方々、家族、本人との連携が必要である。(著者抄録)
  • Analysis of the gut microbiome and plasma short-chain fatty acid profiles in a spontaneous mouse model of metabolic syndrome., Kazuchika Nishitsuji, Jinzhong Xiao, Ryosuke Nagatomo, Hitomi Umemoto, Yuki Morimoto, Hiroyasu Akatsu, Koichi Inoue, Koichi Tsuneyama, Scientific reports, 7, (1) 15876 - 15876,   2017年11月20日, 査読有り, Male Tsumura Suzuki obese diabetes (TSOD) mice spontaneously develop obesity and obesity-related metabolic syndrome. Gut dysbiosis, an imbalance of gut microbiota, has been implicated in the pathogenesis of metabolic syndrome, but its mechanisms are unknown. Short-chain fatty acids (SCFAs) are the main fermentation products of gut microbiota and a link between the gut microbiota and the host's physiology. Here, we investigated a correlation among gut dysbiosis, SCFAs, and metabolic syndrome in TSOD mice. We detected enriched levels of Gram-positive bacteria and corresponding decreases in Gram-negative bacteria in 24-wk-old metabolic syndrome-affected TSOD mice compared with age-matched controls. The abundance of Bacteroidetes species decreased, the abundance of Firmicutes species increased, and nine genera of bacteria were altered in 24-wk-old TSOD mice. The total plasma SCFA level was significantly lower in the TSOD mice than in controls. The major plasma SCFA-acetate-decreased in TSOD mice, whereas propionate and butyrate increased. TSOD mice had no minor SCFAs (valerate and hexanoate) but normal mice did. We thus concluded that gut dysbiosis and consequent disruptions in plasma SCFA profiles occurred in metabolic syndrome-affected TSOD mice. We also propose that the TSOD mouse is a useful model to study gut dysbiosis, SCFAs, and metabolic syndrome.
  • Lysophosphatidylcholine export by human ABCA7., Maiko Tomioka, Yoshinobu Toda, Noralyn B Mañucat, Hiroyasu Akatsu, Manabu Fukumoto, Nozomu Kono, Hiroyuki Arai, Noriyuki Kioka, Kazumitsu Ueda, Biochimica et biophysica acta. Molecular and cell biology of lipids, 1862, (7) 658 - 665,   2017年07月, 査読有り, The ATP-binding cassette transporter A7 (ABCA7), which is highly expressed in the brain, is associated with the pathogenesis of Alzheimer's disease (AD). However, the physiological function of ABCA7 and its transport substrates remain unclear. Immunohistochemical analyses of human brain sections from AD and non-AD subjects revealed that ABCA7 is expressed in neuron and microglia cells in the cerebral cortex. The transport substrates and acceptors were identified in BHK/ABCA7 cells and compared with those of ABCA1. Like ABCA1, ABCA7 exported choline phospholipids in the presence of apoA-I and apoE; however, unlike ABCA1, cholesterol efflux was marginal. Lipid efflux by ABCA7 was saturated by 5μg/ml apoA-I and was not dependent on apoE isoforms, whereas efflux by ABCA1 was dependent on apoA-I up to 20μg/ml and apoE isoforms. Liquid chromatography-tandem mass spectrometry analyses revealed that the two proteins had different preferences for phospholipid export: ABCA7 preferred phosphatidylcholine (PC)≥lysoPC>sphingomyelin (SM)=phosphatidylethanolamine (PE), whereas ABCA1 preferred PC>SM>PE=lysoPC. The major difference in the pattern of lipid peaks between ABCA7 and ABCA1 was the high lysoPC/PC ratio of ABCA7. These results suggest that lysoPC is one of the major transport substrates for ABCA7 and that lysoPC export may be a physiologically important function of ABCA7 in the brain.
  • Lysophosphatidylcholine export by human ABCA7., Tomioka M, Toda Y, Mañucat NB, Akatsu H, Fukumoto M, Kono N, Arai H, Kioka N, Ueda K, Biochimica et biophysica acta, 1862, (7) 658 - 665,   2017年07月, 査読有り
  • Lysophosphatidylcholine export by human ABCA7., Tomioka M, Toda Y, Mañucat NB, Akatsu H, Fukumoto M, Kono N, Arai H, Kioka N, Ueda K, Biochimica et biophysica acta. Molecular and cell biology of lipids, 1862, (7) 658 - 665,   2017年07月, 査読有り
  • Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer's pathology., Zui Zhang, Yoshiko Takeda-Uchimura, Tahmina Foyez, Shiori Ohtake-Niimi, Narentuya, Hiroyasu Akatsu, Kazuchika Nishitsuji, Makoto Michikawa, Tony Wyss-Coray, Kenji Kadomatsu, Kenji Uchimura, Proceedings of the National Academy of Sciences of the United States of America, 114, (14) E2947-E2954 - E2954,   2017年04月04日, 査読有り, We previously showed that microglial keratan sulfate (KS) was induced in amyotrophic lateral sclerosis. However, the functional roles of the glycan and its synthetic enzyme in neurodegenerative diseases, such as Alzheimer's disease (AD), a progressive disorder, are unclear. In our study, KS modified with sialic acids having a molecular mass of 125-220 kDa and the carbohydrate sulfotransferase GlcNAc6ST1 were up-regulated in the brains of two transgenic mouse models (J20 and Tg2576) and the brains of patients with AD. GlcNAc6ST1-deficient J20 (J20/GlcNAc6ST1-/-) mice demonstrated a complete absence of the microglial sialylated KS. J20/GlcNAc6ST1-/- primary microglia showed an increased level of amyloid-β phagocytosis and were hyperresponsive to interleukin 4, a potent antiinflammatory cytokine. Moreover, J20/GlcNAc6ST1-/- mice manifested reduced cerebral amyloid-β deposition. GlcNAc6ST1-synthesizing sialylated KS thus modulates AD pathology. Inhibition of KS synthesis by targeting GlcNAc6ST1 may therefore be beneficial for controlling AD pathogenesis.
  • Downregulation of GNA13-ERK network in prefrontal cortex of schizophrenia brain identified by combined focused and targeted quantitative proteomics., Mio Hirayama-Kurogi, Yohei Takizawa, Yasuto Kunii, Junya Matsumoto, Akira Wada, Mizuki Hino, Hiroyasu Akatsu, Yoshio Hashizume, Sakon Yamamoto, Takeshi Kondo, Shingo Ito, Masanori Tachikawa, Shin-Ichi Niwa, Hirooki Yabe, Tetsuya Terasaki, Mitsutoshi Setou, Sumio Ohtsuki, Journal of proteomics, 158, 31 - 42,   2017年03月31日, 査読有り, Schizophrenia is a disabling mental illness associated with dysfunction of the prefrontal cortex, which affects cognition and emotion. The purpose of the present study was to identify altered molecular networks in the prefrontal cortex of schizophrenia patients by comparing protein expression levels in autopsied brains of patients and controls, using a combination of targeted and focused quantitative proteomics. We selected 125 molecules possibly related to schizophrenia for quantification by knowledge-based targeted proteomics. Among the quantified molecules, GRIK4 and MAO-B were significantly decreased in plasma membrane and cytosolic fractions, respectively, of prefrontal cortex. Focused quantitative proteomics identified 15 increased and 39 decreased proteins. Network analysis identified "GNA13-ERK1-eIF4G2 signaling" as a downregulated network, and proteins involved in this network were significantly decreased. Furthermore, searching downstream of eIF4G2 revealed that eIF4A1/2 and CYFIP1 were decreased, suggesting that downregulation of the network suppresses expression of CYFIP1, which regulates actin remodeling and is involved in axon outgrowth and spine formation. Downregulation of this signaling seems likely to impair axon formation and synapse plasticity of neuronal cells, and could be associated with development of cognitive impairment in the pathology of schizophrenia. BIOLOGICAL SIGNIFICANCE: The present study compared the proteome of the prefrontal cortex between schizophrenia patients and healthy controls by means of targeted proteomics and global quantitative proteomics. Targeted proteomics revealed that GRIK4 and MAOB were significantly decreased among 125 putatively schizophrenia-related proteins in prefrontal cortex of schizophrenia patients. Global quantitative proteomics identified 54 differentially expressed proteins in schizophrenia brains. The protein profile indicates attenuation of "GNA13-ERK signaling" in schizophrenia brain. In particular, EIF4G2 and CYFIP1, which are located downstream of the GNA13-ERK network, were decreased, suggesting that the attenuation of this signal network may cause impairment of axon formation and synapse plasticity in the brain of schizophrenia patients. Our results provide a novel insight into schizophrenia pathology, and could be helpful for drug development.
  • Decreased 16:0/20:4-phosphatidylinositol level in the post-mortem prefrontal cortex of elderly patients with schizophrenia., Junya Matsumoto, Hiroki Nakanishi, Yasuto Kunii, Yuki Sugiura, Dai Yuki, Akira Wada, Mizuki Hino, Shin-Ichi Niwa, Takeshi Kondo, Michihiko Waki, Takahiro Hayasaka, Noritaka Masaki, Hiroyasu Akatsu, Yoshio Hashizume, Sakon Yamamoto, Shinji Sato, Takehiko Sasaki, Mitsutoshi Setou, Hirooki Yabe, Scientific reports, 7, 45050 - 45050,   2017年03月23日, 査読有り, The etiology of schizophrenia includes phospholipid abnormalities. Phospholipids are bioactive substances essential for brain function. To analyze differences in the quantity and types of phospholipids present in the brain tissue of patients with schizophrenia, we performed a global analysis of phospholipids in multiple brain samples using liquid chromatography electrospray ionization mass/mass spectrometry (LC-ESI/MS/MS) and imaging mass spectrometry (IMS). We found significantly decreased 16:0/20:4-phosphatidylinositol (PI) levels in the prefrontal cortex (PFC) in the brains from patients with schizophrenia in the LC-ESI/MS/MS, and that the 16:0/20:4-PI in grey matter was most prominently diminished according to the IMS experiments. Previous reports investigating PI pathology of schizophrenia did not identify differences in the sn-1 and sn-2 fatty acyl chains. This study is the first to clear the fatty acid composition of PI in brains from patients with schizophrenia. Alteration in the characteristic fatty acid composition of PI may also affect neuronal function, and could play a role in the etiology of schizophrenia. Although further studies are necessary to understand the role of reduced 16:0/20:4-PI levels within the prefrontal cortex in the etiology of schizophrenia, our results provide insight into the development of a novel therapy for the clinical treatment of schizophrenia.
  • Increase in α-tubulin modifications in the neuronal processes of hippocampal neurons in both kainic acid-induced epileptic seizure and Alzheimer's disease., Vu HT, Akatsu H, Hashizume Y, Setou M, Ikegami K, Scientific reports, 7, 40205 - 40205,   2017年01月09日, 査読有り
  • Histopathology and Florbetaben PET in Patients Incorrectly Diagnosed with Alzheimer's Disease., Marwan N Sabbagh, Barbara Schäuble, Keshav Anand, Danielle Richards, Shigeo Murayama, Hiroyasu Akatsu, Masaki Takao, Christopher C Rowe, Colin L Masters, Henryk Barthel, Hermann-Josef Gertz, Oliver Peters, Natalie Rasgon, Aleksandar Jovalekic, Osama Sabri, Walter J Schulz-Schaeffer, John Seibyl, Journal of Alzheimer's disease : JAD, 56, (2) 441 - 446,   2017年, 査読有り, Of 57 individuals diagnosed with Alzheimer's disease (AD) in a phase III study, 13 (23%) had amyloid-β (Aβ) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aβ pathology.
  • Factors Associated with Pneumonia-caused Death in Older Adults with Autopsy-confirmed Dementia., Toshie Manabe, Katsuyoshi Mizukami, Hiroyasu Akatsu, Yoshio Hashizume, Takayoshi Ohkubo, Koichiro Kudo, Nobuyuki Hizawa, Internal medicine (Tokyo, Japan), 56, (8) 907 - 914,   2017年, 査読有り, Objective A better understanding of risk factors for pneumonia-caused death may help to improve the clinical management of dementia. Methods A retrospective observational study was conducted by reviewing the medical charts and autopsy reports of 204 patients who were admitted to hospital, underwent a post-mortem examination, and who were neuropathologically diagnosed with dementia. The risk factors for pneumonia-caused death were examined both as underlying and immediate causes of death using logistic regression models. Results A high frequency of pneumonia-caused death was observed both in underlying- (37.3%) and immediate- (44.1%) cause of death, but varied according to the subtypes of dementia. The factors related to pneumonia-caused death (underlying) were subtypes of dementia; Alzheimer's disease (odds ratio [OR], 2.891; 95% confidence interval [CI], 1.459-5.730); argyrophilic grain disease (OR, 3.148; 95% CI, 0.937-10.577); and progressive supranuclear palsy (OR, 34.921; 95% CI, 3.826-318.775), dysphagia (OR, 2.045; 95% CI, 1.047-3.994), diabetes mellitus (OR, 3.084; 95% CI, 1.180-8.061) and conversely related with heart failure (OR, 0.149; 95% CI, 0.026-0.861). Factors relating to pneumonia-caused death (immediate) were incidence of pneumonia during hospitalizations (OR, 32.579; 95%CI, 4.308-246.370), gender-male (OR, 2.060; 95% CI, 1.098-3.864), and conversely related with malignant neoplasm (OR, 0.220; 95% CI, 0.058-0.840). Conclusion The different factors relating to the pneumonia-caused death were evaluated depending on whether pneumonia was the underlying- or immediate-cause of death. Strengthening clinical management on dysphagia and diabetes mellitus, and preventing incidence of pneumonia during hospitalization appear to be the important for the terminal stage of hospitalized patients with dementia.
  • Comparative Analysis of Cortical Microinfarcts and Microbleeds using 3.0-Tesla Postmortem Magnetic Resonance Images and Histopathology., Atsushi Niwa, Yuichiro Ii, Akihiro Shindo, Ko Matsuo, Hidehiro Ishikawa, Akira Taniguchi, Shinichi Takase, Masayuki Maeda, Hajime Sakuma, Hiroyasu Akatsu, Yoshio Hashizume, Hidekazu Tomimoto, Journal of Alzheimer's disease : JAD, 59, (3) 951 - 959,   2017年, 査読有り, Microvascular lesions including cortical microinfarctions (CMIs) and cerebral lobar microbleeds (CMBs) are usually caused by cerebral amyloid angiopathy (CAA) in the elderly and are correlated with cognitive decline. However, their radiological-histopathological coincidence has not been revealed systematically with widely used 3-Tesla (3T) magnetic resonance imaging (MRI). The purpose of the present study is to delineate the histopathological background corresponding to MR images of these lesions. We examined formalin-fixed 10-mm thick coronal brain blocks from 10 CAA patients (five were also diagnosed with Alzheimer's disease, three with dementia with Lewy bodies, and two with CAA only) with dementia and six non CAA patients with neurodegenerative disease. Using 3T MRI, both 3D-fluid attenuated inversion recovery (FLAIR) and 3D-double inversion recovery (DIR) were examined to identify CMIs, and T2* and susceptibility-weighted images (SWI) were examined to identify CMBs. These blocks were subsequently examined histologically and immunohistochemically. In CAA patients, 48 CMIs and 6 lobar CMBs were invariably observed in close proximity to degenerated Aβ-positive blood vessels. Moreover, 16 CMIs (33%) of 48 were detected with postmortem MRI, but none were seen when the lesion size was smaller than 1 mm. In contrast, only 1 undeniable CMI was founded with MRI and histopathology in 6 non CAA patients. Small, cortical high-intensity lesions seen on 3D-FLAIR and 3D-DIR images likely represent CMIs, and low-intensity lesions in T2* and SWI correspond to CMBs with in vivo MRI. Furthermore, a close association between amyloid-laden vessels and these microvascular lesions indicated the contribution of CAA to their pathogenesis.
  • Complement Activation in Capillary Cerebral Amyloid Angiopathy., Matsuo K, Shindo A, Niwa A, Tabei KI, Akatsu H, Hashizume Y, Akiyama H, Ayaki T, Maki T, Sawamoto N, Takahashi R, Oikawa S, Tomimoto H, Dementia and geriatric cognitive disorders, 44, (5-6) 343 - 353,   2017年, 査読有り
  • Decreased VEGFR2 expression and increased phosphorylated Akt1 in the prefrontal cortex of individuals with schizophrenia., Mizuki Hino, Yasuto Kunii, Junya Matsumoto, Akira Wada, Atsuko Nagaoka, Shin-Ichi Niwa, Hitoshi Takahashi, Akiyoshi Kakita, Hiroyasu Akatsu, Yoshio Hashizume, Sakon Yamamoto, Hirooki Yabe, Journal of psychiatric research, 82, 100 - 8,   2016年11月, 査読有り, The Akt signaling pathway involves various cellular processes and depends on extracellular stimuli. Since Akt signaling participates in cytoprotection, synapse plasticity, axon extension, and neurotransmission in the nervous system, alteration in Akt signaling might be a potential cause of schizophrenia. In this study, we performed multiplex fluorescent bead based immunoassays for members of the Akt signaling pathway in postmortem brains of controls and patients with schizophrenia. Vascular endothelial growth factor receptor 2 (VEGFR2/KDR) was significantly decreased in the prefrontal cortex (PFC) of patients with schizophrenia, and the expression level of VEGFR2 was inversely correlated with the positive symptom subscale of the Diagnostic Instrument for Brain Studies (DIBS) in patients with schizophrenia. There was also an increase in phosphorylated Akt1 in the PFC in the patients, though the ratio of phospho/total Akt1 is not significantly different. In the nucleus accumbens (NAcc) there was no significant difference in expression and phosphorylation levels of Akt signaling proteins. Genetic analysis revealed a significant correlation of a SNP of KDR (rs7692791) with ERK1/2 and Akt1 phospho/total rates. Since VEGFR2 participates in angiogenesis and neurotrophic activation, either or both functions might be responsible for onset of schizophrenia.
  • A diagnostic marker for superficial urothelial bladder carcinoma: lack of nuclear ATBF1 (ZFHX3) by immunohistochemistry suggests malignant progression., Makoto Kawaguchi, Noboru Hara, Vladimir Bilim, Hiroshi Koike, Mituko Suzuki, Tae-Sun Kim, Nan Gao, Yu Dong, Sheng Zhang, Yuji Fujinawa, Osamu Yamamoto, Hiromi Ito, Yoshihiko Tomita, Yuchi Naruse, Akira Sakamaki, Yoko Ishii, Koichi Tsuneyama, Masaaki Inoue, Johbu Itoh, Masanori Yasuda, Nobuo Sakata, Cha-Gyun Jung, Satoshi Kanazawa, Hiroyasu Akatsu, Hiroshi Minato, Takayuki Nojima, Kiyofumi Asai, Yutaka Miura, BMC cancer, 16, (1) 805 - 805,   2016年10月18日, 査読有り, BACKGROUND: Pathological stage and grade have limited ability to predict the outcomes of superficial urothelial bladder carcinoma at initial transurethral resection (TUR). AT-motif binding factor 1 (ATBF1) is a tumor suppressive transcription factor that is normally localized to the nucleus but has been detected in the cytoplasm in several cancers. Here, we examined the diagnostic value of the intracellular localization of ATBF1 as a marker for the identification of high risk urothelial bladder carcinoma. METHODS: Seven anti-ATBF1 antibodies were generated to cover the entire ATBF1 sequence. Four human influenza hemagglutinin-derived amino acid sequence-tagged expression vectors with truncated ATBF1 cDNA were constructed to map the functional domains of nuclear localization signals (NLSs) with the consensus sequence KR[X10-12]K. A total of 117 samples from initial TUR of human bladder carcinomas were analyzed. None of the patients had received chemotherapy or radiotherapy before pathological evaluation. RESULTS: ATBF1 nuclear localization was regulated synergistically by three NLSs on ATBF1. The cytoplasmic fragments of ATBF1 lacked NLSs. Patients were divided into two groups according to positive nuclear staining of ATBF1, and significant differences in overall survival (P = 0.021) and intravesical recurrence-free survival (P = 0.013) were detected between ATBF1+ (n = 110) and ATBF1- (n = 7) cases. Multivariate analysis revealed that ATBF1 staining was an independent prognostic factor for intravesical recurrence-free survival after adjusting for cellular grading and pathological staging (P = 0.008). CONCLUSIONS: Cleavage of ATBF1 leads to the cytoplasmic localization of ATBF1 fragments and downregulates nuclear ATBF1. Alterations in the subcellular localization of ATBF1 due to fragmentation of the protein are related to the malignant character of urothelial carcinoma. Pathological evaluation using anti-ATBF1 antibodies enabled the identification of highly malignant cases that had been overlooked at initial TUR. Nuclear localization of ATBF1 indicates better prognosis of urothelial carcinoma.
  • Influence of pneumonia complications on the prognosis of patients with autopsy-confirmed Alzheimer's disease, dementia with Lewy bodies, and vascular dementia., Toshie Manabe, Katsuyoshi Mizukami, Hiroyasu Akatsu, Shinji Teramoto, Kazue Yamaoka, Seiji Nakamura, Takayoshi Ohkubo, Koichiro Kudo, Nobuyuki Hizawa, Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society, 16, (5) 305 - 14,   2016年09月, 査読有り, BACKGROUND: Pneumonia is a major, complicated disease in patients with dementia. However, the influence of pneumonia on the prognosis of patients with varying types of dementia has not been fully evaluated. METHODS: We retrospectively analyzed the data from medical and autopsy reports. All study patients had been hospitalized and underwent brain autopsy in a hospital in Toyohashi, Japan, between 2005 and 2014. The patients with subtypes of dementia, specifically Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or vascular dementia (VaD), were neuropathologically diagnosed and examined. Pneumonia incidence, cause of death, and the clinical time-course of dementia were compared among the dementia subtypes. The time to death from dementia onset (survival time) was compared by the Kaplan-Meier method among subtypes of dementia with or without pneumonia. Risk factors for survival time on all study patients were analyzed with the Cox proportional hazard model. RESULTS: Of the 157 eligible patients, 63 (40.1%) had AD, 42 (26.8%) had DLB, and 52 (33.1%) had VaD. Pneumonia complication was observed with high incidence in each subtype of dementia, especially in DLB (90.5%). The median total duration from dementia onset to death was 8 years in AD and DLB, and 5 years in VaD. The VaD subtype had more male patients than AD or DLB (P = 0.010), and age of death in this group was the youngest among the three groups (P = 0.018). A significant difference was observed in the survival time by the Kaplan-Meier method among the three groups (P < 0.001) and among the groups with pneumonia (P = 0.002). The factors associated with shorter survival time were male gender, pneumonia complications, diabetes mellitus, age of dementia onset ≥ 75 years, and VaD. CONCLUSIONS: Pneumonia complications shortened the survival time of patients with AD, DLB, and VaD.
  • Neuronal expression of ILEI/FAM3C and its reduction in Alzheimer's disease., Lei Liu, Naoki Watanabe, Hiroyasu Akatsu, Masaki Nishimura, Neuroscience, 330, 236 - 46,   2016年08月25日, 査読有り, Decrease in brain amyloid-β (Aβ) accumulation is a leading strategy for treating Alzheimer's disease (AD). However, the intrinsic mechanism of the regulation of brain Aβ production is largely unknown. Previously, we reported that ILEI (also referred to as FAM3C) binds to the γ-secretase complex and suppresses Aβ production without inhibiting γ-secretase activity. In this study, we examined ILEI expression in mouse brain using immunohistochemistry and subcellular fractionation. Brain ILEI showed widespread expression in neurons and ependymal cells but not in glial and vascular endothelial cells. Neuronal ILEI resided in perinuclear vesicular structures, which were positive for a marker protein of the trans-Golgi network. Although ILEI immunostaining was negative at synaptic terminals, synaptosome fractionation analysis suggested that ILEI was enriched in presynaptic terminals, particularly in the active zone-docked synaptic vesicles. ILEI expression levels in brain peaked during the postnatal period and declined with age. In comparison with age-matched control brains, the number of ILEI-immunoreactive neurons decreased in AD brains, although the subcellular localization was unaltered. Our results suggest that a decline of ILEI expression may cause accumulation of Aβ in the brain and the eventual development of AD.
  • Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study., John Seibyl, Ana M Catafau, Henryk Barthel, Kenji Ishii, Christopher C Rowe, James B Leverenz, Bernardino Ghetti, James W Ironside, Masaki Takao, Hiroyasu Akatsu, Shigeo Murayama, Santiago Bullich, Andre Mueller, Norman Koglin, Walter J Schulz-Schaeffer, Anja Hoffmann, Marwan N Sabbagh, Andrew W Stephens, Osama Sabri, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 57, (6) 900 - 6,   2016年06月, 査読有り, UNLABELLED: Training for accurate image interpretation is essential for the clinical use of β-amyloid PET imaging, but the role of interpreter training and the accuracy of the algorithm for routine visual assessment of florbetaben PET scans are unclear. The aim of this study was to test the robustness of the visual assessment method for florbetaben scans, comparing efficacy readouts across different interpreters and training methods and against a histopathology standard of truth (SoT). METHODS: Analysis was based on data from an international open-label, nonrandomized, multicenter phase-3 study in patients with or without dementia (ClinicalTrials.gov: NCT01020838). Florbetaben scans were assessed visually and quantitatively, and results were compared with amyloid plaque scores. For visual assessment, either in-person training (n = 3 expert interpreters) or an electronic training method (n = 5 naïve interpreters) was used. Brain samples from participants who died during the study were used to determine the histopathologic SoT using Bielschowsky silver staining (BSS) and immunohistochemistry for β-amyloid plaques. RESULTS: Data were available from 82 patients who died and underwent postmortem histopathology. When visual assessment results were compared with BSS + immunohistochemistry as SoT, median sensitivity was 98.2% for the in-person-trained interpreters and 96.4% for the e-trained interpreters, and median specificity was 92.3% and 88.5%, respectively. Median accuracy was 95.1% and 91.5%, respectively. On the basis of BSS only as the SoT, median sensitivity was 98.1% and 96.2%, respectively; median specificity was 80.0% and 76.7%, respectively; and median accuracy was 91.5% and 86.6%, respectively. Interinterpreter agreement (Fleiss κ) was excellent (0.89) for in-person-trained interpreters and very good (0.71) for e-trained interpreters. Median intrainterpreter agreement was 0.9 for both in-person-trained and e-trained interpreters. Visual and quantitative assessments were concordant in 88.9% of scans for in-person-trained interpreters and in 87.7% of scans for e-trained interpreters. CONCLUSION: Visual assessment of florbetaben images was robust in challenging scans from elderly end-of-life individuals. Sensitivity, specificity, and interinterpreter agreement were high, independent of expertise and training method. Visual assessment was accurate and reliable for detection of plaques using BSS and immunohistochemistry and well correlated with quantitative assessments.
  • Immunohistochemical analysis of hippocampal butyrylcholinesterase: Implications for regional vulnerability in Alzheimer's disease., Katsuyoshi Mizukami, Hiroyasu Akatsu, Eric E Abrahamson, Zhiping Mi, Milos D Ikonomovic, Neuropathology : official journal of the Japanese Society of Neuropathology, 36, (2) 135 - 45,   2016年04月, 査読有り, Studies of acetylcholine degrading enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in Alzheimer's disease (AD) have suggested their potential role in the development of fibrillar amyloid-β (Aβ) plaques (amyloid plaques). A recent genome-wide association study analysis identified a novel association between genetic variations in the BCHE locus and amyloid burden. We studied BChE immunoreactivity in hippocampal tissue sections from AD and control cases, and examined its relationship with amyloid plaques, neurofibrillary tangles (NFT), dystrophic neurites (DN) and neuropil threads (NT). Compared to controls, AD cases had greater BChE immunoreactivity in hippocampal neurons and neuropils in CA2/3, but not in the CA1, CA4 and dentate gyrus. The majority of amyloid plaques (> 80%, using a pan-amyloid marker X-34) contained discrete neuritic clusters which were dual-labeled with antibodies against BChE and phosphorylated tau (clone AT8). There was no association between overall regional BChE immunoreaction intensity and amyloid plaque burden. In contrast to previous reports, BChE was localized in only a fraction (~10%) of classic NFT (positive for X-34). A similar proportion of BChE-immunoreactive pyramidal cells were AT8 immunoreactive. Greater NFT and DN loads were associated with greater BChE immunoreaction intensity in CA2/3, but not in CA1, CA4 and dentate gyrus. Our results demonstrate that in AD hippocampus, BChE accumulates in neurons and plaque-associated neuritic clusters, but only in a small proportion of NFT. The association between greater neurofibrillary pathology burden and markedly increased BChE immunoreactivity, observed selectively in CA2/3 region, could reflect a novel compensatory mechanism. Since CA2/3 is generally considered more resistant to AD pathology, BChE upregulation could impact the cholinergic modulation of glutamate neurotransmission to prevent/reduce neuronal excitotoxicity in AD hippocampus.
  • Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains., Fuyuki Kametani, Tomokazu Obi, Takeo Shishido, Hiroyasu Akatsu, Shigeo Murayama, Yuko Saito, Mari Yoshida, Masato Hasegawa, Scientific reports, 6, 23281 - 23281,   2016年03月16日, 査読有り, TDP-43 is the major disease-associated protein involved in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions linked to TDP-43 pathology (FTLD-TDP). Abnormal phosphorylation, truncation and cytoplasmic mis-localization are known to be the characteristics for the aggregated forms of TDP-43, and gain of toxic abnormal TDP-43 or loss of function of physiological TDP-43 have been suggested as the cause of neurodegeneration. However, most of the post-translational modifications or truncation sites in the abnormal TDP-43 in brains of patients remain to be identified by protein chemical analysis. In this study, we carried out a highly sensitive liquid chromatography-mass spectrometry analysis of Sarkosyl-insoluble pathological TDP-43 from brains of ALS patients and identified several novel phosphorylation sites, deamidation sites, and cleavage sites. Almost all modifications were localized in the Gly-rich C-terminal half. Most of the cleavage sites identified in this study are novel and are located in N-terminal half, suggesting that these sites may be more accessible to proteolytic enzymes. The data obtained in this study provide a foundation for the molecular mechanisms of TDP-43 aggregation and ALS pathogenesis.
  • Enhanced vaccination effect against influenza by prebiotics in elderly patients receiving enteral nutrition., Hiroyasu Akatsu, Shinya Nagafuchi, Rina Kurihara, Kenji Okuda, Takeshi Kanesaka, Norihiro Ogawa, Takayoshi Kanematsu, Satoshi Takasugi, Taketo Yamaji, Masao Takami, Takayuki Yamamoto, Hirotaka Ohara, Mitsuo Maruyama, Geriatrics & gerontology international, 16, (2) 205 - 13,   2016年02月, 査読有り, AIM: We investigated the effect of prebiotics on the immunological response after influenza vaccination in enterally fed elderly individuals. The intervention group was given an enteral formula containing lactic acid bacteria-fermented milk products. In addition, two different types of other prebiotics, galacto-oligosaccharide and bifidogenic growth stimulator, were also given. The two prebiotics improved intestinal microbiota differently. In a control group, a standard formula without prebiotics was given. METHODS: An enteral formula with (intervention group [F]) or without (control group [C]) prebiotics was given through percutaneous endoscopic gastrostomy to elderly participants for 10 weeks. Influenza vaccine was inoculated at week 4. Nutritional and biochemical indices, intestinal micro bacteria and immunological indices were analyzed. RESULTS: The Bifidobacterium count in groups F and C at week 0 was 6.4 ± 1.9 and 6.6 ± 3.0 (log10 [count/g feces]), respectively. Although the count in group C decreased at week 10, the count in group F increased. The Bacteroides count in group F increased from 10.7 ± 0.9 to 11.4 ± 0.5, but decreased in group C from 11.2 ± 0.2 to 10.7 ± 0.4. Although the enhanced titers of H1N1, H3N2 and B antigens against the vaccine decreased thereafter in group C, these enhanced titers in group F could be maintained. CONCLUSION: Our findings suggest that prebiotics affect the intestinal microbiota and might maintain the antibody titers in elderly individuals.
  • Immunohistochemical detection of the delayed formation of nonfibrillar large amyloid-β aggregates., Ochiishi T, Itakura A, Liu L, Akatsu H, Kohno H, Nishimura M, Yoshimune K, Genes to cells : devoted to molecular & cellular mechanisms, 21, (2) 200 - 11,   2016年02月, 査読有り
  • Prognostic Factors Related to Dementia with Lewy Bodies Complicated with Pneumonia: An Autopsy Study, Toshie Manabe, Katsuyoshi Mizukami, Hiroyasu Akatsu, Yoshio Hashizume, Shinji Teramoto, Seiji Nakamura, Koichiro Kudo, Nobuyuki Hizawa, INTERNAL MEDICINE, 55, (19) 2771 - 2776,   2016年, 査読有り, Objective In patients demonstrating dementia with Lewy bodies (DLB), pneumonia is a common complication. However, the prognostic factors for the survival time in DLB with pneumonia have not been investigated by autopsy in patients with neuropathologically confirmed DLB. Methods We conducted a retrospective study of the medical and autopsy reports of 42 patients admitted to a Japanese hospital between 2005 and 2014. The patients were neuropathologically diagnosed as having DLB by post-mortem examinations. We analyzed the effects of various factors on the time from DLB onset to death. Results Thirty-nine of the 42 patients with DLB (92.9%) developed pneumonia during hospitalization. The median age at DLB onset was 78 years and the median time from DLB onset to death was 8 years. The Cox proportional hazard model demonstrated cerebral infarction [Hazard Ratio (HR), 2.36 (95% CI 1.12-4.96), p=0.023], muscle weakness [HR, 2.04 (0.95-4.39), p=0.067], male sex [HR, 2.84 (1.24-6.50), p=0.014], and age at onset (>= 78 years.) [HR, 4.71 (1.82-12.18), p=0.001] to be prognostic factors for a shorter time from DLB onset to death. Conclusion Careful treatment of cerebral infarction and muscle weakness of the lower extremities is crucial for DLB patients with pneumonia, especially for those over 78 years of age, in order to maximize the patients' life expectancies.
  • A novel approach for LC-MS/MS-based chiral metabolomics fingerprinting and chiral metabolomics extraction using a pair of enantiomers of chiral derivatization reagents., Takahiro Takayama, Toshiki Mochizuki, Kenichiro Todoroki, Jun Zhe Min, Hajime Mizuno, Koichi Inoue, Hiroyasu Akatsu, Ichiro Noge, Toshimasa Toyo'oka, Analytica chimica acta, 898, 73 - 84,   2015年10月22日, 査読有り, Chiral metabolites are found in a wide variety of living organisms and some of them are understood to be physiologically active compounds and biomarkers. However, the overall analysis of chiral metabolomics is quite difficult due to the high number of metabolites, the significant diversity in their physicochemical properties, and concentration range from metabolite-to-metabolite. To solve this difficulty, we developed a novel approach for chiral metabolomics fingerprinting and chiral metabolomics extraction, which is based on the labeling of a pair of enantiomers of chiral derivatization reagents (i.e., DMT-(S,R)-Pro-OSu and DMT-3(S,R)-Apy) and precursor ion scan chromatography of the derivatives. The multivariate statistics is also required for this strategy. The proposed procedures were evaluated by the detection of a diagnostic marker (i.e., d-lactic acid) using the saliva of diabetic patients. This method was used for the determination of biomarker candidates of chiral amines and carboxyls in Alzheimer's disease (AD) brain homogenates. As the results, l-phenylalanine (L-Phe) and l-lactic acid (L-LA) were identified as the decreased and increased biomarker candidates in the AD brain, respectively. Therefore, the proposed approach seems to be helpful for the determination of non-target chiral metabolomics possessing amines and carboxyls.
  • Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer's disease: phase 3 study., Osama Sabri, Marwan N Sabbagh, John Seibyl, Henryk Barthel, Hiroyasu Akatsu, Yasuomi Ouchi, Kohei Senda, Shigeo Murayama, Kenji Ishii, Masaki Takao, Thomas G Beach, Christopher C Rowe, James B Leverenz, Bernardino Ghetti, James W Ironside, Ana M Catafau, Andrew W Stephens, Andre Mueller, Norman Koglin, Anja Hoffmann, Katrin Roth, Cornelia Reininger, Walter J Schulz-Schaeffer, Alzheimer's & dementia : the journal of the Alzheimer's Association, 11, (8) 964 - 74,   2015年08月, 査読有り, BACKGROUND: Evaluation of brain β-amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias. METHODS: Open-label, nonrandomized, multicenter, phase 3 study to validate the (18)F-labeled β-amyloid tracer florbetaben by comparing in vivo PET imaging with post-mortem histopathology. RESULTS: Brain images and tissue from 74 deceased subjects (of 216 trial participants) were analyzed. Forty-six of 47 neuritic β-amyloid-positive cases were read as PET positive, and 24 of 27 neuritic β-amyloid plaque-negative cases were read as PET negative (sensitivity 97.9% [95% confidence interval or CI 93.8-100%], specificity 88.9% [95% CI 77.0-100%]). In a subgroup, a regional tissue-scan matched analysis was performed. In areas known to strongly accumulate β-amyloid plaques, sensitivity and specificity were 82% to 90%, and 86% to 95%, respectively. CONCLUSIONS: Florbetaben PET shows high sensitivity and specificity for the detection of histopathology-confirmed neuritic β-amyloid plaques and may thus be a valuable adjunct to clinical diagnosis, particularly for the exclusion of AD. TRIAL REGISTRATION: ClinicalTrials.govNCT01020838.
  • A genome-wide association study of late-onset Alzheimer's disease in a Japanese population., Atsushi Hirano, Tomoyuki Ohara, Atsushi Takahashi, Masayuki Aoki, Yuta Fuyuno, Kyota Ashikawa, Takashi Morihara, Masatoshi Takeda, Kouzin Kamino, Etsuko Oshima, Yuko Okahisa, Nobuto Shibata, Heii Arai, Hiroyasu Akatsu, Masashi Ikeda, Nakao Iwata, Toshiharu Ninomiya, Akira Monji, Takanari Kitazono, Yutaka Kiyohara, Michiaki Kubo, Shigenobu Kanba, Psychiatric genetics, 25, (4) 139 - 46,   2015年08月, 査読有り, OBJECTIVE: Although a number of genome-wide association studies (GWASs) of late-onset Alzheimer's disease (LOAD) have been carried out, there have been little GWAS data on East Asian populations. DESIGN: To discover the novel susceptibility loci of LOAD, we carried out a GWAS using 816 LOAD cases and 7992 controls with a replication analysis using an independent panel of 1011 LOAD cases and 7212 controls in a Japanese population. In addition, we carried out a stratified analysis by APOE-ε4 status to eliminate the established effect of APOE region. RESULTS: Our data indicated that 18p11.32 (rs1992269, P = 9.77 × 10(-7)), CNTNAP2 (rs802571, P = 1.26 × 10(-6)), and 12q24.23 (rs11613092, P = 6.85 × 10(-6)) were suggestive loci for susceptibility to LOAD. CONCLUSION: We identified three suggestive loci for susceptibility to LOAD in a Japanese population. Among these, rs802571, located at intron 1 of CNTNAP2, was considered to be a plausible candidate locus from a functional perspective.
  • Effects of a Formula Containing Two Types of Prebiotics, Bifidogenic Growth Stimulator and Galacto-oligosaccharide, and Fermented Milk Products on Intestinal Microbiota and Antibody Response to Influenza Vaccine in Elderly Patients: A Randomized Controlled Trial., Shinya Nagafuchi, Taketo Yamaji, Akihiro Kawashima, Yukiko Saito, Takeshi Takahashi, Takayuki Yamamoto, Mitsuo Maruyama, Hiroyasu Akatsu, Pharmaceuticals (Basel, Switzerland), 8, (2) 351 - 65,   2015年06月18日, 査読有り, We investigated the effect of a formula containing two different prebiotics (bifidogenic growth stimulator and galacto-oligosaccharide) and fermented milk products on intestinal microbiota and antibody responses to an influenza vaccine in enterally fed elderly in-patients. Patients were administered either formula containing prebiotics and fermented milk products (group F: n = 12, 79.9 ± 9.5 years old) or standard formula (group C: n = 12, 80.7 ± 10.1 years old) via percutaneous endoscopic gastrostomy during a 14-week intervention period. Subjects were immunized with an influenza vaccine (A/H1N1, A/H3N2, and B) at week 4 of the intervention. Blood biochemical indices, intestinal bacteria populations and antibody titers were analyzed. Bifidobacterium counts increased significantly in group F compared with group C. The enhanced antibody titers against A/H1N1 were maintained in group F for a longer period compared with group C. The titers against A/H3N2 were unchanged between both groups, and those against B were significantly lower in group F than in group C, although few subjects had seroprotective titers against A/H3N2 and B. These results suggest that administration of the formula containing prebiotics and fermented milk products may maintain antibody titers for longer periods through the improvement of intestinal microbiota.
  • Amyloid-β sequester proteins as blood-based biomarkers of cognitive decline., Uchida K, Shan L, Suzuki H, Tabuse Y, Nishimura Y, Hirokawa Y, Mizukami K, Akatsu H, Meno K, Asada T, Alzheimer's & dementia (Amsterdam, Netherlands), 1, (2) 270 - 80,   2015年06月, 査読有り
  • Alpha1-chimaerin, a Rac1 GTPase-activating protein, is expressed at reduced mRNA levels in the brain of Alzheimer's disease patients., Tomoko Kato, Yoshihiro Konishi, Shun Shimohama, Thomas G Beach, Hiroyasu Akatsu, Ikuo Tooyama, Neuroscience letters, 591, 19 - 24,   2015年03月30日, 査読有り, Alpha1-chimaerin is a GTPase-activating protein (GAP) for Rac1, a member of the Rho small GTPase family, whose action leads to the inactivation of Rac1. Rac1 activity is upregulated in Alzheimer's disease, but little is known about the role of α1-chimaerin. In this study, we investigated the expression and localization of α1-chimaerin mRNA in postmortem human brains from patients with Alzheimer's disease and control subjects. In situ hybridization studies demonstrated that α1-chimaerin was expressed by neurons in the neo-cortex of the temporal lobe and the hippocampus of both controls and Alzheimer's disease cases, with the signal intensity dramatically decreased in patients with Alzheimer's disease. Real-time PCR analysis confirmed a significant reduction of α1-chimaerin mRNA expression in the temporal cortex of Alzheimer's disease cases. In contrast, α2-chimaerin mRNA levels showed no significant difference between the groups. The present study showed reduced α1-chimaerin expression in the brain of Alzheimer's disease cases, suggesting a role in the upregulation of Rac1 activity during the disease process.
  • ATBF1 is a novel amyloid-β protein precursor (AβPP) binding protein that affects AβPP expression., Uhm KO, Kim MJ, Kawaguchi M, Akatsu H, Miura Y, Misumi S, Hida H, Choi EK, Kim YS, Michikawa M, Jung CG, Journal of Alzheimer's disease : JAD, 43, (1) 243 - 57,   2015年, 査読有り
  • Blood-based diagnosis of Alzheimer's disease using fingerprinting metabolomics based on hydrophilic interaction liquid chromatography with mass spectrometry and multivariate statistical analysis., Koichi Inoue, Hirofumi Tsuchiya, Takahiro Takayama, Hiroyasu Akatsu, Yoshio Hashizume, Takayuki Yamamoto, Noriyuki Matsukawa, Toshimasa Toyo'oka, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 974, 24 - 34,   2015年01月01日, 査読有り, Early and definitive diagnosis of Alzheimer's disease (AD) can lead to a better and more-targeted treatment and/or prevention for patients. In the diagnostic biomarkers of AD, the blood sample represents a more non-invasive, inexpensive and acceptable sources for repeated measurements than the cerebrospinal fluid. In this study, the fingerprinting metabolomics was proposed for the challenge of the blood-based diagnosis of defined AD by hydrophilic interaction liquid chromatography mass spectrometry (HILIC/MS). These plasma samples were selected from postmortem specimens based on these pathological examinations. Firstly, we compared these HILIC columns for the non-targeted metabolic assay using pooled plasma. The principal component analysis plot of these seven columns was performed using the repeatability of these chromatograms, and can be used to visualize trends in data sets by three-dimensional dispersion, contributory standard deviation and the number of detections. Based on these results, TSK-Amide 80 and TSKgel-NH₂ columns are used as a reliable HILIC/MS assay of blood-based AD metabolomics that showed metabolic profiling of the AD pathology in MS chromatograms that ranged from 1182 to 2284 compounds. A total of 54 peaks were evaluated in order to identify useful ion signal candidates using an orthogonal partial least-squares-discriminant analysis. These peaks were then specifically analyzed using the HILIC-tandem MS assay by a receiver operating characteristic curve and linear discriminant analysis for the diagnosis of the defined AD. The fingerprinting metabolomics can overcome the limitations of previous challenging blood-based diagnosis of AD, and directly evaluates the specific comparative statistical values from the raw data.
  • Phosphatidylinositol-glycan-phospholipase D is involved in neurodegeneration in prion disease., Jae-Kwang Jin, Byungki Jang, Hyoung Tae Jin, Eun-Kyoung Choi, Cha-Gyun Jung, Hiroyasu Akatsu, Jae-Il Kim, Richard I Carp, Yong-Sun Kim, PloS one, 10, (4) ,   2015年, 査読有り, PrPSc is formed from a normal glycosylphosphatidylinositol (GPI)-anchored prion protein (PrPC) by a posttranslational modification. Most GPI-anchored proteins have been shown to be cleaved by GPI phospholipases. Recently, GPI-phospholipase D (GPI-PLD) was shown to be a strictly specific enzyme for GPI anchors. To investigate the involvement of GPI-PLD in the processes of neurodegeneration in prion diseases, we examined the mRNA and protein expression levels of GPI-PLD in the brains of a prion animal model (scrapie), and in both the brains and cerebrospinal fluids (CSF) of sporadic and familial Creutzfeldt-Jakob disease (CJD) patients. We found that compared with controls, the expression of GPI-PLD was dramatically down-regulated in the brains of scrapie-infected mice, especially in the caveolin-enriched membrane fractions. Interestingly, the observed decrease in GPI-PLD expression levels began at the same time that PrPSc began to accumulate in the infected brains and this decrease was also observed in both the brain and CSF of CJD patients; however, no differences in expression were observed in either the brains or CSF specimens from Alzheimer's disease patients. Taken together, these results suggest that the down-regulation of GPI-PLD protein may be involved in prion propagation in the brains of prion diseases.
  • DHA-PC and PSD-95 decrease after loss of synaptophysin and before neuronal loss in patients with Alzheimer's disease, Dai Yuki, Yuki Sugiura, Nobuhiro Zaima, Hiroyasu Akatsu, Shiro Takei, Ikuko Yao, Masato Maesako, Ayae Kinoshita, Takayuki Yamamoto, Ryo Kon, Keikichi Sugiyama, Mitsutoshi Setou, SCIENTIFIC REPORTS, 4,   2014年11月, 査読有り, Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by senile plaques, neurofibrillary tangles, synaptic disruption, and neuronal loss. Several studies have demonstrated decreases of docosahexaenoic acid-containing phosphatidylcholines (DHA-PCs) in the AD brain. In this study, we used matrix-assisted laser desorption/ionization imaging mass spectrometry in postmortem AD brain to show that PC molecular species containing stearate and DHA, namely PC(18:0/22:6), was selectively depleted in the gray matter of patients with AD. Moreover, in the brain regions with marked amyloid beta (A beta) deposition, the magnitude of the PC(18:0/22:6) reduction significantly correlated with disease duration. Furthermore, at the molecular level, this depletion was associated with reduced levels of the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin. Interestingly, this reduction in PC(18:0/22:6) levels did not correlate with the degrees of A beta deposition and neuronal loss in AD. The analysis of the correlations of key factors and disease duration showed that their effects on the disease time course were arranged in order as Ab deposition, presynaptic disruption, postsynaptic disruption coupled with PC(18:0/22:6) reduction, and neuronal loss.
  • Disease-Modifying Effect of Adiponectin in Model of α-Synucleinopathies., Sekiyama K, Waragai M, Akatsu H, Sugama S, Takenouchi T, Takamatsu Y, Fujita M, Sekigawa A, Rockenstein E, Inoue S, La Spada AR, Masliah E, Hashimoto M, Annals of clinical and translational neurology, 1, (7) 479 - 489,   2014年07月, 査読有り
  • Distinction between mild cognitive impairment and Alzheimer's disease by CSF amyloid β40 and β42, and protein-conjugated acrolein., Mizoi M, Yoshida M, Saiki R, Waragai M, Uemura K, Akatsu H, Kashiwagi K, Igarashi K, Clinica chimica acta; international journal of clinical chemistry, 430, 150 - 5,   2014年03月20日, 査読有り
  • Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-β accumulation modifier., Morihara T, Hayashi N, Yokokoji M, Akatsu H, Silverman MA, Kimura N, Sato M, Saito Y, Suzuki T, Yanagida K, Kodama TS, Tanaka T, Okochi M, Tagami S, Kazui H, Kudo T, Hashimoto R, Itoh N, Nishitomi K, Yamaguchi-Kabata Y, Tsunoda T, Takamura H, Katayama T, Kimura R, Kamino K, Hashizume Y, Takeda M, Proceedings of the National Academy of Sciences of the United States of America, 111, (7) 2638 - 43,   2014年02月18日, 査読有り
  • Simultaneous determination of post-translational racemization and isomerization of N-terminal amyloid-β in Alzheimer's brain tissues by covalent chiral derivatized ultraperformance liquid chromatography tandem mass spectrometry., Inoue K, Hosaka D, Mochizuki N, Akatsu H, Tsutsumiuchi K, Hashizume Y, Matsukawa N, Yamamoto T, Toyo'oka T, Analytical chemistry, 86, (1) 797 - 804,   2014年01月07日, 査読有り
  • Increased levels of plasma p3-alcα35, a major fragment of Alcadeinα by γ-secretase cleavage, in Alzheimer's disease., Omori C, Kaneko M, Nakajima E, Akatsu H, Waragai M, Maeda M, Morishima-Kawashima M, Saito Y, Nakaya T, Taru H, Yamamoto T, Asada T, Hata S, Suzuki T, Japanese Alzheimer’s, Disease Neuroimaging Initiative, Journal of Alzheimer's disease : JAD, 39, (4) 861 - 70,   2014年, 査読有り
  • Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population., Akinori Miyashita, Yanan Wen, Nobutaka Kitamura, Etsuro Matsubara, Takeshi Kawarabayashi, Mikio Shoji, Naoki Tomita, Katsutoshi Furukawa, Hiroyuki Arai, Takashi Asada, Yasuo Harigaya, Masaki Ikeda, Masakuni Amari, Haruo Hanyu, Susumu Higuchi, Masatoyo Nishizawa, Masaichi Suga, Yasuhiro Kawase, Hiroyasu Akatsu, Masaki Imagawa, Tsuyoshi Hamaguchi, Masahito Yamada, Takashi Morihara, Masatoshi Takeda, Takeo Takao, Kenji Nakata, Ken Sasaki, Ken Watanabe, Kenji Nakashima, Katsuya Urakami, Terumi Ooya, Mitsuo Takahashi, Takefumi Yuzuriha, Kayoko Serikawa, Seishi Yoshimoto, Ryuji Nakagawa, Yuko Saito, Hiroyuki Hatsuta, Shigeo Murayama, Akiyoshi Kakita, Hitoshi Takahashi, Haruyasu Yamaguchi, Kohei Akazawa, Ichiro Kanazawa, Yasuo Ihara, Takeshi Ikeuchi, Ryozo Kuwano, Journal of Alzheimer's disease : JAD, 41, (4) 1031 - 8,   2014年, 査読有り, Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimer's disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002-0.0059); however, no significant association with LOAD was observed in these variants. Considering low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese.
  • Quantitative clinical proteomic study of autopsied human infarcted brain specimens to elucidate the deregulated pathways in ischemic stroke pathology., Arnab Datta, Hiroyasu Akatsu, Klaus Heese, Siu Kwan Sze, Journal of proteomics, 91, 556 - 68,   2013年10月08日, 査読有り, UNLABELLED: Ischemic stroke, still lacking an effective neuroprotective therapy is the third leading cause of global mortality and morbidity. Here, we have applied an 8-plex iTRAQ-based 2D-LC-MS/MS strategy to study the commonly regulated infarct proteome from three different brain regions (putamen, thalamus and the parietal lobe) of female Japanese patients. Infarcts were compared with age-, post-mortem interval- and location-matched control specimens. The iTRAQ experiment confidently identified 1520 proteins with 0.1% false discovery rate. Bioinformatics data mining and immunochemical validation of pivotal perturbed proteins revealed a global failure of the cellular energy metabolism in the infarcted tissues as seen by the parallel down-regulation of proteins related to glycolysis, pyruvate dehydrogenase complex, TCA cycle and oxidative phosphorylation. The concomitant down-regulation of all participating proteins (SLC25A11, SLC25A12, GOT2 and MDH2) of malate-aspartate shuttle might be responsible for the metabolic in-coordination between the cytosol and mitochondria resulting in the failure of energy metabolism. The levels of proteins related to reactive gliosis (VIM, GFAP) and anti-inflammatory response (ANXA1, ANXA2) showed an increasing trend. The elevation of ferritin (FTL, FTH1) may indicate an iron-mediated oxidative imbalance aggravating the mitochondrial failure and neurotoxicity. The deregulated proteins could be useful as potential therapeutic targets or biomarkers for ischemic stroke. BIOLOGICAL SIGNIFICANCE: Clinical proteomics of stroke has been lagging behind other areas of clinical proteomics like Alzheimer's disease or schizophrenia. Our study is the first quantitative clinical proteomics study where iTRAQ-2D-LC-MS/MS has been utilized in the area of ischemic stroke to obtain a comparative profile of human ischemic infarcts and age-, sex-, location- and post-mortem interval-matched control brain specimens. Different pathological attributes of ischemic stroke well-known through basic and pre-clinical research such as failure of cellular energy metabolism, reactive gliosis, activation of anti-inflammatory response and aberrant iron metabolism have been observed at the bedside. Our dataset could act as a reference for similar studies done in the future using ischemic brain samples from various brain banks across the world. A meta-analysis of these studies could help to map the pathological proteome specific to ischemic stroke that will guide the scientific community to better evaluate the pros and cons of the pre-clinical models for efficacy and mechanistic studies. Infarct being the core of injury should have the most intense regulation for several key proteins involved in the pathophysiology of ischemic stroke. Hence, a part of the up-regulated proteome could leak into the general circulation that may offer candidates of interest as potential biomarkers. In support of our proposed hypothesis, we report ferritin in the current study as one of the most elevated proteins in the infarct, which has been documented as a biomarker in the context of ischemic stroke by an independent study. Overall, our approach has the potential to identify probable therapeutic targets and biomarkers in the area of ischemic stroke.
  • Lactobacillus in jelly enhances the effect of influenza vaccination in elderly individuals., Hiroyasu Akatsu, Kazuyuki Arakawa, Takayuki Yamamoto, Takayoshi Kanematsu, Noriyuki Matsukawa, Hirotaka Ohara, Mitsuo Maruyama, Journal of the American Geriatrics Society, 61, (10) 1828 - 30,   2013年10月, 査読有り
  • LACTOBACILLUS IN JELLY ENHANCES THE EFFECT OF INFLUENZA VACCINATION IN ELDERLY INDIVIDUALS, Hiroyasu Akatsu, Kazuyuki Arakawa, Takayuki Yamamoto, Takayoshi Kanematsu, Noriyuki Matsukawa, Hirotaka Ohara, Mitsuo Maruyama, JOURNAL OF THE AMERICAN GERIATRICS SOCIETY, 61, (10) 1828 - 1830,   2013年10月, 査読有り
  • Brain site-specific proteome changes in aging-related dementia., Arulmani Manavalan, Manisha Mishra, Lin Feng, Siu Kwan Sze, Hiroyasu Akatsu, Klaus Heese, Experimental & molecular medicine, 45,   2013年09月06日, 査読有り, This study is aimed at gaining insights into the brain site-specific proteomic senescence signature while comparing physiologically aged brains with aging-related dementia brains (for example, Alzheimer's disease (AD)). Our study of proteomic differences within the hippocampus (Hp), parietal cortex (pCx) and cerebellum (Cb) could provide conceptual insights into the molecular mechanisms involved in aging-related neurodegeneration. Using an isobaric tag for relative and absolute quantitation (iTRAQ)-based two-dimensional liquid chromatography coupled with tandem mass spectrometry (2D-LC-MS/MS) brain site-specific proteomic strategy, we identified 950 proteins in the Hp, pCx and Cb of AD brains. Of these proteins, 31 were significantly altered. Most of the differentially regulated proteins are involved in molecular transport, nervous system development, synaptic plasticity and apoptosis. Particularly, proteins such as Gelsolin (GSN), Tenascin-R (TNR) and AHNAK could potentially act as novel biomarkers of aging-related neurodegeneration. Importantly, our Ingenuity Pathway Analysis (IPA)-based network analysis further revealed ubiquitin C (UBC) as a pivotal protein to interact with diverse AD-associated pathophysiological molecular factors and suggests the reduced ubiquitin proteasome degradation system (UPS) as one of the causative factors of AD.
  • Clinical effects of probiotic Bifidobacterium longum BB536 on immune function and intestinal microbiota in elderly patients receiving enteral tube feeding., Hiroyasu Akatsu, Noriyuki Iwabuchi, Jin-Zhong Xiao, Zenjiro Matsuyama, Rina Kurihara, Kenji Okuda, Takayuki Yamamoto, Mitsuo Maruyama, JPEN. Journal of parenteral and enteral nutrition, 37, (5) 631 - 40,   2013年09月, 査読有り, BACKGROUND: Immune system function declines with age. We evaluated the effects of supplementation with the probiotic Bifidobacterium longum BB536 on immune function and intestinal microbiota in the elderly. MATERIALS AND METHODS: In a double-blind study, 45 elderly patients fed by enteral tube feeding (mean [SD] age 81.7 [8.7] years) were given BB536 (n = 23) or a placebo powder (n = 22) for 12 weeks and were observed for an additional 4 weeks posttreatment. At week 4, all patients received an influenza vaccination (A/H1N1, A/H3N2, and B). Clinical data were assessed, including body temperature, bowel movements, fecal microbiota, and immunological biomarkers in blood. RESULTS: BB536 intake significantly increased cell numbers of bifidobacteria in fecal microbiota. There was a tendency toward an increase (P = .085 at week 4 and P = .070 at week 16) of serum IgA in the BB536 group compared with the placebo group. BB536 intake did not significantly affect hemagglutination inhibition (HI) titers in response to the influenza vaccine. Natural killer (NK) cell activity decreased significantly in the placebo group during the intervention but not in the BB536 group. Among those subjects with low NK cell activity (<55%, n = 10 for each group), a significant intergroup difference (P < .05) was observed in the changed values from baseline of NK cell activity at weeks 8 and 12. CONCLUSIONS: These results shed new light on the potential of long-term ingestion of BB536 in increasing the cell number of bifidobacteria in intestinal microbiota and modulating immune function in the elderly.
  • Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease., Nobuyuki Okamura, Shozo Furumoto, Ryuichi Harada, Tetsuro Tago, Takeo Yoshikawa, Michelle Fodero-Tavoletti, Rachel S Mulligan, Victor L Villemagne, Hiroyasu Akatsu, Takayuki Yamamoto, Hiroyuki Arai, Ren Iwata, Kazuhiko Yanai, Yukitsuka Kudo, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 54, (8) 1420 - 7,   2013年08月, 査読有り, UNLABELLED: Neurofibrillary tangles in Alzheimer disease (AD) brains are composed of the microtubule-associated protein tau. Noninvasive monitoring of tau protein aggregates in the living brain will provide useful information regarding tau pathophysiology in AD. However, no PET probes are currently available for selective detection of tau pathology in AD. We have previously reported (18)F-labeled THK-523 ((18)F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel (18)F-labeled arylquinoline derivatives, (18)F-THK-5105 and (18)F-THK-5117, for use as tau imaging PET tracers. METHODS: (18)F-labeled compounds were prepared from the corresponding tosylated precursors. The binding affinity of compounds to synthetic tau aggregates and tau-rich AD brain homogenates was determined by saturation and competition binding assays. The binding selectivity of compounds to tau pathology was evaluated by autoradiography of AD brain sections. The pharmacokinetics of compounds were assessed in biodistribution studies in normal mice. A 14-d toxicity study with intravenous administration of compounds was performed using rats and mice. RESULTS: In vitro binding assays demonstrated higher binding affinity of THK-5105 and THK-5117 than THK-523 to tau protein aggregates and tau-rich AD brain homogenates. Autoradiographic analyses of AD brain sections showed that these radiotracers preferentially bound to neurofibrillary tangles and neuropil threads, which colocalized with Gallyas-positive and immunoreactive tau protein deposits. The distribution of this radiotracer binding in AD brain sections was completely different from that of (11)C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than (18)F-THK-523 and other reported (18)F-labeled radiotracers. THK-5105 and THK-5117 showed no toxic effects related to the administration of these compounds in mice and rats and no significant binding for various neuroreceptors, ion channels, and transporters at 1-μM concentrations. CONCLUSION: (18)F-labeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.
  • Prion-like properties of pathological TDP-43 aggregates from diseased brains., Takashi Nonaka, Masami Masuda-Suzukake, Tetsuaki Arai, Yoko Hasegawa, Hiroyasu Akatsu, Tomokazu Obi, Mari Yoshida, Shigeo Murayama, David M A Mann, Haruhiko Akiyama, Masato Hasegawa, Cell reports, 4, (1) 124 - 34,   2013年07月11日, 査読有り, TDP-43 is the major component protein of ubiquitin-positive inclusions in brains of patients with frontotemporal lobar degeneration (FTLD-TDP) or amyotrophic lateral sclerosis (ALS). Here, we report the characterization of prion-like properties of aggregated TDP-43 prepared from diseased brains. When insoluble TDP-43 from ALS or FTLD-TDP brains was introduced as seeds into SH-SY5Y cells expressing TDP-43, phosphorylated and ubiquitinated TDP-43 was aggregated in a self-templating manner. Immunoblot analyses revealed that the C-terminal fragments of insoluble TDP-43 characteristic of each disease type acted as seeds, inducing seed-dependent aggregation of TDP-43 in these cells. The seeding ability of insoluble TDP-43 was unaffected by proteinase treatment but was abrogated by formic acid. One subtype of TDP-43 aggregate was resistant to boiling treatment. The insoluble fraction from cells harboring TDP-43 aggregates could also trigger intracellular TDP-43 aggregation. These results indicate that insoluble TDP-43 has prion-like properties that may play a role in the progression of TDP-43 proteinopathy.
  • Microsomal prostaglandin E synthase-1 is induced in alzheimer's disease and its deletion mitigates alzheimer's disease-like pathology in a mouse model., Yoshiharu Akitake, Yoshihito Nakatani, Daisuke Kamei, Masato Hosokawa, Hiroyasu Akatsu, Satoshi Uematsu, Shizuo Akira, Ichiro Kudo, Shuntaro Hara, Mitsuo Takahashi, Journal of neuroscience research, 91, (7) 909 - 19,   2013年07月, 査読有り, Epidemiological studies have suggested that long-term use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX) activity can moderate the onset or progression of Alzheimer's disease (AD). Thus it has been suggested that prostaglandin E2 (PGE2 ), a major end-product of COX, may play a pathogenic role in AD, but the involvement of PGE synthase (PGES), a terminal enzyme downstream from COX, has not been fully elucidated. Here we found that, among three PGES enzymes, only microsomal PGES-1 (mPGES-1) is induced, and its expression is associated with β-amyloid (Aβ) plaques in the cerebral cortex in human AD patients and in Tg2576 mice, a transgenic AD mouse model. Furthermore, to investigate whether mPGES-1 contributes to AD-like pathology, we bred mPGES-1-deficient mice with Tg2576 mice. We found that mPGES-1 deletion reduced the accumulation of microglia around senile plaques and attenuated learning impairments in Tg2576 mice. These results indicated that mPGES-1 is induced in the AD brain and thus plays a role in AD pathology. Blockage of mPGES-1 could form the basis for a novel therapeutic strategy for patients with AD.
  • Brain homogenates from human tauopathies induce tau inclusions in mouse brain., Florence Clavaguera, Hiroyasu Akatsu, Graham Fraser, R Anthony Crowther, Stephan Frank, Jürgen Hench, Alphonse Probst, David T Winkler, Julia Reichwald, Matthias Staufenbiel, Bernardino Ghetti, Michel Goedert, Markus Tolnay, Proceedings of the National Academy of Sciences of the United States of America, 110, (23) 9535 - 40,   2013年06月04日, 査読有り, Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer's disease, tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer's disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner.
  • Spliceosome integrity is defective in the motor neuron diseases ALS and SMA., Hitomi Tsuiji, Yohei Iguchi, Asako Furuya, Ayane Kataoka, Hiroyuki Hatsuta, Naoki Atsuta, Fumiaki Tanaka, Yoshio Hashizume, Hiroyasu Akatsu, Shigeo Murayama, Gen Sobue, Koji Yamanaka, EMBO molecular medicine, 5, (2) 221 - 34,   2013年02月, 査読有り, Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS/TLS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons.
  • SORL1 is genetically associated with neuropathologically characterized late-onset Alzheimer's disease., Yanan Wen, Akinori Miyashita, Nobutaka Kitamura, Tamao Tsukie, Yuko Saito, Hiroyuki Hatsuta, Shigeo Murayama, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyasu Akatsu, Takayuki Yamamoto, Kenji Kosaka, Haruyasu Yamaguchi, Kohei Akazawa, Yasuo Ihara, Ryozo Kuwano, Journal of Alzheimer's disease : JAD, 35, (2) 387 - 94,   2013年, 査読有り, SORL1 was shown to be genetically associated with late-onset Alzheimer's disease (LOAD) in a large-scale genome-wide association study (GWAS) involving clinically verified subjects. Here, we attempted to replicate the association of SORL1 in Japanese neuropathologically characterized brain donor subjects (LOAD, 213; control, 370) through a single-nucleotide polymorphism (SNP)-based genetic study involving 19 SNPs: 11 SNPs were selected from the initial study reported by Rogaeva et al. (2007), and the other eight were from our GWAS. Among these SNPs, five exhibited a significant association with LOAD after multiple test correction (p < 2.63E-03 [ = 0.05/19]), which was supported by means of multiple logistic regression analysis with adjustment for age, gender, and carrier status of the APOE ε4 allele. Three of these SNPs (rs985421, rs12364988 [Rogaeva's SNP 7], and rs4598682) were encompassed by a 5' linkage disequilibrium (LD) region, and the remaining two (rs3781834 and rs3781836) by a 3' LD region. Strong LD among SNPs was observed within each LD region, implying that there are two genomic regions showing association with LOAD in SORL1. Case-control haplotype analysis demonstrated that some haplotypes are associated with LOAD in both LD regions. Our replication study strongly supports the preceding evidence that SORL1 is likely one of the genes associated with LOAD.
  • SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians., Akinori Miyashita, Asako Koike, Gyungah Jun, Li-San Wang, Satoshi Takahashi, Etsuro Matsubara, Takeshi Kawarabayashi, Mikio Shoji, Naoki Tomita, Hiroyuki Arai, Takashi Asada, Yasuo Harigaya, Masaki Ikeda, Masakuni Amari, Haruo Hanyu, Susumu Higuchi, Takeshi Ikeuchi, Masatoyo Nishizawa, Masaichi Suga, Yasuhiro Kawase, Hiroyasu Akatsu, Kenji Kosaka, Takayuki Yamamoto, Masaki Imagawa, Tsuyoshi Hamaguchi, Masahito Yamada, Takashi Morihara, Masatoshi Takeda, Takeo Takao, Kenji Nakata, Yoshikatsu Fujisawa, Ken Sasaki, Ken Watanabe, Kenji Nakashima, Katsuya Urakami, Terumi Ooya, Mitsuo Takahashi, Takefumi Yuzuriha, Kayoko Serikawa, Seishi Yoshimoto, Ryuji Nakagawa, Jong-Won Kim, Chang-Seok Ki, Hong-Hee Won, Duk L Na, Sang Won Seo, Inhee Mook-Jung, Peter St George-Hyslop, Richard Mayeux, Jonathan L Haines, Margaret A Pericak-Vance, Makiko Yoshida, Nao Nishida, Katsushi Tokunaga, Ken Yamamoto, Shoji Tsuji, Ichiro Kanazawa, Yasuo Ihara, Gerard D Schellenberg, Lindsay A Farrer, Ryozo Kuwano, PloS one, 8, (4) ,   2013年, 査読有り, To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10(-9)) and rs3781834 (P = 1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10(-5)) and rs744373 near BIN1 (P = 1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.
  • Metabolic profiling of Alzheimer's disease brains., Koichi Inoue, Haruhito Tsutsui, Hiroyasu Akatsu, Yoshio Hashizume, Noriyuki Matsukawa, Takayuki Yamamoto, Toshimasa Toyo'oka, Scientific reports, 3, 2364 - 2364,   2013年, 査読有り, Alzheimer's disease (AD) is an irreversible, progressive brain disease and can be definitively diagnosed after death through an examination of senile plaques and neurofibrillary tangles in several brain regions. It is to be expected that changes in the concentration and/or localization of low-molecular-weight molecules are linked to the pathological changes that occur in AD, and determining their identity would provide valuable information regarding AD processes. Here, we propose definitive brain metabolic profiling using ultra-performance liquid chromatography coupled with electrospray time-of-flight mass spectrometry analysis. The acquired data were subjected to principal components analysis to differentiate the frontal and parietal lobes of the AD/Control groups. Significant differences in the levels of spermine and spermidine were identified using S-plot, mass spectra, databases and standards. Based on the investigation of the polyamine metabolite pathway, these data establish that the downstream metabolites of ornithine are increased, potentially implicating ornithine decarboxylase activity in AD pathology.
  • Characterization of the novel protein P9TLDR (temporal lobe down-regulated) with a brain-site-specific gene expression modality in Alzheimer's disease brain., Tomoko Yokota, Hiroyasu Akatsu, Takashi Miyauchi, Klaus Heese, FEBS letters, 586, (24) 4357 - 61,   2012年12月14日, 査読有り, Alzheimer's disease (AD) is an aging-related neurodegenerative disorder characterized by irreversible loss of higher cognitive functions. The disease is characterized by the presence of amyloid plaques and neurofibrillary tangles (NFT). In the current study we isolated from an intra-cerebral brain-site-specific (AD temporal lobe vs. AD occipital lobe) polymerase chain reaction (PCR)-select cDNA suppression subtractive hybridization (PCR-cDNA-SSH) expression analysis the novel gene P9TLDR, potentially a microtubule-associated protein involved in neuronal migration, with an altered expression pattern: down-regulated in the temporal lobe cortex of early stage AD brains. In an in vitro AD-related cell model, amyloid-β peptide (Aβ)-treated neurons, reduced P9TLDR expression correlated with increased tau protein phosphorylation. In conclusion, interference with the P9TLDR signalling pathways might be a therapeutic strategy for the treatment of AD.
  • Multiple findings in elderly adults with confirmed Alzheimer's disease., Hiroyasu Akatsu, Norihiro Ogawa, Takeshi Kanesaka, Chie Taniguchi, Maya Mimuro, Mari Yoshida, Zenjirou Matsuyama, Rina Kurihara, Osamu Kohashi, Akira Hori, Takayuki Yamamoto, Yoshio Hashizume, Journal of the American Geriatrics Society, 60, (11) 2169 - 70,   2012年11月, 査読有り
  • Heparan sulfate subdomains that are degraded by Sulf accumulate in cerebral amyloid ß plaques of Alzheimer's disease: evidence from mouse models and patients., Hosono-Fukao T, Ohtake-Niimi S, Hoshino H, Britschgi M, Akatsu H, Hossain MM, Nishitsuji K, van Kuppevelt TH, Kimata K, Michikawa M, Wyss-Coray T, Uchimura K, The American journal of pathology, 180, (5) 2056 - 67,   2012年05月, 査読有り
  • Transition metal abnormalities in progressive dementias., Hiroyasu Akatsu, Akira Hori, Takayuki Yamamoto, Mari Yoshida, Maya Mimuro, Yoshio Hashizume, Ikuo Tooyama, Eric M Yezdimer, Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine, 25, (2) 337 - 50,   2012年04月, 査読有り, Abnormal distributions of transition metals inside the brain are potential diagnostic markers for several central nervous system diseases, including Alzheimer's disease (AD), Parkinson's disease, dementia with Lewy bodies (DLB), bipolar disorders and depression. To further explore this possibility, the total concentrations of iron, zinc, copper, manganese, aluminum, chromium and cadmium were measured in post-mortem hippocampus and amygdala tissues taken from AD, DLB and Control patients. A statistically significant near fifty percent reduction in the total copper levels of AD patients was observed in both the hippocampus and amygdala. The statistical power of the hippocampus and amygdala copper analysis was found to be 86 and 74% respectively. No statistically significant deviations in the total metal concentrations were found for zinc, manganese, chromium or aluminum. Iron was found to be increased by 38% in AD amygdala tissues, but was unchanged in AD hippocampus tissues. Accounting for differences in tissue water content, as a function of both tissue type and disease state, revealed more consistencies with previous literature. To aid in the design of future experiments, the effect sizes for all tissue types and metals studied are also presented.
  • Mitsugumin 29 is transcriptionally induced in senile plaque-associated astrocytes., Kazuki Satoh, Hiroyasu Akatsu, Takayuki Yamamoto, Kenji Kosaka, Hiroshi Yokota, Tatsuo Yamada, Brain research, 1441, 9 - 16,   2012年03月02日, 査読有り, Astrocytes associated with beta-amyloid (Aβ)-deposited senile plaques are a common neuropathological feature of Alzheimer's disease (AD). There is little doubt that the association of Aβ with the major component in the central nervous system cells significantly influences disease progression, however, the molecular mechanisms by which Aβ contributes to the astrocyte-mediated neuropathological changes have not been well established. In an effort to identify astrocyte-derived molecules that may be closely associated with exacerbation of AD, we identified a novel Aβ-induced rat gene, whose mouse counterpart, mitsugumin 29 (MG29), is known to be involved in intracellular Ca²⁺ homeostasis in skeletal muscle. To evaluate the roles of human MG29 in AD, we investigated its expression in AD brain. In non-AD brains, MG29 mRNA has been detected in neurons, but not in quiescent astrocytes. On the contrary, in AD brains, MG29 is expressed in activated astrocytes associated with senile plaques, but not expressed in neurons around lesions. Human MG29-transfected cells express the protein in the endoplasmic reticulum and the level of expression is involved in Ca²⁺-dependent exocytosis mechanisms. Increased MG29 expression in senile plaques-associated activated astrocytes suggests that intracellular Ca²⁺ turnovers may be changed in these astrocytes. This might be related in sustained Ca²⁺-dependent exocytosis of various transmitters including glutamate, leading to the acceleration of neurodegeneration in the lesion observed in AD.
  • Coordinated increase of γ-secretase reaction products in the plasma of some female Japanese sporadic Alzheimer's disease patients: quantitative analysis of p3-Alcα with a new ELISA system., Konno T, Hata S, Hamada Y, Horikoshi-Sakuraba Y, Nakaya T, Saito Y, Yamamoto T, Yamamoto T, Maeda M, Ikeuchi T, Gandy S, Akatsu H, Suzuki T, Japanese Alzheimer's, Disease Neuroimaging Initiative, Molecular neurodegeneration, 6, 76 - 76,   2011年11月08日, 査読有り
  • An immunohistochemical study of the serotonin 1A receptor in the hippocampus of subjects with Alzheimer's disease., Katsuyoshi Mizukami, Masanori Ishikawa, Hiroyasu Akatsu, Eric E Abrahamson, Milos D Ikonomovic, Takashi Asada, Neuropathology : official journal of the Japanese Society of Neuropathology, 31, (5) 503 - 9,   2011年10月, 査読有り, Alzheimer's disease (AD) is associated with neuronal degeneration, synaptic loss and deficits in multiple neurotransmitter systems. Alterations in the serotonin 1A (5-HT1A) receptor can contribute to impaired cognitive function in AD, and both in vitro binding and Positron emission tomography (PET) imaging studies have demonstrated that 5-HT1A receptors in the hippocampus/medial temporal cortex are affected early in AD. This neuropathological study examined the localization and immunoreaction intensity of 5-HT1A receptor protein in AD hippocampus with the goal to determine whether neuronal receptor levels are influenced by the severity of NFT severity defined by Braaks' pathological staging and to provide immunohistochemical confirmation of the binding assays and PET imaging studies. Subjects included AD patients and non-AD controls (NC) stratified into three Braaks' stages (Braak 0-II, NC; Braak III/IV and V/VI, AD). In the Braak 0-II group, 5-HT1A-immunoreactivity (ir) was prominent in the neuropil of the CA1 and subiculum, moderate in the dentate gyrus molecular layer (DGml), and low in the CA3 and CA4. No changes in 5-HT1A-ir were observed in the hippocampus of AD subjects in the Braak III/IV group. Hippocampal 5-HT1A-ir intensity was markedly decreased in the CA1 region in 6/11 (54.5%) subjects in the Braak V/VI group. Across all three groups combined, there was a statistically significant association between reduced 5HT1A-ir and neuronal loss in the CA1, but not in the CA3. The present data demonstrate that hippocampal 5-HT1A receptors are mainly preserved until the end-stage of NFT progression in AD. Thus, the utility of PET imaging using a 5-HT1A-specific radiolabeled probe as a marker of hippocampal neuronal loss may be limited to the CA1 field in advanced stage AD cases.
  • HYDROXYLATED AND NON-HYDROXYLATED SULFATIDE ARE DISTINCTLY DISTRIBUTED IN THE HUMAN CEREBRAL CORTEX, D. Yuki, Y. Sugiura, N. Zaima, H. Akatsu, Y. Hashizume, T. Yamamoto, M. Fujiwara, K. Sugiyama, M. Setou, NEUROSCIENCE, 193, 44 - 53,   2011年10月, Sulfatide (ST) is a sphingolipid with an important role in the central nervous system as a major component of the myelin sheath. ST contains a structurally variable ceramide moiety, with a fatty acid substituent of varying carbon-chain length and double-bond number. Hydroxylation at the alpha-2 carbon position of the fatty acid is found in half the population of ST molecules. Recent genetic studies of fatty acid 2-hydroxylase (FA2H) indicate that these hydroxylated sphingolipids influence myelin sheath stability. However, their distribution is unknown. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) enables the analysis of distinct distributions of individual ST molecular species in tissue section. We examined human cerebral cortex tissue sections with MALDI-IMS, identifying and characterizing the distributions of 14 ST species. The distribution analysis reveals that the composition ratios of non-hydroxylated/hydroxylated STs are clearly reversed at the border between white and gray matter; the hydroxylated group is the dominant ST species in the gray matter. These results suggest that hydroxylated STs are highly expressed in oligodendrocytes in gray matter and might form stable myelin sheaths. As a clinical application, we analyzed a brain with Alzheimer's disease (AD) as a representative neurodegenerative disease. Although previous studies of AD pathology have reported that the amount of total ST is decreased in the cerebral cortex, as far as the compositional distributions of STs are concerned, AD brains were similar to those in control brains. In conclusion, we suggest that MALDI-IMS is a useful tool for analysis of the distributions of various STs and this application might provide novel insight in the clinical study of demyelinating diseases. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Longitudinal study on MRI intensity changes of Machado-Joseph disease: correlation between MRI findings and neuropathological changes., Yoshihiko Horimoto, Mitsuhiro Matsumoto, Hiroyasu Akatsu, Akihiro Kojima, Mari Yoshida, Kazuya Nokura, Hiroyuki Yuasa, Eiichi Katada, Takayuki Yamamoto, Kenji Kosaka, Yoshio Hashizume, Hiroko Yamamoto, Shigehisa Mitake, Journal of neurology, 258, (9) 1657 - 64,   2011年09月, 査読有り, To disclose the neuropathological progression course of Machado-Joseph disease (MJD), magnetic resonance imaging (MRI) findings of six genetically confirmed MJD cases (four males and two females, including an autopsied female, all unrelated to one another) were further investigated on neurodegeneration. Brain MRI studies were repeated in all cases at different stages of the disease. Ages at the first MRI study ranged from 47 to 65 years (55.2 ± 7.1), with observation periods from 4.5 to 10.6 years (6.95 ± 2.48). We paid particular attention to two types of previously reported MRI findings detectable using T2-weighted images. One is located just outside the internal capsules, and another in the pons. A linear high-intensity change along the internal capsules was detected in all cases, and showed progression during the observation period. A comparison between MRI and autopsy findings suggested that the lesion might reflect degeneration with neuronal loss, astrocytosis, and gliosis in the internal segment of the globus pallidus. A cross-shaped high-intensity change in the pons was well advanced but still incomplete in all cases. In this region, pontine transverse fibers were atrophic, while longitudinal fibers remained intact. Pontine nuclei showed apparent nerve cell loss, and the remaining cells had many 1C2-positive intranuclear inclusions. Since these findings were detected both by lifetime images and by postmortem examination, MRI intensity changes could track the progression of neurodegeneration. Based on a comparison between MRI findings and neuropathology, the degeneration of an internal segment of the globus pallidus (one of the pathological features of MJD) had progressed following the initial symptoms.
  • The novel protein MANI modulates neurogenesis and neurite-cone growth., Manisha Mishra, Hiroyasu Akatsu, Klaus Heese, Journal of cellular and molecular medicine, 15, (8) 1713 - 25,   2011年08月, 査読有り, Neuronal regeneration and axonal re-growth in the injured mammalian central nervous system remains an unsolved field. To date, three myelin-associated proteins [Nogo or reticulon 4 (RTN4), myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG)] are known to inhibit axonal regeneration via activation of the neuronal glycosylphosphatidylinositol-anchored Nogo receptor [NgR, together with p75 neurotrophin receptor (p75NTR) and Lingo-1]. In the present study we describe the novel protein MANI (myelin-associated neurite-outgrowth inhibitor) that localizes to neural membranes. Functional characterization of MANI overexpressing neural stem cells (NSCs) revealed that the protein promotes differentiation into catecholaminergic neurons. Yeast two-hybrid screening and co-immunoprecipitation experiments confirmed the cell division cycle protein 27 (Cdc27) as an interacting partner of Mani. The analyses of Mani-overexpressing PC12 cells demonstrated that Mani retards neuronal axonal growth as a positive effector of Cdc27 expression and activity. We show that knockdown of Cdc27, a component of the anaphase-promoting complex (APC), leads to enhanced neurite outgrowth. Our finding describes the novel MANI-Cdc27-APC pathway as an important cascade that prevents neurons from extending axons, thus providing implications for the potential treatment of neurodegenerative diseases.
  • Abnormal phospholipids distribution in the prefrontal cortex from a patient with schizophrenia revealed by matrix-assisted laser desorption/ionization imaging mass spectrometry., Junya Matsumoto, Yuki Sugiura, Dai Yuki, Takahiro Hayasaka, Naoko Goto-Inoue, Nobuhiro Zaima, Yasuto Kunii, Akira Wada, Qiaohui Yang, Keisuke Nishiura, Hiroyasu Akatsu, Akira Hori, Yoshio Hashizume, Takayuki Yamamoto, Keiko Ikemoto, Mitsutoshi Setou, Shin-ichi Niwa, Analytical and bioanalytical chemistry, 400, (7) 1933 - 43,   2011年06月, 査読有り, Schizophrenia is one of the major psychiatric disorders, and lipids have focused on the important roles in this disorder. In fact, lipids related to various functions in the brain. Previous studies have indicated that phospholipids, particularly ones containing polyunsaturated fatty acyl residues, are deficient in postmortem brains from patients with schizophrenia. However, due to the difficulties in handling human postmortem brains, particularly the large size and complex structures of the human brain, there is little agreement regarding the qualitative and quantitative abnormalities of phospholipids in brains from patients with schizophrenia, particularly if corresponding brain regions are not used. In this study, to overcome these problems, we employed matrix-assisted laser desorption/ionization imaging mass spectrometry (IMS), enabling direct microregion analysis of phospholipids in the postmortem brain of a patient with schizophrenia via brain sections prepared on glass slides. With integration of traditional histochemical examination, we could analyze regions of interest in the brain at the micrometric level. We found abnormal phospholipid distributions within internal brain structures, namely, the frontal cortex and occipital cortex. IMS revealed abnormal distributions of phosphatidylcholine molecular species particularly in the cortical layer of frontal cortex region. In addition, the combined use of liquid chromatography/electrospray ionization tandem mass spectrometry strengthened the capability for identification of numerous lipid molecular species. Our results are expected to further elucidate various metabolic processes in the neural system.
  • Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction., Hata S, Fujishige S, Araki Y, Taniguchi M, Urakami K, Peskind E, Akatsu H, Araseki M, Yamamoto K, Martins RN, Maeda M, Nishimura M, Levey A, Chung KA, Montine T, Leverenz J, Fagan A, Goate A, Bateman R, Holtzman DM, Yamamoto T, Nakaya T, Gandy S, Suzuki T, Annals of neurology, 69, (6) 1026 - 31,   2011年06月, 査読有り
  • Higher activity of peripheral blood angiotensin-converting enzyme is associated with later-onset of Alzheimer's disease., Hiroyasu Akatsu, Norihiro Ogawa, Takeshi Kanesaka, Akira Hori, Takayuki Yamamoto, Noriyuki Matsukawa, Makoto Michikawa, Journal of the neurological sciences, 300, (1-2) 67 - 73,   2011年01月15日, 査読有り, According to the amyloid theory, the balance between amyloid-β (Aβ) production and degradation is key to the development of Alzheimer's disease (AD). Several enzymes including angiotensin-converting enzyme (ACE) have been reported as candidate enzymes involved in Aβ degradation. We previously identified the relationship between ACE activity and AD. We present a comparison between AD and non-AD patients in the inpatient care unit of a geriatric hospital and have included the onset age and age at sampling in the comparison. We performed a colorimetric assay to determine ACE activity and a sandwich enzyme-linked immunosorbent assay (ELISA) to quantify blood plasma Aβ 1-40 and 1-42 levels. Our 676 subjects, none of whom had received ACE inhibitor medication, included 147 AD patients. Clinical diagnoses were carried out to separate subjects into the AD and non-AD groups on the basis of the criteria of the International Classification of Diseases (ICD-10) and the Consortium to Establish a Registry for AD (CERAD). We found that the later the onset of AD, the higher the ACE activity, but there was no correlation between ACE activity and the Aβ level in peripheral blood. In this report, we suggest that peripheral ACE activity may affect the age at AD onset.
  • Homocysteine, another risk factor for Alzheimer disease, impairs apolipoprotein E3 function., Hirohisa Minagawa, Atsushi Watanabe, Hiroyasu Akatsu, Kayo Adachi, Chigumi Ohtsuka, Yasuo Terayama, Takashi Hosono, Satoshi Takahashi, Hideaki Wakita, Cha-Gyun Jung, Hiroto Komano, Makoto Michikawa, The Journal of biological chemistry, 285, (49) 38382 - 8,   2010年12月03日, 査読有り, Apolipoprotein E (apoE) ε4 and hyperhomocysteinemia are risk factors for Alzheimer disease (AD). The dimerization of apoE3 by disulfide bonds between cysteine residues enhances apoE3 function to generate HDL. Because homocysteine (Hcy) harbors a thiol group, we examined whether Hcy interferes with the dimerization of apoE3 and thereby impairs apoE3 function. We found that Hcy inhibits the dimerization of apoE3 and reduces apoE3-mediated HDL generation to a level similar to that by apoE4, whereas Hcy does not affect apoE4 function. Western blot analysis of cerebrospinal fluid showed that the ratio of apoE3 dimers was significantly lower in the samples from the patients with hyperhomocysteinemia than in those that from control subjects. Hyperhomocysteinemia induced by subcutaneous injection of Hcy to apoE3 knock-in mice decreased the level of the apoE3 dimer in the brain homogenate. Because apoE-HDL plays a role in amyloid β-protein clearance, these results suggest that two different risk factors, apoE4 and hyperhomocysteinemia, may share a common mechanism that accelerates the pathogenesis of AD in terms of reduced HDL generation.
  • [Collaboration between Fukushimura Brain Bank,based in a private geriatric hospital and a national/international network]., Hiroyasu Akatsu, Brain and nerve = Shinkei kenkyu no shinpo, 62, (10) 1043 - 52,   2010年10月, 査読有り, Fukushimura Brain Bank (FBB) was established in 1994, and to date, has accumulated 477 fresh frozen brain tissue samples. Our brain bank is based in Choju Medical Institute, Fukushimura Hospital, Toyohashi in Japan. At the time of its foundation, the institute could not establish working relationships with clinicopathological investigators and others engaged in basic neuroscience research. At this stage, we received the assistance of Yokohama City University in setting up standards for neuropathological diagnosis as well as the aid of Chiba University in establishing a method for Vancouver style snap-frozen sampling of brain tissue. However, both systems require considerable manpower and time. We now plan to introduce several improvements in these systems. At its inception, the Brain Bank operated without financial support from grants or foundation funding and was managed only as a hospital expense. However, since 1998, we have collaborated with researchers from several institutes, and the results of our labors have been presented at congresses, in journal publications and in foundation reports. In 2004, we obtained the status required to apply for a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Fukushimura Hospital is a geriatric institution that specializes in dementia. There are no other hospitals or nursing homes in the Toyohashi area that specialize in this field. Half of our patients have Alzheimer's disease,and a number of them have enormous plaques and huge neurofibrillary tangles patient for over 10 years. In general,private geriatric hospitals that care for such patients with severe AD lack the systems required for performing autopsies. Research carried out with animal models are not comparable with neuropathological and biochemical investigations using human tissues,and in terms of the quality,the range and size of our collection at FBB is unique. In the future,we intend to expand our network in order to share samples of interest,and to optimize the network by establishing similar sampling protocols and diagnostic standards. It is with great pleasure that we at the FBB look forward to our collaboration with the Comprehensive Brain Science.
  • Sexually Dimorphic Effect of the Val66Met Polymorphism of BDNF on Susceptibility to Alzheimer's Disease: New Data and Meta-Analysis, Noriko Fukumoto, Takashi Fujii, Onofre Combarros, M. Ilyas Kamboh, Shin-Jen Tsai, Sachio Matsushita, Benedetta Nacmias, David E. Comings, Humberto Arboleda, Martin Ingelsson, Bradley T. Hyman, Hiroyasu Akatsu, Andrew Grupe, Agnes Lumi Nishimura, Mayana Zatz, Kari M. Mattila, Juha Rinne, Yu-ichi Goto, Takashi Asada, Shun Nakamura, Hiroshi Kunugi, AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 153B, (1) 235 - 242,   2010年01月, 査読有り, Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain-derived neurotrophic factor gene (RDNF) confer susceptibility to Alzheimer's disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (P = 0.063), but not for C270T. After stratification by sex, we found a significant allelic association between Val66Met and AD in women (P = 0.017), but not in men. To confirm these observations, we collected genotyping data for each sex from 16 research centers worldwide (4,711 patients and 4,537 controls in total). The meta-analysis revealed that there was a clear sex difference in the allelic association; the Met66 allele confers susceptibility to AD in women (odds ratio = 1.14, 95% CI 1.05-1.24, P = 0.002), but not in men. Our results provide evidence that the Met66 allele of BDNF has a sexually dimorphic effect on susceptibility to AD. (C) 2009 Wiley-Liss, Inc.
  • Alcadein cleavages by amyloid beta-precursor protein (APP) alpha- and gamma-secretases generate small peptides, p3-Alcs, indicating Alzheimer disease-related gamma-secretase dysfunction., Saori Hata, Sayaka Fujishige, Yoichi Araki, Naoko Kato, Masahiko Araseki, Masaki Nishimura, Dieter Hartmann, Paul Saftig, Falk Fahrenholz, Miyako Taniguchi, Katsuya Urakami, Hiroyasu Akatsu, Ralph N Martins, Kazuo Yamamoto, Masahiro Maeda, Tohru Yamamoto, Tadashi Nakaya, Sam Gandy, Toshiharu Suzuki, The Journal of biological chemistry, 284, (52) 36024 - 33,   2009年12月25日, 査読有り, Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alc(alpha), Alc(beta), and Alc(gamma). The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP alpha-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent gamma-secretase complex, thereby generating "APP p3-like" and non-aggregative Alc peptides (p3-Alcs). We determined the complete amino acid sequence of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma), whose major species comprise 35, 37, and 31 amino acids, respectively, in human cerebrospinal fluid. We demonstrate here that variant p3-Alc C termini are modulated by FAD-linked presenilin 1 mutations increasing minor beta-amyloid species Abeta42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma) were not equivalent, suggesting that one type of gamma-secretase dysfunction does not appear in the phenotype equivalently in the cleavage of type I membrane proteins. Because these C-terminal alterations are detectable in human cerebrospinal fluid, the use of a substrate panel, including Alcs and APP, may be effective to detect gamma-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects.
  • SORL1 is genetically associated with Alzheimer disease in a Japanese population., Ryo Kimura, Mitsuko Yamamoto, Takashi Morihara, Hiroyasu Akatsu, Takashi Kudo, Kouzin Kamino, Masatoshi Takeda, Neuroscience letters, 461, (2) 177 - 80,   2009年09月18日, 査読有り, A recent study reported that variants of the neuronal sortilin-related receptor gene (SORL1) increased the risk of late-onset Alzheimer disease (AD) in several populations. Here, we examined the risk effect in a large, well-characterized group of 437 late-onset AD patients and 451 control subjects in a Japanese population. Among eight single-nucleotide polymorphisms (SNPs) of the SORL1 gene for which association has been reported, we found a significant association for four of them, located between exon 24 and intron 37. This risk was evident in non-carriers of the apolipoprotein E-epsilon 4 allele, but not in its carriers. Our results support the evidence that genetic variants of SORL1 affect susceptibility to late-onset AD.
  • Analysis of DNA variations in promoter region of HCNP gene with Alzheimer's disease, Kenji Okita, Noriyuki Matsukawa, Mina Maki, Hideka Nakazawa, Eiichi Katada, Manabu Hattori, Hiroyasu Akatsu, Cesario V. Borlongan, Kosei Ojika, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 379, (2) 272 - 276,   2009年02月, 査読有り, Hippocampal cholinergic neurostimulating peptide (HCNP), which enhances acetylcholine synthesis and induces cholinergic phenotype development of the septohippocampal system, is derived from HCNP precursor protein (HCNPpp), also known as phosphatidylethanolamine binding protein (PEBP) and Raf kinase inhibitor protein (RKIP). Our previous study demonstrated that expression of HCNPpp mRNA was decreased in the hippocampi of autopsied brains of Alzheimer's disease (AD) patients, indicating the association of HCNP with the pathogenesis of AD. To clarify the involvement of gene variations in the promoter region of the gene encoding HCNPpp in this mRNA reduction, we analyzed DNA polymorphisms or mutations within this gene promoter region in AD patients by direct sequencing. The promoter was found to contain a CpG island without a TATA box, an element of housekeeping gene promoters. Moreover, no disease-specific polymorphisms or mutations were identified, Suggesting that the decrease of mRNA can be ascribed to transcriptional or posttranscriptional changes in activity. (C) 2008 Elsevier Inc. All rights reserved.
  • Inclusion-positive cell types in adult-onset intranuclear inclusion body disease: implications for clinical diagnosis., Liu Y, Mimuro M, Yoshida M, Hashizume Y, Niwa H, Miyao S, Ujihira N, Akatsu H, Acta neuropathologica, 116, (6) 615 - 623,   2008年12月, 査読有り
  • Potential neural progenitor cells in fetal liver and regenerating liver., Komatsu F, Farkas I, Akatsu H, Kojima K, Fukushima T, Okada H, Cytotechnology, 56, (3) 209 - 217,   2008年03月, 査読有り
  • Dynamin 2 gene is a novel susceptibility gene for late-onset Alzheimer disease in non-APOE-epsilon4 carriers., Aidaralieva NJ, Kamino K, Kimura R, Yamamoto M, Morihara T, Kazui H, Hashimoto R, Tanaka T, Kudo T, Kida T, Okuda J, Uema T, Yamagata H, Miki T, Akatsu H, Kosaka K, Takeda M, Journal of human genetics, 53, (4) 296 - 302,   2008年, 査読有り
  • Sugar chains of cerebrospinal fluid transferrin as a new biological marker of Alzheimer's disease., Taniguchi M, Okayama Y, Hashimoto Y, Kitaura M, Jimbo D, Wakutani Y, Wada-Isoe K, Nakashima K, Akatsu H, Furukawa K, Arai H, Urakami K, Dementia and geriatric cognitive disorders, 26, (2) 117 - 122,   2008年, 査読有り
  • Reduced expression of endogenous secretory receptor for advanced glycation endproducts in hippocampal neurons of Alzheimer's disease brains, Ichiro Nozaki, Takuo Watanabe, Makoto Kawaguchi, Hiroyasu Akatsu, Koichi Tsuneyama, Yasuhiko Yamamoto, Kazuyo Ohe, Hideto Yonekura, Masahito Yamada, Hiroshi Yamamoto, ARCHIVES OF HISTOLOGY AND CYTOLOGY, 70, (5) 279 - 290,   2007年12月, 査読有り, The receptor for advanced glycation end-products (RAGE) is a cell-surface multiligand receptor, which interacts with amyloid beta (A beta), a key protein in Alzheimer's disease (AD). RAGE-A beta interaction is thought to be associated with pathological progression in AD. A splice variant of RAGE, endogenous secretory RAGE (esRAGE) can act as a decoy receptor for RAGE ligands that would prevent the progression of some pathologic conditions. In this study, the expression of esRAGE in the hippocampal tissues from AD brains compared with control (non-AD) was examined by immunohistochemistry and Western blot analysis. Semiquantitative immunohistochemical analysis of hippocampal tissues using esRAGE-specific antibody revealed significantly decreased immunoreactivities in pyramidal cells in CA1 and CA3 regions of AD compared with non-AD. On the other hand, immunoreactivities of astrocytes for esRAGE significantly increased in those regions. Dentate granule cells and astrocytes showed essentially invariant immunoreactivities between AD and non-AD. Changes in esRAGE immunoreactivity in CA3 neurons and astrocytes were observed from the early pathological stages. Moreover, the esRAGE-immunoreactive bands of AD samples were weaker than those of non-AD samples in Western blot analysis. The results indicate that low expression of esRAGE in the hippocampus would be associated with the development of AD.
  • Enhanced lysosomal pathology caused by beta-synuclein mutants linked to dementia with Lewy bodies, Jianshe Wei, Masayo Fujita, Masaaki Nakai, Masaaki Waragai, Kazuhiko Watabe, Hiroyasu Akatsu, Edward Rockenstein, Eliezer Masliah, Makoto Hashimoto, JOURNAL OF BIOLOGICAL CHEMISTRY, 282, (39) 28904 - 28914,   2007年09月, 査読有り, Two missense mutations (P123H and V70M) of beta-synuclein (beta-syn), the homologue of alpha-syn, have been recently identified in dementia with Lewy bodies. However, the mechanism through which these mutations influence the pathogenesis of dementia with Lewy bodies is unclear. To investigate the role of the beta-syn mutations in neurodegeneration, each mutant was stably transfected into B103 neuroblastoma cells. Cells overexpressing mutated beta-syn had eosinophilic cytoplasmic inclusion bodies immunopositive for mutant beta-syn, and electron microscopy revealed that these cells were abundant in various cytoplasmic membranous inclusions resembling the histopathology of lysosomal storage disease. Consistent with these findings, the inclusion bodies were immunopositive for lysosomal markers, including cathepsin B, LAMP-2, GM2 ganglioside, and ATP13A2, which has recently been linked to PARK9. Notably, formation of these lysosomal inclusions was greatly stimulated by co-expression of alpha-syn, was dependent on the phosphorylation of beta-syn at Ser-129, and was more efficient with the A53T familial mutant of alpha-syn compared with wild type. Furthermore, the inclusion formation in cells overexpressing mutant beta-syn and transfected with alpha-syn was significantly suppressed by treatment with autophagy-lysosomal inhibitors, which were associated with impaired clearance of syn proteins and enhanced apoptosis, indicating that formation of lysosomal inclusions might be protective. Collectively, the results demonstrated unambiguously that overexpression of beta-syn mutants ( P123H and V70M) in neuroblastoma cells results in an enhanced lysosomal pathology. We suggest that these missense mutations of beta-syn might play a causative role in stimulating neurodegeneration.
  • Plasma levels of DJ-1 as a possible marker for progression of sporadic Parkinson's disease, Masaaki Waragai, Masaaki Nakai, Jianshe Wei, Masayo Fujita, Hideya Mizuno, Gilbert Ho, Eliezer Masliah, Hiroyasu Akatsu, Fusako Yokochi, Makoto Hashimoto, NEUROSCIENCE LETTERS, 425, (1) 18 - 22,   2007年09月, 査読有り, DJ-1 is a multifunctional protein whose loss of function by gene mutations may play a causative role for familial Parkinson's disease (PD). A recent study has shown that the expression of this molecule is upregulated in both brains and cerebrospinal fluids (CSF) in various neurological disorders, including sporadic PD, Alzheimer's disease (AD) and stroke, raising a possibility that DJ-1 could be a potential biomarker for these diseases. In this context, the main objective of the present study was to determine if DJ-1 was increased in the plasma of PD patients. For this purpose, blood plasma samples collected from sporadic PD patients, dementia with Lewy bodies (DLB) and healthy age-matched controls were analyzed by immunoblotting and enzyme-linked immunosorbent assay. The results showed that the plasma DJ-1 levels in PD (n = 104) were higher than those in control (n = 80) (p < 0.05). Moreover, the plasma DJ-1 levels in the advanced stage of PD (n = 52, Yahr III-IV) were higher than those in the early stage of PD (n = 52, Yahr I-II) (p < 0.05), demonstrating that the plasma DJ- I was correlated with the disease severity in PD. Plasma DJ-1 levels were also significantly higher in DLB (n = 30) compared with both controls and early stage of PD (p < 0.01). Taken together, these results suggest that the plasma DJ-1 could be a useful biomarker for the evaluation of the disease severity in PD and possibly in other Lewy body diseases. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
  • Angiotensin-converting enzyme converts amyloid beta-protein 1-42 (A beta(1-42)) to A beta(1-40), and its inhibition enhances brain a beta deposition, Kun Zou, Haruyasu Yamaguchi, Hiroyasu Akatsu, Takaaki Sakamoto, Mihee Ko, Kazushige Mizoguchi, Jian-Sheng Gong, Wenxin Yu, Takayuki Yamamoto, Kenji Kosaka, Katsuhiko Yanagisawa, Makoto Michikawa, JOURNAL OF NEUROSCIENCE, 27, (32) 8628 - 8635,   2007年08月, 査読有り, The abnormal deposition of the amyloid beta-protein (A beta) in the brain appears crucial to the pathogenesis of Alzheimer's disease (AD). Recent studies have suggested that highly amyloidogenic A beta(1-42) is a cause of neuronal damage leading to AD pathogenesis and that monomeric A beta(1-40) has less neurotoxicity than A beta(1-42). We found that mouse and human brain homogenates exhibit an enzyme activity converting A beta(1-42) to A beta(1-40) and that the major part of this converting activity is mediated by the angiotensin-converting enzyme (ACE). Purified human ACE converts A beta(1-42) to A beta(1-40) as well as decreases A beta(1-42)/ A beta(1-40) ratio and degrades A beta(1-42) and A beta(1-40). Importantly, the treatment of Tg2576 mice with an ACE inhibitor, captopril, promotes predominant A beta(1-42) deposition in the brain, suggesting that ACE regulates A beta(1-42)/A beta(1-40) ratio in vivo by converting secreted A beta(1-42) to A beta(1-40) and degrading A beta s. The upregulation of ACE activity can be a novel therapeutic strategy for AD.
  • Expression of alpha-synuclein, a presynaptic protein implicated in Parkinson's disease, in erythropoietic lineage, Masaaki Nakai, Masayo Fujita, Masaaki Waragai, Shuei Sugama, Jianshe Wei, Hiroyasu Akatsu, Chiaki Ohtaka-Maruyama, Haruo Okado, Makoto Hashimoto, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 358, (1) 104 - 110,   2007年06月, 査読有り, The present study investigated expression of alpha-synuclein (alpha-syn), a presynaptic protein involved in the pathogenesis of Parkinson's disease, in erythroid cells. Using various immunological procedures, immunoreactivity of alpha-syn was unambiguously demonstrated in erythroid lineage in murine bone marrows and peripheral erythrocytes. Expression of alpha-syn mRNA was also confirmed by in situ hybridization. Furthermore, flow cytometry analysis revealed that approximately 80% of erythroid cells in murine bone marrows expressed alpha-syn, while more than 90% of peripheral erythrocytes expressed alpha-syn. Nonetheless, alpha-syn null mice exhibited apparently no phenotypic changes in erythroid cells as was the case in their brains, suggesting that there might be underlying some redundant mechanisms. Together with previous reports showing the expression of alpha-syn in lymphocytes and platelets, the present finding supports a contention that alpha-syn might play some important functions in hematopoietic system. (c) 2007 Elsevier Inc. All rights reserved.
  • Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism, Satoshi Makino, Ryuji Kaji, Satoshi Ando, Maiko Tomizawa, Katsuhito Yasuno, Satoshi Goto, Shinnichi Matsumoto, Ma. Daisy Tabuena, Elma Maranon, Marita Dantes, Lillian V. Lee, Kazumasa Ogasawara, Ikuo Tooyama, Hiroyasu Akatsu, Masataka Nishimura, Gen Tamiya, AMERICAN JOURNAL OF HUMAN GENETICS, 80, (3) 393 - 406,   2007年03月, 査読有り, X-linked dystonia- parkinsonism (XDP) is a movement disorder endemic to the Philippines. The disease locus, DYT3, has been mapped to Xq13.1. In a search for the causative gene, we performed genomic sequencing analysis, followed by expression analysis of XDP brain tissues. We found a disease- specific SVA ((s) under bar hort interspersed nuclear element, (v) under bar ariable number of tandem repeats, and (A) under bar lu composite) retrotransposon insertion in an intron of the TATA- binding protein-associated factor 1 gene (TAF1), which encodes the largest component of the TFIID complex, and significantly decreased expression levels of TAF1 and the dopamine receptor D2 gene (DRD2) in the caudate nucleus. We also identified an abnormal pattern of DNA methylation in the retrotransposon in the genome from the patient's caudate, which could account for decreased expression of TAF1. Our findings suggest that the reduced neuron-specific expression of the TAF1 gene is associated with XDP.
  • The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease, Ryo Kimura, Kouzin Kamino, Mitsuko Yamamoto, Aidaralieva Nuripa, Tomoyuki Kida, Hiroaki Kazui, Ryota Hashimoto, Toshihisa Tanaka, Takashi Kudo, Hidehisa Yamagata, Yasuharu Tabara, Tetsuro Miki, Hiroyasu Akatsu, Kenji Kosaka, Eishi Funakoshi, Kouhei Nishitomi, Gaku Sakaguchi, Akira Kato, Hideyuki Hattori, Takeshi Uema, Masatoshi Takeda, HUMAN MOLECULAR GENETICS, 16, (1) 15 - 23,   2007年01月, 査読有り, We scanned throughout chromosome 21 to assess genetic associations with late-onset Alzheimer disease (AD) using 374 Japanese patients and 375 population-based controls, because trisomy 21 is known to be associated with early deposition of beta-amyloid (A beta) in the brain. Among 417 markers spanning 33 Mb, 22 markers showed associations with either the allele or the genotype frequency (P < 0.05). Logistic regression analysis with age, sex and apolipoprotein E (APOE)-14 dose supported genetic risk of 17 markers, of which eight markers were linked to the SAMSN1, PRSS7, NCAM2, RUNX1, DYRK1A and KCNJ6 genes. In logistic regression, the DYRK1A (dual-specificity tyrosine-regulated kinase 1A) gene, located in the Down syndrome critical region, showed the highest significance [OR 5 2.99 (95% CI: 1.72-5.19), P = 0.001], whereas the RUNX1 gene showed a high odds ratio [OR 5 23.3 (95% CI: 2.76-196.5), P = 0.038]. DYRK1A mRNA level in the hippocampus was significantly elevated in patients with AD when compared with pathological controls (P < 0.01). DYRK1A mRNA level was upregulated along with an increase in the A beta-level in the brain of transgenic mice, overproducing A beta at 9 months of age. In neuroblastoma cells, A beta induced an increase in the DYRK1A transcript, which also led to tau phosphorylation at Thr 212 under the overexpression of tau. Therefore, the upregulation of DYRK1A transcription results from Ab loading, further leading to tau phosphorylation. Our result indicates that DYRK1A could be a key molecule bridging between beta-amyloid production and tau phosphorylation in AD.
  • Plasma levels of unactivated thrombin activatable fibrinolysis inhibitor (TAFI) are down-regulated in young adult women: Analysis of a normal Japanese population, Hiroyasu Akatsu, Masae Ishiguro, Norihiro Ogawa, Takeshi Kanesaka, Noriko Okada, Takayuki Yamamoto, William Campbell, Hidechika Okada, MICROBIOLOGY AND IMMUNOLOGY, 51, (5) 507 - 517,   2007年, 査読有り, Thrombin-activatable fibrinolysis inhibitor (TAFI) is an anaphylatoxin-inactivating enzyme generated by proteolytic cleavage of its zymogen, and is the same enzyme as that first designated by our group as procarboxypeptidase R (proCPR). TAFI in plasma is presumed to influence vascular disease in its role as a fibrinolysis inhibitor. The activity of TAFI is strongly influenced by genetic polymorphism, especially at amino acids Thr/Ala-147 and Thr/Ile-325. In this study, we analyzed 202 healthy controls who were not on any medication, had no unusual medical history and whose blood data were normal. In a previous report, we established an enzyme-linked immunosorbent assay (ELISA) specific for non-activated TAFI (proCPR), and investigated levels of unactivated TAFI as an estimate of anti-fibrinolytic capacity. In this study, we determined normal Japanese TAFI levels for each age, sex, and genetic polymorphism of Thr/Ala-147 and Thr/Ile-325, and also showed that the TAFI level in young adult women is lower than in aged women.
  • Could serum antibody to poly(ADP-ribose) and/or histone H1 be marker for senile dementia of Alzheimer type?, Yoshiyuki Kanai, Hiroyasu Akatsu, Hideki Iizuka, Chikao Morimoto, AUTOIMMUNITY, PART A: BASIC PRINCIPLES AND NEW DIAGNOSTIC TOOLS, 1109, 338 - 344,   2007年, 査読有り, Poly(ADP-ribosyl)ation has been focused on ischemic injury in the brain in relation to Alzheimer's disease (AD). We have measured IgG antibodies against poly adenosine diphosphate-ribose (pADPR) as well as histone H1 (H1) in 26 patients with either AD or with senile dementia of Alzheimer type (SDAT), and found that 80.7% (21/26) were positive for anti-pADPR IgG antibodies. Anti-H1 IgG antibodies were less positive (57.6%) (15/26) than anti-pADPR IgG antibodies, however, titers of both antibodies were well correlated (r = 0.768). Meanwhile, similar studies on 32 patients with systemic lupus erythematosus (SLE) who were positive for anti-pADPR antibody showed poor correlation (r = 0.184) and the difference in the correlation was statistically significant (r < 0.01). It is worthy of remark that anti-double-stranded (ds) DNA antibody, which is the hallmark of SLE, was negative in all dementia patients. Together with the findings that major subclass in dementia is both IgG1 and IgG2 and that in SLE was IgG2, the mode of production of anti-pADPR antibody in AD and SDAT is under different regulation mechanisms from that in SLE. Given the evidence that major target for ADP-ribosylation is H1 molecule, the association between anti-pADPR and anti-H1 in AD/SDAT makes sense and supports the concept that modification of proteins renders them immunogenic. Whatever the regulation is, parallel assay of two antibodies above would be of use not only for monitoring the disease process but also as a prodrome for possible subsets of SDAT and AD.
  • A novel membrane protein, encoded by the gene covering KIAA0233, is transcriptionally induced in senile plaque-associated astrocytes, Kazuki Satoh, Mitsumi Hata, Seiji Takahara, Hidetoshi Tsuzaki, Hiroshi Yokota, Hiroyasu Akatsu, Takayuki Yamamoto, Kenji Kosaka, Tatsuo Yamada, BRAIN RESEARCH, 1108, (1) 19 - 27,   2006年09月, 査読有り, Beta-amyloid (A beta) deposition and senile plaque-associated astrocytes are common neuropathological features of Alzheimer's disease (AD). Although the molecular mechanisms by which A beta contributes to the progression of neuropathologic changes have not been entirely established, there is little doubt that the association of A beta with astrocytes, the predominant cell type in brain, significantly influences exacerbation of the disease. In an effort to identify astrocyte-derived molecules that may be intimately associated with progression of AD, we identified a novel A beta-induced rat gene, designated Mib, whose human counterpart covers KIAA0233. Mib-transfected C6 cells express Mib protein in the endoplasmic reticulum and endplasmic reticulum-Golgi-intermediate compartment. To evaluate roles of Mib in AD, we investigated its expression in the AD brain. In non-AD brains, Mib mRNA has been detected in neurons but not in quiescent astrocytes. On the contrary, in AD brains, Mib mRNA is expressed in activated astrocytes associated with senile plaques, but not expressed in neurons around lesions. From these observations, Mib appears to be a novel A beta-responsive gene that may play a role in astrocyte inflammatory activation around senile plaques in the AD brain. (c) 2006 Elsevier B.V. All rights reserved.
  • Vascular complications in dementia with Lewy bodies: A postmortem study, Daisuke Isojima, Takashi Togo, Kenji Kosaka, Hiroshige Fujishiro, Hiroyasu Akatsu, Omi Katsuse, Shuji Iritani, Toshihiko Matsumoto, Yoshio Hirayasu, NEUROPATHOLOGY, 26, (4) 293 - 297,   2006年08月, 査読有り, The effects of cerebrovascular lesions on DLB are not yet fully understood, whereas the development of Alzheimer's disease (AD) is known to be associated with cerebrovascular lesions. In this study, we investigated the frequency of concomitant cerebrovascular pathologies in autopsy-proven DLB cases (n = 25) in comparison with AD cases (n = 63). We also investigated the correlation between cerebrovascular pathologies and the clinical features of DLB cases. On gross inspection, five cases of DLB and seven cases of AD were complicated by cerebral hemorrhages and the difference was significant; most of the lesions in DLB were subdural hemorrhages, possibly related to trauma. Nine cases of DLB and 25 cases of AD had grossly identified infarctions, but no significant difference was observed. Three cases of DLB and four cases of AD had concomitant hemorrhages, while 10 cases of DLB and 43 cases of AD had infarcts on microscopic inspection. There was a significant difference in the frequency of microscopic infarcts between DLB and AD, whereas no significant difference was noted in the frequency of microscopic hemorrhages. In DLB cases without vascular complications, memory disturbance was common as the initial symptom, while parkinsonism was more common in those with vascular complications. However, no significant difference was observed between DLB cases with and without vascular complications with respect to the frequency of individual clinical symptoms over the whole clinical course. These findings suggest that grossly identified hemorrhages are more common in DLB because of trauma, while microinfarcts are less common in DLB than AD, although the reason remains unclear. Such vascular complications might affect the clinical manifestations, in particular, the initial symptom, of DLB.
  • Increased level of DJ-1 in the cerebrospinal fluids of sporadic Parkinson's disease, M Waragai, JS Wei, M Fujita, M Nakai, GJ Ho, E Masliah, H Akatsu, T Yamada, M Hashimoto, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 345, (3) 967 - 972,   2006年07月, 査読有り, DJ-I is an antioxidant protein whose loss of function by gene mutations has been linked to familial Parkinson's disease (PD). The main objective of the present study was to determine if this molecule was also involved in the pathogenesis of sporadic PD. For this purpose, quantitative immunoblot assays were performed to evaluate DJ-1 in cerebrospinal fluids (CSF) collected from sporadic PD patients (n = 40) and non-PD controls (n = 38). The results showed that the CSF DJ-1 levels in PD were significantly higher than those in non-PD controls. Especially, upregulation of CSF DJ-1 in the early stage of PD (Yahr I-II) were distinct compared to those in the advanced stage of PD (Yahr III-IV) and non-PD controls (p < 0.001 by ANOVA with post hoc Bonferroni's test), suggesting a protective role of DJ-1 against oxidative stress during the early stage. Thus, we propose that CSF DJ-1 could be a possible biomarker for early sporadic PD. (c) 2006 Elsevier Inc. All rights reserved.
  • Brief research communication - Ethnicity-dependent genetic association of ABCA2 with sporadic Alzheimer's disease, MA Wollmer, E Kapaki, M Hersberger, J Muntwyler, F Brunner, M Tsolaki, H Akatsu, K Kosaka, M Michikawa, D Molyva, GP Paraskevas, D Lutjohann, A von Eckardstein, C Hock, RM Nitsch, A Papassotiropoulos, AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 141B, (5) 534 - 536,   2006年07月, 査読有り, A recent study demonstrated a significant genetic association between the ATP-binding cassette transporter A2 (ABCA2) and the risk for Alzheimer's disease (AD) in a large Caucasian sample. The rare T allele of the synonymous exonic single nucleotide polymorphism (SNP) rs908832 was overrepresented in early-onset AD patients as compared to cognitively healthy controls. Here we confirm the association of rs908832 with AD in a Western European population (n=291, P=0.008). In a second sample from Southern Europe, rs908832 was not associated with AD. Interestingly, rs908832 was not polymorphic in a Japanese sample. Furthermore, rs908832 was not associated with either serum cholesterol levels or with the risk for coronary artery disease, but seemed to be related to cholesterol levels in the cerebrospinal fluid. These data suggest that ABCA2 may exert population-dependent effects on the genetic risk for sporadic AD and support a role of ABC lipid transporters in the pathogenesis of this disease. (c) 2006 Wiley-Liss, Inc.
  • A novel alternative splice variant of nicastrin and its implication in Alzheimer disease, N Mitsuda, HD Yamagata, WT Zhong, M Aoto, H Akatsu, N Uekawa, K Kamino, K Taguchi, T Yamamoto, M Maruyama, K Kosaka, M Takeda, Kondo, I, T Miki, LIFE SCIENCES, 78, (21) 2444 - 2448,   2006年04月, 査読有り, Nicastrin interacts with gamma-secretase complex components predominantly via the N-terminal third of the transmembrane domain. The authentic transmembrane domain is critically required for the interaction with gamma-secretase complex components and for formation of an active gamma-secretase complex. In this study, we have identified a novel alternatively spliced transcript of nicastrun in human brain tissue. This transcript (NCSTN-Delta E16) lacks exon 16 of nicastrin mRNA, which leads to deletion of 71 amino acids just upstream of its transmembrane domain. Its expression pattern was analyzed in the hippocampus of patients with pathologically diagnosed Alzheimer disease (cases) and non-Alzheimer dementia (controls). In patients with the APOE-epsilon 4 allele, the frequency of Alzheimer disease appeared to be increased in the NCSTN-Delta E16-positive group, but the association was not statistically significant. In conclusion, the expression of NCSTN-Delta E16 transcript may confer some additional risk for developing Alzheimer disease beyond the risk due to ApoE-epsilon 4 allele. Further investigation in larger scale population would be necessary to address its potential implication in Alzheimer disease. (c) 2005 Elsevier Inc All rights reserved.
  • Alzheimer's disease--an interactive perspective., Heese K, Akatsu H, Current Alzheimer research, 3, (2) 109 - 121,   2006年04月, 査読有り
  • Depletion of cholinergic neurons in the nucleus of the medial septum and the vertical limb of the diagonal band in dementia with Lewy bodies, H Fujishiro, H Umegaki, D Isojima, H Akatsu, A Iguchi, K Kosaka, ACTA NEUROPATHOLOGICA, 111, (2) 109 - 114,   2006年02月, 査読有り, The cholinergic basal forebrain is divided into four subregions (Ch1-4), and cholinergic neuronal loss in the nucleus basalis of Meynert (Ch4) has been correlated with cognitive impairments in both Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). However, the Ch1-2 regions, which provide the major cholinergic innervation to the hippocampus, have not been investigated in DLB. The purpose of this study was to reveal the cholinergic neuronal changes in the medial septum (Ch1) and the nucleus of the vertical limb of the diagonal band (Ch2) of DLB brains. Using choline acetyltransferase (ChAT) immunohistochemistry, we showed that the number of ChAT-immunoreactive neurons in DLB brains was significantly lower than the numbers in AD and non-demented (control) brains. No significant difference in the number of ChAT-immunoreactive neurons was found between the AD and control brains. Moreover, the size of the ChAT-immunoreactive neurons was significantly smaller in the AD and DLB brains than in the control brains. These results show that cholinergic neurons of the Ch1-2 regions are more severely affected in DLB than in AD. Our DLB cases did not fulfill the neuropathologic criteria for definite AD. Furthermore, some Lewy bodies were observed in the Ch1-2 regions. Thus, cholinergic neuronal loss in the Ch1-2 regions might be specific to the pathology of DLB. Taking the distribution of cholinergic fibers in the hippocampus into consideration, this study suggests a possibility that hippocampal cholinergic projection is involved in Lewy-related neurites in the CA2-3 regions, the origin of which remains unclear.
  • Variations in the BDNF gene in autopsy-confirmed Alzheimer's disease and dementia with Lewy bodies in Japan, Hiroyasu Akatsu, Hidehisa D. Yamagata, Jun Kawamata, Kouzin Kamino, Masatoshi Takeda, Takayuki Yamamoto, Tetsuro Miki, Ikuo Tooyama, Shun Shimohama, Kenji Kosaka, DEMENTIA AND GERIATRIC COGNITIVE DISORDERS, 22, (3) 216 - 222,   2006年, 査読有り, Background/Aim: Brain-derived neurotrophic factor ( BDNF) is associated with the hippocampus and the nigrostriatal dopaminergic function. Data showing that its level was reduced in Alzheimer's disease ( AD) and Parkinson's disease (PD) suggested that the BDNF function must play an important role in the pathogenetics of these diseases. Indeed, variation in the BDNF gene may confer susceptibility to AD and PD development. Recently, a functional BDNF Val66Met polymorphism has been found to be associated with episodic memory and hippocampal function, with intracellular trafficking, and with activity-dependent secretion of BDNF. To date, there have been several conflicting reports on the correlation between AD or PD and Val66Met or C270T polymorphism in the BDNF promoter region, although no data on this relationship have been published with respect to dementia with Lewy bodies (DLB). In the present study, we investigated a possible association between such BDNF polymorphisms and susceptibility to AD or DLB. Methods: BDNF genotyping was carried out by the polymerase chain reaction-restriction fragment length polymorphism method in autopsy-confirmed human samples. Results and Conclusion: On comparing patients and controls, the distribution of BDNF genotypes and alleles did not differ significantly. Our findings suggest that it is unlikely that these BDNF polymorphisms play a major role in the pathogenesis of AD and DLB in the Japanese population. Copyright (C) 2006 S. Karger AG, Basel.
  • Albumin gene encoding free fatty acid and β-amyloid transporter is genetically associated with Alzheimer disease., Kimura R, Kamino K, Yamamoto M, Kida T, Akatsu H, Uema T, Kobayashi T, Hattori H, Nuripa A, Nessa BN, Kazui H, Ikejiri Y, Tanaka T, Tanii H, Kudo T, Yoneda H, Yamagata H, Miki T, Takeda M, Psychiatry Clin Neurosci, 60, (Suppl 1) s34 - s39,   2006年
  • アルツハイマー病脳内のタウ蛋白を検出する新規PETプローブ, 伊藤 啓, 岡村 信行, 加藤 元久, 谷内 一彦, 古本 祥三, 工藤 幸司, 赤津 裕康, 山本 孝之, 澤田 徹, 日本薬理学雑誌, 127, (1) 12P - 12P,   2006年01月
  • Clinical features of argyrophilic grain disease - A retrospective survey of cases with neuropsychiatric symptoms, T Togo, D Isojima, H Akatsu, K Suzuki, H Uchikado, O Katsuse, E Iseki, K Kosaka, Y Hirayasu, AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY, 13, (12) 1083 - 1091,   2005年12月, 査読有り, Objective: Although argyrophilic grain disease (AGD) appears common in post-mortem series, its clinical features are not widely known. The aim of this study was to explore such clinical features in neuropathologically-confirmed AGD cases. Methods: After completing a neuropathological assessment of 386 patients, 33 cases (8.5%) were diagnosed as having AGD; 10 were diagnosed as "pure" cases. These subjects had been admitted to geriatric wards of mental hospitals because of behavioral or neuropsychiatric symptoms requiring medical management. Assessment of the clinical features of the pure cases was based on the evaluations in medical records. Results: The average age at onset was 82.2 years. Amnesia was the most common initial symptom; irritability and agitation were also common as initial symptoms. During the course of the illness, irritability was the most frequently observed, followed by delusions (mostly delusions of persecution), dysphoria, and then agitation, and apathy. In contrast to the severity of amnesia, other cognitive functions were relatively spared, and the sensorimotor symptoms were not remarkable. Conclusions: AGD is a late-onset dementing disorder clinically characterized by amnesia, with other cognitive functions relatively spared, and prominent neuropsychiatric features. These features may correlate with the high level of AGD seen in limbic structures. Future studies are needed to elucidate whether these features are common to all AGD patients or to a clinical subtype with neuropsychiatric symptoms.
  • Lymphocyte-specific protein tyrosine kinase is a novel risk gene for Alzheimer disease, WT Zhong, HD Yamagata, K Taguchi, H Akatsu, K Kamino, T Yamamoto, K Kosaka, M Takeda, Kondo, I, T Miki, JOURNAL OF THE NEUROLOGICAL SCIENCES, 238, (1-2) 53 - 57,   2005年11月, 査読有り, Lymphocyte-specific protein tyrosine kinase (LCK) is a lymphoid-specific, Src family protein tyrosine kinase that is known to play a pivotal role in T-cell activation and interact with the T-cell coreceptors, CD4 and CD8. It has been shown to be significantly down-regulated in Alzheimer disease (AD) hippocampus compared with non-demented controls. Furthermore, it is located in a previously identified genetic linkage region (1p34-36) associated with AD. Therefore, we consider it to be a candidate gene for AD. We examined the relationship between AD and the LCK and apolipoprotein E (APOE) genes in 376 AD (including 323 late-onset AD (LOAD) cases and 53 early-onset AD (EOAD) cases) and 378 non-demented controls using a single nucleotide polyrnorphism (SNP). The polymorphism in intron 1 (+6424 A/G) was significantly associated with AD risk. The odds ratio (OR) for total AD associated with the GG genotype was 1.41 (95% CI = 1.06-1.87) and that for LOAD was 1.37 (95% CI = 1.02-1.85), while that for APOE-epsilon 4 was 5.06 (95% CI = 3.60-7.12). In the APOE-epsilon 4 non-carrier subgroup, the GG genotype also showed significant association (OR = 1.66; 95% CI = 1.16-2.38). These results indicate that the LCK is a novel risk gene for AD regardless of the APOE genotype. (c) 2005 Elsevier B.V. All rights reserved.
  • Quinoline and benzimidazole derivatives: Candidate probes for in vivo imaging of tau pathology in Alzheimer's disease, N Okamura, T Suemoto, S Furumoto, M Suzuki, H Shimadzu, H Akatsu, T Yamamoto, H Fujiwara, M Nemoto, M Maruyama, H Arai, K Yanai, T Sawada, Y Kudo, JOURNAL OF NEUROSCIENCE, 25, (47) 10857 - 10862,   2005年11月, 査読有り, Neurofibrillary tangles ( NFTs), neuropil threads, and neuritic elements of senile plaques predominantly comprise hyperphosphorylated tau protein and represent pathological characteristics of Alzheimer's disease ( AD). These lesions occur before the presentation of clinical symptoms and correlate with the severity of dementia. In vivo detection of these lesions would thus prove useful for preclinical diagnosis of AD and for tracking disease progression. The present study introduces three novel compounds, 4-[2-(2-benzoimidazolyl)ethenyl]-N,N-diethylbenzenamine ( BF-126), 2-[( 4- methylamino) phenyl] quinoline ( BF-158), and 2-( 4- aminophenyl) quinoline ( BF-170), as candidate probes for in vivo imaging of tau pathology in the AD brain. When solutions of these compounds are injected intravenously into normal mice, these agents exhibit excellent brain uptake and rapid clearance from normal brain tissue. These compounds display relatively lower binding affinity to beta-amyloid fibrils and higher binding affinity to tau fibrils, compared with previously reported probe BF-168. In neuropathological examination using AD brain sections, BF-126, BF-158, and BF-170 clearly visualize NFTs, neuropil threads, and paired helical filament-type neuritis. Autoradiography using C-11-labeled BF-158 further demonstrated labeling of NFTs in AD brain sections. These findings suggest the potential usefulness of quinoline and benzimidazole derivatives for in vivo imaging of tau pathology in AD.
  • Dose effect of apolipoprotein A-II (TG) repeat on age-at-onset in APOE-e4(+) late-onset Alzheimer disease by splicing modification., Kamino K, Kida T, Tanaka T, Kudo T, Yamamoto M, Kimura R, Akatsu H, Uema T, yoneda H, Miki T, Hattori H, Imagawa M, Ihara S, Ohta S, Proceeding of 55th Annual meeting of The American Society of Human Genetics,   2005年10月
  • Lib, transcriptionally induced in senile plaque-associated astrocytes, promotes glial migration through extracellular matrix, K Satoh, M Hata, T Shimizu, H Yokota, H Akatsu, T Yamamoto, K Kosaka, T Yamada, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 335, (2) 631 - 636,   2005年09月, 査読有り, In an effort to identify astrocyte-derived molecules that may be intimately associated with progression of Alzheimer's disease (AD), Lib, a type I transmembrane protein belonging to leucine-rich repeat superfamily, has been identified as a distinctly inducible gene, responsive to beta-amyloid as well as pro-inflammatory cytokines in astrocytes. To evaluate the roles of Lib in AD, we investigated Lib expression in AD brain. In non-AD brain, Lib mRNA has been detected in neurons but not in quiescent astrocytes. On the contrary, in AD brain, Lib mRNA is expressed in activated astrocytes associated with senile plaques, but not expressed in neurons around lesions. Lib-expressing glioma cells displayed promotion of migration ability through reconstituted extracellular matrix and recombinant Lib protein bound to constituents of extracellular matrix. These observations suggest that Lib may contribute to regulation of cell-matrix adhesion interactions with respect to astrocyte recruitment around senile plaques in AD brain. (c) 2005 Elsevier Inc. All rights reserved.
  • Non-uniformity in the regional pattern of Lewy pathology in brains of dementia with Lewy bodies, R Yamamoto, E Iseki, W Marui, T Togo, O Katsuse, M Kato, D Isojima, H Akatsu, K Kosaka, H Arai, NEUROPATHOLOGY, 25, (3) 188 - 194,   2005年09月, 査読有り, We examined the regional pattern of Lewy pathology in brains of dementia with Lewy bodies (DLB) to clarify whether Lewy pathology uniformly progresses or not. Thirty-five autopsied DLB cases were examined using alpha-synuclein-immunohistochemistry, and the regional degree of Lewy pathology in the brainstem, diencephalon and cerebral cortex was quantitatively evaluated. Consequently, we found that the regional pattern of Lewy pathology differed according to the pathological subtype, and was divided into three types: type 1 showed a brainstem-predominant pattern, type 2 was almost equal for the brainstem and cerebral cortex, and type 3 showed a cerebral cortex-predominant pattern. The limbic type/pure and common forms were mainly composed of type 1, whereas the neocortical type/common and Alzheimer's disease (AD) forms were mainly composed of type 3. These findings suggest the possibility that Lewy pathology of the limbic type/pure and common forms mainly progresses from the brainstem to the cerebrum, whereas that of the neocortical type/common and AD forms mainly progresses from the cerebrum to the brainstem. Cases with type 1 Lewy pathology mainly developed parkinsonism, whereas those with type 3 Lewy pathology mainly developed dementia. This corresponded to most of the limbic type/pure and common forms which developed parkinsonism, whereas most of the neocortical type/common and AD forms developed dementia. Type 1 cases may thus be clinically diagnosed as having Parkinson's disease (PD) with dementia. These findings suggest that PD has clinico-pathological continuity with DLB, and that the regional pattern of Lewy pathology is not uniform.
  • Identification of hippocampus-related candidate genes for Alzheimer's disease, K Taguchi, HD Yamagata, WT Zhong, K Kamino, H Akatsu, R Hata, T Yamamoto, K Kosaka, M Takeda, Kondo, I, T Miki, ANNALS OF NEUROLOGY, 57, (4) 585 - 588,   2005年04月, 査読有り, Alzheimer's disease (AD) is a complex multifactorial disease in which many genetic and environmental factors are involved. We performed an association study using 376 AD patients and 376 control subjects. We studied 35 single nucleotide polymorphisms in 35 genes that were significantly downregulated or upregulated only in the AD hippocampus compared with control and found that 9 single nucleotide polymorphisms were associated with AD. Our data indicated that single nucleotide polymorphisms could highly reflect differences in gene expression. Furthermore, an intronic polymorphism. (+9943T/C) in POU2F1 was most significantly associated with AD (p = 0.0007). Our results suggest that POU2F1 is a candidate gene for AD.
  • TAFI polymorphisms at amino acids 147 and 325 are not risk factors for cerebral infarction, H Akatsu, H Yamagata, Y Chen, T Miki, K Kamino, M Takeda, W Campbell, Kondo, I, K Kosaka, T Yamamoto, H Okada, BRITISH JOURNAL OF HAEMATOLOGY, 127, (4) 440 - 447,   2004年11月, 査読有り, Thrombin-activatable fibrinolysis inhibitor (TAFI) was reported as an anaphylatoxin-inactivating enzyme generated by proteolytic cleavage of its zymogen, and is the same enzyme as that first designated by our group as procarboxypeptidase R (proCPR). Its level in plasma appears to influence vascular disease. In addition, TAFI activity is strongly influenced by genetic polymorphism, especially at amino acids 147 and 325. We investigated whether these TAFI polymorphisms would act as a risk factor for cerebral infarction (CI) by examining 253 samples in which the diagnosis was cliniconeuropathologically confirmed. We found little that was statistically significant in terms of these polymorphisms among patients with no vascular problems or in a population-based control group. In the present study of an elderly Japanese group, our samples revealed a lower percentage of the Ile allele at Thr/Ile-325 compared with western counterparts. Although patients with severe infarcts had a lower percentage of the Ile allele (10%) at amino acid position 325 compared with the slightly and moderately affected patients and the population-based control group (15-18%), no statistical significance was found. None of our results showed any statistical correlation between TAFI polymorphisms and CI.
  • Pathological entity of dementia with Lewy bodies and its differentiation from Alzheimer's disease, W Marui, E Iseki, M Kato, H Akatsu, K Kosaka, ACTA NEUROPATHOLOGICA, 108, (2) 121 - 128,   2004年08月, 査読有り, We reclassified the pathological subtypes of dementia with Lewy bodies (DLB), based on both Lewy pathology and Alzheimer pathology, to clarify the pathological entity of DLB and the boundary between DLB and Alzheimer's disease (AD) in autopsied cases, using both pathological and immunohistochemical methods. DLB was classified as either limbic type or neocortical type according to the degree of Lewy pathology including Lewy bodies (LB) and LB-related neurites by our staging, and was classified as pure form, common form or AD form according to the degree of Alzheimer pathology including neurofibrillary tangles (NFT) and amyloid deposits by Braak staging. These combined subtypes were lined up on a spectrum, not only with Lewy pathology but also with other DLB-related pathologies including Alzheimer pathology, neuronal loss in the substantia nigra, spongiform change in the transentorhinal cortex and LB-related neurites in the CA2-3 region. In contrast, the Lewy pathology of AD did not meet the stages of Lewy pathology in DLB, and there were scarcely any similarities in other DLB-related pathologies between AD and DLB. In addition, the Lewy pathology of AD had characteristics different from that of DLB, including the coexistence rate of LB with NFT, and the immunohistochemical and immunoelectron microscopic findings of LB and LB-related neurites. These findings suggest that DLB is a distinctive pathological entity that can be differentiated from AD, although it shows some pathological subtypes.
  • Promoter polymorphism in fibroblast growth factor 1 gene increases risk of definite Alzheimer's disease, H Yamagata, Y Chen, H Akatsu, K Kamino, J Ito, S Yokoyama, T Yamamoto, K Kosaka, T Miki, Kondo, I, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 321, (2) 320 - 323,   2004年08月, 査読有り, Fibroblast growth factor I (FGF1, also known as acidic FGF) protects selective neuronal populations against neurotoxic effects such as those in Alzheimer's disease (AD) and HIV encephalitis. The FGF1 gene is therefore a strong candidate gene for AD. Using the promoter polymorphism of the FGF1 gene, we examined the relationship between AD and the FGF1 and apolipoprotein E (APOE) genes in 100 Japanese autopsy-confirmed late-onset AD patients and 106 age-matched non-demented controls. The promoter polymorphism (-1385 A/G) was significantly associated with AD risk. The odds ratio for AD associated with the GG vs non-GG genotype was 2.02 (95% CI = 1.16-3.52), while that of epsilon4 vs non-epsilon4 in APOE4 gene was 5.19 (95% CI = 2.68-10.1). The odds ratio for APOEepsilon4 and FGF1 GG carriers was 20.5 (95% CI = 6.88-60.9). The results showed that the FGF1 gene is associated with autopsy-confirmed AD. (C) 2004 Elsevier Inc. All rights reserved.
  • Prevention of gastroesophageal reflux using an application of half-solid nutrients in patients with percutaneous endoscopic gastrostomy feeding, J Kanie, Y Suzuki, A Iguchi, H Akatsu, T Yamamoto, H Shimokata, JOURNAL OF THE AMERICAN GERIATRICS SOCIETY, 52, (3) 466 - 467,   2004年03月, 査読有り
  • Styrylbenzoxazole derivatives for in vivo imaging of amyloid plaques in the brain, N Okamura, T Suemoto, H Shimadzu, M Suzuki, T Shiomitsu, H Akatsu, T Yamamoto, M Staufenbiel, K Yanai, H Arai, H Sasaki, Y Kudo, T Sawada, JOURNAL OF NEUROSCIENCE, 24, (10) 2535 - 2541,   2004年03月, 査読有り, Progressive deposition of senile plaques (SPs) is one of the major neuropathological features of Alzheimer's disease ( AD) that precedes cognitive decline. Noninvasive detection of SPs could, therefore, be a potential diagnostic test for early detection of AD patients. For imaging SPs in the living brain, we have developed a series of styrylbenzoxazole derivatives that achieve high binding affinity for amyloid-beta (Abeta) fibrils. One of these compounds, 6-(2-Fluoroethoxy)- 2-[2-(4-methylaminophenil) ethenyl] benzoxazole (BF-168), selectively binds SPs in AD brain sections and recognizes Abeta1-42-positive diffuse plaques as well as neuritic plaques in AD brain sections. Intravenous injection of BF-168 in PS1/APP and APP23 transgenic mice resulted in specific in vivo labeling to both compact and diffuse amyloid deposits in the brain. In addition, F-18-radiolabeled BF-168 demonstrated abundant initial brain uptake (3.9% injected dose/gm at 2 min after injection) and fast clearance (t(1/2) = 24.7 min) after intravenous administration in normal mice. Furthermore, autoradiograms of brain sections from APP23 transgenic mice at 180 min after intravenous injection of [F-18] BF-168 showed selective labeling of brain amyloid deposits with little nonspecific binding. These findings strongly suggest that styrylbenzoxazole derivatives are promising candidate probes for positron emission tomography and single-photon emission computed tomography imaging for early detection of amyloid plaque formation.
  • In vivo labeling of amyloid with BF-108, T Suemoto, N Okamura, T Shiomitsu, M Suzuki, H Shimadzu, H Akatsu, T Yamamoto, Y Kudo, T Sawada, NEUROSCIENCE RESEARCH, 48, (1) 65 - 74,   2004年01月, 査読有り, Detection of aggregated amyloid-beta (Abeta) with a non-invasive imaging modality such as positron emission tomography (PET) was suggested to be ideal for the diagnosis of Alzheimer's disease (AD) prior to the onset of clinical symptoms. We have been searching for imaging probe candidates with a high affinity for aggregated Abeta in vitro and in vivo and high lipophilicity, a characteristic that allows for the permeation of the blood-brain barrier (BBB). As analyzed by Thioflavin T (ThT) assay and octanol/water partition coefficient test (P-C), 3-diethylamino-6-(2-fluoroethyl)ethylaminoacridine (BF-108) were found to have high affinity for Abeta aggregates in vitro and high lipophilicity. Intravenously administrated BF-108 labeled Abeta aggregates injected into the amygdala as observed under a fluorescence microscope, showing this compound's permeability of BBB and an ability to label Abeta in vivo. BF-108 also labeled neuritic senile plaques (SPs), neurofibrillary tangles, and amyloid-laden vessels in temporal and hippocampal sections from AD patients. Following intravenous administration of BF-108. to an APP23 transgenic (TG) mouse, in vivo labeling of endogenous plaques was seen in brain sections by fluorescence microscopy. These properties suggest the potential utility of BF-108 for in vivo imaging of AD pathology. (C) 2003 Elsevier Ireland Ltd and The Japan Neuroscience Society. All rights reserved.
  • A novel imaging probe for in vivo detection of neuritic and diffuse amyloid plaques in the brain, N Okamura, T Suemoto, T Shiomitsu, M Suzuki, H Shimadzu, H Akatsu, T Yamamoto, H Arai, H Sasaki, K Yanai, M Staufenbiel, Y Kudo, T Sawada, JOURNAL OF MOLECULAR NEUROSCIENCE, 24, (2) 247 - 255,   2004年, 査読有り, Extensive deposition of neuritic and diffuse amyloid plaques in the brain is a critical event for the pathogenesis of Alzheimer's disease (AD) and considered to start before the appearance of clinical symptoms. In vivo detection of these brain beta-amyloid (Abeta) deposits using positron emission tomography (PET), therefore, would be a useful marker for presymptomatic detection of AD. To develop a new agent for PET probe of imaging neuritic and diffuse amyloid deposits, novel fluorescent compounds, including styryl-fluorobenzoxazole derivatives, were examined. These compounds showed a high binding affinity for both synthetic Abeta1-40 and Abeta1-42 aggregates. Some of these compounds also displayed distinct staining of neuritic and diffuse amyloid plaques in AD brain sections. A biodistribution study of styryl-fluorobenzoxazole derivatives in normal mice exhibited excellent brain uptakes (4.5-5.5% injected dose/g at 2 min postinjection). Furthermore, iv administration of BF-145, a styryl-fluorobenzoxazole derivative, demonstrated specific in vivo labeling of compact and diffuse amyloid deposits in an APP23 transgenic mouse brain, in contrast to no accumulation in a wild-type mouse brain. These findings suggest that BF-145 is a potential candidate as a probe for imaging early brain pathology in AD patients.
  • The splicing regulatory protein p18SRP is down-regulated in Alzheimer's disease brain, K Heese, M Fujita, H Akatsu, T Yamamoto, K Kosaka, Y Nagai, T Sawada, JOURNAL OF MOLECULAR NEUROSCIENCE, 24, (2) 269 - 275,   2004年, 査読有り, Alzheimer's disease (AD) is the most common neurodegenerative disorder of aging, accounting for an estimated two-thirds of all cases of senile dementia. Using bioinformatics, the yeast two-hybrid-system, reverse transcription polymerase chain reaction, and fluorescence microscopy analysis, we demonstrate here that the new putative splicing regulatory protein p18SRP is a lysine-rich zinc finger domain-containing protein that interacts with the serine-arginine (SR)-rich splicing regulatory protein SRrp86. The additional finding of its down-regulation in the brain of AD subjects points to a possible pivotal role of p18SRP in the control of cellular survival.
  • Prevention of late complications by half-solid enteral nutrients in percutaneous endoscopic gastrostomy tube feeding, J Kanie, Y Suzuki, H Akatsu, M Kuzuya, A Iguchi, GERONTOLOGY, 50, (6) 417 - 419,   2004年, 査読有り, Background: Percutaneous endoscopic gastrostomy feeding is accompanied by unique complications, which are not easily controlled. Objective: In an attempt to decrease complications, we used half-solid nutrients for percutaneous endoscopic gastrostomy feeding in an 85-year-old woman. The patient had been receiving enteral nutrients via percutaneous endoscopic gastrostomy, and we examined whether this approach can reduce complications. She presented with regurgitation of enteral nutrients and recurrent respiratory infections. Methods: Half-solid enteral nutrients, prepared by mixing liquid enteral nutrients with agar powder, were administered via percutaneous endoscopic gastrostomy. Results: Symptoms of gastroesophageal reflux disappeared immediately after the start of half-solid enteral nutrient feeding. Conclusion: Gastroesophageal reflux and leakage, two intractable late complications of percutaneous endoscopic gastrostomy tube feeding, can be alleviated by the solidification of enteral nutrients. Since this method allows quick administration of nutrients, it is also expected to help prevent the occurrence of decubitus ulcers and reduce the burden to the caregiver. Copyright (C) 2004 S. Karger AG, Basel.
  • Cognitive conditions of pathologically confirmed dementia with Lewy bodies and Parkinson's disease with dementia, Y Horimoto, M Matsumoto, H Nakazawa, H Yuasa, M Morishita, H Akatsu, H Ikari, T Yamamoto, K Kosaka, JOURNAL OF THE NEUROLOGICAL SCIENCES, 216, (1) 105 - 108,   2003年12月, 査読有り, The relationship between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) has been insufficiently described, and it is still problematic. Twenty-nine cases of DLB and 10 cases of PDD were investigated in the present study. DLB cases disclosed a significantly older disease onset and shorter disease duration than PDD cases (p<0.01 each). However, they showed no significant difference in dementia onset or dementia duration (p>0.05 each). Motor symptoms (parkinsonism) were suspected as the cause of the younger disease onset in PDD cases. Compared with 10 age-matched cases of definite Alzheimer's disease, both 19 DLB cases and 6 PDD cases had significantly better scores in the final test of mini-mental state examination (MMSE) and revised version of Hasegawa's Dementia Scale (HDSR) within 12 months before death, although no significant differences between DLB and PDD were indicated. DLB and PDD were suspected to show cognitive impairment of similar severity in the terminal stage. They would thus be difficult to classify as completely different entities. (C) 2003 Elsevier B.V. All rights reserved.
  • Expression of matrix metalloproteinases 2 and 7 in tumor cells correlates with the world health organization classification subtype and clinical stage of thymic epithelial tumors, E Takahashi, H Tateyama, H Akatsu, Fukai, I, Y Yamakawa, Y Fujii, T Eimoto, HUMAN PATHOLOGY, 34, (12) 1253 - 1258,   2003年12月, 査読有り, To investigate the roles of matrix metalloproteinases (MMPs) in thymic epithelial tumors, we examined the expression of MMP-2, -7, and -9; membrane-type 1 (MT1)-MMP; and tissue inhibitor of metalloproteinase-2 (TIMP-2) in 57 tumors by immunohistochemistry and in selected 15 cases by in situ hybridization. The tumors consisted of 5 type A, 12 type AB, 11 type B1, 11 type B2, 9 type B3, and 9 type C thymomas according to the World Health Organization histologic classification system and of 22 stage I, 13 stage II, 8 stage III, and 14 stage IV thymomas according to the Masaoka staging system. In the positive cases, MMPs and TIMP-2 were expressed in both tumor cells and stromal cells. The cellular localization of MMPs detected by immunohistochemistry was almost identical with that of the mRNA signals detected by in situ hybridization. MMP-2 and MMP-7 were predominantly expressed in type B3 thymoma and type C thymoma, respectively. Expression of MT1-MMP and TIMP-2 correlated with that of MMP-2, indicating a proteolytic activation of the latter. MMP-9 was prominent in type B2 thymoma. Expression in tumor cells of MMP-2 or MMP-7 was also correlated with clinical stage. The present study suggests that certain MMPs may play an important role in the tumor progression of different subtypes of thymic epithelial tumors and that MMP-2 and MMP-7 may contribute to the tumor aggressiveness and malignant potential. (C) 2003 Elsevier Inc. All rights reserved.
  • Complement C3a receptors in the pituitary gland: a novel pathway by which an innate immune molecule releases hormones involved in the control of inflammation, K Francis, BM Lewis, H Akatsu, PN Monk, SA Cain, MF Scanlon, BP Morgan, J Ham, P Gasque, FASEB JOURNAL, 17, (13) 2266 - +,   2003年10月, 査読有り, Two-way communication exists between the endocrine and immune systems using molecules such as hormones and cytokines. Here we describe a new pathway by which C3a, a complement-derived cytokine, stimulates anterior pituitary hormone release and activates the hypothalamic-pituitary-adrenal axis, a reflex central to the stress response and to the control of inflammation. We show that C3a receptors are expressed in pituitary hormone secreting and non-hormone secreting (folliculostellate) cells and that both C3a and C3adesArg (a non-inflammatory metabolite) stimulate pituitary cell cultures to release prolactin, growth hormone, and adrenocorticotropin. Serum levels of these hormones, together with adrenal corticosterone, increase dose dependently with recombinant C3a and C3adesArg administration in vivo. Pertussis toxin blocks the response to C3a but not C3adesArg, which indicates the presence of two receptors, only one of which is coupled to G(alphai)-proteins. We propose that the complement innate immune molecules (cytokines) modulate tissue-specific and systemic inflammatory responses through communication with the endocrine pituitary gland.
  • 新規化合物BF-168のアミロイドイメージング用プローブとしての有効性の検討, 岡村 信行, 末元 隆寛, 鈴木 雅子, 塩満 剛, 島津 浩, 赤津 裕康, 山本 孝之, 谷内 一彦, 荒井 啓行, 工藤 幸司, 澤田 徹, Dementia Japan, 17, (2) 166 - 166,   2003年08月
  • Complement C5a receptor-mediated signaling may be involved in neurodegeneration in Alzheimer's disease, Farkas, I, M Takahashi, A Fukuda, N Yamamoto, H Akatsu, L Baranyi, H Tateyama, T Yamamoto, N Okada, H Okada, JOURNAL OF IMMUNOLOGY, 170, (11) 5764 - 5771,   2003年06月, 査読有り, In our earlier results, we demonstrated that bells expressing the complement C5aR are vulnerable since abnormal activation of C5aR caused apoptosis of these cells. In this study, we demonstrate that activation of C5aR by antisense homology box (AHB) peptides synthesized in multiple antigenic peptide form and representing putative interaction sites of the C5a/C5aR evoked calcium influx in TGW neuroblastoma cells. Dose-dependent inhibition of the response was found when the cells were pretreated with C5a, suggesting that C5aR was involved in this process. In addition, pretreatment with monomeric forms of the AHB peptides resulted in attenuation of the calcium signals, supporting the idea of the role of C5aR in this process. Cells of a neuron-rich primary culture and pyramidal cells of rat brain slices also responded to the AHB peptide activation with an increase in the intracellular calcium level, showing that calcium metabolism might be affected in these cells. TUNEL staining demonstrated that C5aR-mediated apoptosis could be induced both in cells of the primary culture as well as in cortical pyramidal neurons of the rat brain. In addition, we investigated expression of C5aR in the hippocampal and cortical neurons of human brains of healthy and demented patients using two anti-human C5aR Abs. Pyramidal cells of the hippocampus and cortex and granular cells of the hippocampus were immunopositive on staining. Although staining was also positive in the vascular dementia brain, it disappeared in the brain with Alzheimer's disease. These results provide further support that C5aR may be involved in neurodegeneration.
  • Autonomic dysfunctions in dementia with Lewy bodies, Y Horimoto, M Matsumoto, H Akatsu, H Ikari, K Kojima, T Yamamoto, Y Otsuka, K Ojika, R Ueda, K Kosaka, JOURNAL OF NEUROLOGY, 250, (5) 530 - 533,   2003年05月, 査読有り, Twenty-nine cases of both clinically and neuropathologically diagnosed dementia with Lewy bodies (DLB) were retrospectively examined for autonomic symptoms. Twenty-eight cases showed some kind of autonomic dysfunction. Urinary incontinence (97%) and constipation (83%) were the two most common. Although urinary retention and episodic hypotension causing syncopal attacks were less common, the frequency was still high (28% each). There were 18 cases (62 with severe autonomic failure. These 28 cases showed similar tendencies, with no significant differences between the subtypes of DLB (brainstem, limbic, and neocortical types or common and pure forms). We found that DLB of all pathological subtypes exhibits some kind and level of autonomic symptoms.
  • Preferential detection of pro-carboxypeptidase R by enzyme-linked immunosorbent assay, S Tani, H Akatsu, Y Ishikawa, N Okada, H Okada, MICROBIOLOGY AND IMMUNOLOGY, 47, (4) 295 - 300,   2003年, 査読有り, We generated two monoclonal antibodies (mAbs), 2A16 and 10G1, against pro-carboxypeptidase R (proCPR), also known as thrombin activatable fibrinolysis inhibitor (TAFI). By use of these mAbs, we developed a sandwich enzyme-linked immunosorbent assay (ELISA) system to detect proCPR. Since the amount of the antigen detectable by the ELISA was essentially the same in fresh plasma and serum incubated at 37 C for 1 hr, we concluded that the ELISA system detected not only proCPR, but also inactivated CPR generated from proCPR. However, an appreciable amount of proCPR remained unactivated in serum. For extensive activation of proCPR in plasma, thrombin and thrombomodulin complexes (T-TM) can be used together with CaCl2. Following extensive conversion of proCPR to CPR by T-TM and CaCl2, converting plasma to serum (T-TM serum), antigenicity became undetectable by ELISA. Further analysis revealed that 2A16 reacts only with proCPR although 10G1 reacts with proCPR, active CPR and inactivated CPR. Therefore, we concluded that the ELISA system preferentially detects proCPR and not CPR. Our sandwich ELISA system utilizing 2A16 and 10G1 provides a suitable method for detecting proCPR and can be used to determine levels of proCPR in plasma samples from patients.
  • Mechanism of the development of gastric ulcer after percutaneous endoscopic gastrostomy, J Kanie, H Akatsu, Y Suzuki, H Shimokata, A Iguchi, ENDOSCOPY, 34, (6) 480 - 482,   2002年06月, 査読有り, Background and Study Aims: The present study was carried out in order to elucidate the mechanism of the development of gastric ulcer, one of the serious complications of PEG tube placement. Patients and Methods: This retrospective study included 92 patients who underwent gastric endoscopy after PEG tube placement. Gastric ulcers detected at gastroscopy were examined in relation to the length of the protrusion from the PEG tubes intra-gastric bumper and the use of histamine H-2-receptor antagonists. Results: Gastric ulcers were found in nine of the 92 patients, and in all nine the ulcer was found on the posterior wall of the gastric body, where the tip of the PEG tube was attached. Seven of the 21 patients (33.3%) who had a PEG tube with a long protrusion from the intragastric bumper developed gastric ulcer. By contrast, only two of the 71 patients (2.8%) who had a PEG tube with a short protrusion developed gastric ulcer. The use of H-2-blockers had no significant impact on the development of gastric ulcer. Conclusions: The occurrence of gastric ulcer after PEG placement was attributable to the shape of the PEG tube within the intragastric space, and not to the use of H-2-blockers, suggesting that appropriate placement of the PEG tube is an important factor in preventing gastric ulcer.
  • Human C1qRp is identical with CD93 and the mNI-11 antigen but does not bind C1q, EP McGreal, N Ikewaki, H Akatsu, BP Morgan, P Gasque, JOURNAL OF IMMUNOLOGY, 168, (10) 5222 - 5232,   2002年05月, 査読有り, It has been suggested that the human C1qRp is a receptor for the complement component C1q, however, there is no direct evidence for an interaction between C1q and C1qRp. In this study, we demonstrate that C1q does not show enhanced binding to C1qRp-transfected cells compared with control cells. Furthermore, a soluble recombinant C1qRp-Fc chimera failed to interact with immobilized C1q. The proposed role of C1qRp in the phagocytic response in vivo is also unsupported in that we demonstrate that this molecule is not expressed by macrophages in a variety of human tissues and the predominant site of expression is on endothelial cells. Studies on the rodent homolog of C1qRp, known as AA4, have suggested that this molecule may function as an Intercellular adhesion molecule. Here we show that C1qRp is the Ag recognized by several previously described mAbs, mNI-11 and two anti-CD93 Abs (clones X2 and VIMD2b). Interestingly, mNI-11 (Fab') has been shown to promote monocyte-monocyte and monocyte-endothelial cell adhesive interactions. We produced a recombinant C1qRp-Fc chimera containing the C-type lectin-like domain of C1qRp and found specific binding to vascular endothelial cells in sections of inflamed human tonsil, indicating the presence of a C1qRp ligand at this site. This interaction was Ca2+ independent and was not blocked by our anti-C1qRp mAb BIIG-4, but was blocked by the proadhesive mAb mNI-11. Collectively, these data indicate that C1qRp is not a receptor for C1q, and they support the emerging role of C1qRp (here renamed CD93) in functions relevant to intercellular adhesion.
  • Subtype analysis of neuropathologically diagnosed patients in a Japanese geriatric hospital, H Akatsu, M Takahashi, N Matsukawa, Y Ishikawa, N Kondo, T Sato, H Nakazawa, T Yamada, H Okada, T Yamamoto, K Kosaka, JOURNAL OF THE NEUROLOGICAL SCIENCES, 196, (1-2) 63 - 69,   2002年04月, 査読有り, Dementia is a social problem in Japan. as it is in other countries. Recently, there has been an increase in the number of patients with Alzheimer-type dementia (ATD) in the population. We analyzed 239 cases of patients autopsied at Fukushimura Hospital over a 10-year period. Clinicopathologically, 66% of these cases (158 cases) presented with dementia symptoms. The predominant form of illness was ATD. We found dementia with Lewy bodies (DLB) to be as frequent as vascular dementia (VD). Although the numbers were small, limbic neurofibrillary tangle dementia (LNTD) and Pick's disease (PiD) followed a clinical course typical of these diseases. On the other hand, senile dementia of the Alzheimer's type (SDAT) and the common form of neocortical type DLB (diffuse Lewy body disease; DLBD) were difficult to distinguish from each other. We attempted to uncover differences between these dementias in terms of how they affect male and female patients. The clinical course of the male patients with the common form of neocortical type DLB was more or less typical, while that of the female patients was not. (C) 2002 Elsevier Science B.V. All rights reserved.
  • Regional quantitative analysis of NFT in brains of non-demented elderly persons: Comparisons with findings in brains of late-onset Alzheimer's disease and limbic NFT dementia, E Iseki, S Tsunoda, K Suzuki, N Takayama, H Akatsu, T Yamamoto, K Kosaka, NEUROPATHOLOGY, 22, (1) 34 - 39,   2002年03月, 査読有り, Brains of non-demented elderly people were divided into two groups according to the presence or absence of senile plaques (SP(+) and SP(-)). The regional number of NFT in each group were then quantitatively investigated and compared with that in the late-onset Alzheimer's disease (AD) group and the limbic NFT dementia (LNTD) group. NFT were divided into type 1, type 2 and type 3 according to the developmental stage. In addition, polymorphism of the apolipoprotein E (Apo E) gene was analyzed in all groups. The most frequent regions of NFT common to all groups were the transentorhinal cortex, the entorhinal cortex, the subiculum and cornu ammonis (CA)1 of the hippocampus. In the SP(+) group the proportion of type 3 was high in the transentorhinal cortex and entorhinal cortex, while type 1 or 2 were high in the subiculum and CA1, suggesting that NFT formation progresses from the parahippocampal cortex to the hippocampus. In the SP(-) group the proportion of type 3 was higher in the subiculum and CA1 than in the transentorhinal cortex and entorhinal cortex, suggesting that NFT formation is accelerated in the hippocampus. The late-onset AD group and LNTD group showed the patterns of NFT formation similar to those of the SP(+) group and SP(-) group, respectively. The frequency of the epsilon4 allele of the Apo E gene was significantly higher in the late-onset AD group and SP(+) group than in the LNTD group and SP(-) group, respectively. From these findings it is suggested that persons in the SP(+) group are likely to remain non-demented elderly persons or become a developmental matrix of late-onset AD with a risk factor of the epsilon4 allele, while those in the SP(-) group are likely to remain non-demented elderly persons or pass into LNTD without a risk factor of the epsilon4 allele.
  • Effects of human soluble thrombomodulin on experimental glomerulonephritis, H Ikeguchi, S Maruyama, Y Morita, Y Fujita, T Kato, Y Natori, H Akatsu, W Campbell, N Okada, H Okada, Y Yuzawa, S Matsuo, KIDNEY INTERNATIONAL, 61, (2) 490 - 501,   2002年02月, 査読有り, Background. Coagulation and inflammation are both important processes that contribute to glomerular injury. The present study was performed to evaluate the effects of recombinant human soluble thrombomodulin (RHS-TM) in a lethal model of thrombotic glomerulonephritis and to investigate the possible mechanisms. Methods. Thrombotic glomerulonephritis was induced in rats by administration of lipopolysaccharide and rabbit anti-rat glomerular basement membrane antibody. One hour later, RHS-TM or heparin was administered, and the histological findings, renal functions, and coagulation parameters were evaluated. To evaluate the contribution of carboxypeptidase R (CPR) to the results obtained in rats treated with RHS-TM, plasma CPR levels were measured. Then, carboxypeptidase inhibitor (CPI), which prevents the function of CPR, was administered. Results. Massive glomerular thrombosis and lung hemorrhage developed within five hours of disease induction, and all rats died within 24 hours. RHS-TM (3 mg/kg) prevented the progression of the disease and all rats survived. Heparin (250 U/kg/h) showed similar anti-thrombotic effect, but induced massive hemorrhage in the lungs or stomach. RHS-TM attenuated leukocyte/neutrophil infiltration in the glomerulus but heparin did not, suggesting that RHS-TM has anti-inflammatory properties. CPR levels in plasma were about threefold higher in rats treated with RHS-TM compared to those in rats treated with heparin. Furthermore, the inhibitory effect of RHS-TM on leukocyte/neutrophil infiltration was significantly diminished by injection of CPI. Conclusion. RHS-TM effectively attenuates the injuries of thrombotic glomerulonephritis in rats. The results indicate that RHS-TM, in addition to its anti-thrombotic action, may exert its anti-inflammatory properties by converting proCPR to CPR, which then inactivates anaphylatoxins. RHS-TM is a potential novel therapeutic tool for thrombotic glomerular injury and related disorders.
  • Decreased expression of hippocampal cholinergic neurostimulating peptide precursor protein mRNA in the hippocampus in Alzheimer disease, M Maki, N Matsukawa, H Yuasa, Y Otsuka, T Yamamoto, H Akatsu, T Okamoto, R Ueda, K Ojika, JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 61, (2) 176 - 185,   2002年02月, 査読有り, Hippocampal cholinergic neurostimulating peptide (HCNP) is involved in the phenotype development of the septo-hippocampal system. HCNP precursor protein (HCNP-pp) is known to interact with other molecules including phosphatidylethanolamine and Raf-1 kinase, and is also known as phosphatidylethanolamine-binding protein and raf kinase-inhibitory protein. To assess whether HCNP-pp is involved in the pathogenesis of Alzheimer disease (AD), the expression levels of its mRNA in the hippocampus of autopsy brains from patients with dementia (including AD and ischemic vascular dementia) were compared with those of non-demented control subjects. The in situ hybridization analysis revealed that the expression of HCNP-pp mRNA in patients with clinically late-onset AD was decreased in the hippocampal CA1 field, but not in the CA3 field or the dentate gyrus. The early-onset AD patients showed a wide range of expression levels in the hippocampal sub-regions. Northern blot analysis of HCNP-pp mRNA in brain tissue supported these observations. Since HCNP is known to stimulate the enzymatic activity of choline acetyltransferase in neurons, its low expression in the CA1 field of AD patients may explain the downregulation of cholinergic neurons seen in these patients and may thus contribute to the pathogenic processes underlying AD.
  • Characterizing CGI-94 (comparative gene identification-94) which is down-regulated in the hippocampus of early stage Alzheimer's disease brain, K Heese, T Nakayama, R Hata, M Masumura, H Akatsu, F Li, Y Nagai, T Yamamoto, K Kosaka, T Suemoto, T Sawada, EUROPEAN JOURNAL OF NEUROSCIENCE, 15, (1) 79 - 86,   2002年01月, 査読有り, The treatment of Alzheimer's disease (AD) remains a major challenge because of the incomplete understanding of the triggering events that lead to the selective neurodegeneration characteristic of AD brains, Here we describe a new protein, CGI-94, that is down-regulated at the mRNA level in the hippocampus of early stage AD brain. Transfection experiments with CGI-94 as a green fluorescent protein (GFP)-fusion-protein show that this protein is translocated into the nucleus of the cell. The finding that this protein, which has a bipartite nuclear localization signal, is also observed in the cytoplasm and extracellular space points to a multifunctional protein. Immunohistochemical analyses reveal that CGI-94 is mainly expressed in neurons of the hippocampal formation and the cortex but not in the cerebellar nucleus. In conclusion, the expression of the nucleolar phosphoprotein CGI-94 appears to be disturbed in early processes of neuronal degeneration.
  • Distribution of rat C5a anaphylatoxin receptor, H Akatsu, M Abe, T Miwa, H Tateyama, S Maeda, N Okada, K Kojima, H Okada, MICROBIOLOGY AND IMMUNOLOGY, 46, (12) 863 - 874,   2002年, 査読有り, The anaphylatoxim, complement 5a (C5a), plays a key role in mediating various inflammatory reactions following complement activation. Several investigators have reported that C5a receptor (C5aR) is expressed in non-myeloid cells under certain conditions or in different cell lines. In our study, the abundance of C5aR-positive myeloid cells in rats depended on the organs examined. C5aR was usually expressed at the site of exposure to pathogens, such as in salivary gland or lung, and was up-regulated in liver in the inflammatory state induced by lipopolysaccharide (LPS) administration. Furthermore, the increased expression of C5aR antigen was not accompanied by an increase in C5aR mRNA in Kupffer cells following LPS challenge.
  • Molecular cloning and partial characterization of rat procarboxypeptidase R and carboxypeptidase N, T Kato, H Akatsu, T Sato, S Matsuo, T Yamamoto, W Campbell, N Hotta, N Okada, H Okada, MICROBIOLOGY AND IMMUNOLOGY, 44, (8) 719 - 728,   2000年, 査読有り, Carboxypeptidase R (EC 3.4.17.20) (CPR) and carboxypeptidase N (EC 3.4.17.3) (CPN) cleave carboxy-terminal arginine or lysine residues from biologically active peptides such as kinins or anaphylatoxins in the circulation thereby regulating their activities, Although CPN is present in a stable active form in plasma, CPR is generated from proCPR, a plasma zymogen, by proteolytic enzymes such as thrombin, thrombin-thrombomodulin complex and plasmin, We have isolated rat proCPR and CPN cDNA clones which can induce enzymatic activities in culture supernatants of the transfected cells, mRNA of proCPR was detected only in rat liver by Northern hybridization and showed hepatocyte-specific expression. Expression of proCPR mRNA was enhanced following LPS injection, indicating that proCPR production is increased under inflammatory conditions.
  • Complication following percutaneous endoscopic gastrostomy: Acute respiratory infection and local skin infection, Kanie J, Shimokata H, Akatsu H, Yamamoto T, Iguchi A, Dig Endosc, 10, (3) 205 - 210,   1998年, 査読有り
  • SELECTIVE LOCALIZATION OF GELATINASE-A, AN ENZYME DEGRADING BETA-AMYLOID PROTEIN, IN WHITE-MATTER MICROGLIA AND IN SCHWANN-CELLS, T YAMADA, K MIYAZAKI, N KOSHIKAWA, M TAKAHASHI, H AKATSU, T YAMAMOTO, ACTA NEUROPATHOLOGICA, 89, (3) 199 - 203,   1995年03月, 査読有り, Gelatinase A is an enzyme capable of cleaving soluble beta-amyloid protein (beta AP), and may function as an alpha-secretase to produce secretory forms of amyloid precursor protein. We examined gelatinase A immunoreactivity in the brains and posterior roots of neurologically normal, lacunar stroke, Alzheimer disease (AD), amyotrophic lateral sclerosis, progressive supranuclear palsy and myasthenia gravis cases. The gelatinase A antibody stained only microglial cells in the white matter in all the brain tissues. In AD brain, the reactive microglia located in the center of classical senile plaques, as well as in other microglial cells in the gray matter, showed no immunoreactivity. Gelatinase A in white matter microglial cells may play a role in preventing local deposition of beta AP. In the posterior root, Schwann cells had positive immunoreactivity. As with other metalloproteases, gelatinase A in Schwann cells may play an antiproliferative role.

MISC

  • ワイドターゲットメタボロミクスによるアルツハイマー型認知症の早期診断マーカー探索, 六車 宜央, 筒井 陽仁, 井之上 浩一, 赤津 裕康, Dementia Japan, 33, (4) 566 - 566,   2019年10月
  • ヒト死後脳におけるAPP・APOEの遺伝子発現解析, Lixin Liu, 宮下 哲典, 村上 涼太, Bin Zhu, 原 範和, 菊地 正隆, 月江 珠緒, 樋口 陽, 春日 健作, 中谷 明弘, 赤津 裕康, 柿田 明美, 村山 繁雄, 池内 健, Dementia Japan, 33, (4) 519 - 519,   2019年10月
  • Flotillin is a novel diagnostic blood marker of Alzheimer’s disease, 道川誠, 木村成志, 赤津裕康, 橋詰良夫, タスリマ フェルドス, 鄒鶤, 松原悦朗, アブドラ モハンマド, Dementia Japan, 33, (4) 557 - 557,   2019年10月
  • 診断が遅延した播種性クリプトコックス症の1例, 田中 創始, 鈴木 美菜, 和知野 千春, 荒川 和幸, 正木 克由規, 兼松 孝好, 鈴木 幹三, 赤津 裕康, 中村 敦, 大原 弘隆, 日本病院総合診療医学会雑誌, 15, (5) 456 - 457,   2019年09月
  • 誘導体化反応を利用するLC-MSメタボロミクスの最前線 誘導体化LC-MS法による低分子代謝物分析の現在, 高山 卓大, 柳 浩由紀, 水野 初, 豊岡 利正, 井之上 浩一, 赤津 裕康, 轟木 堅一郎, JSBMS Letters, 44, (Suppl.) 52 - 52,   2019年08月
  • 認知症種別の早期鑑別診断を目指した多変量解析を用いる新規バイオマーカー探索, 六車 宜央, 赤津 裕康, 井之上 浩一, JSBMS Letters, 44, (Suppl.) 85 - 85,   2019年08月
  • 誘導体化反応を利用するLC-MSメタボロミクスの最前線 誘導体化LC-MS/MSを用いたディープラーニング搭載ワイドターゲットメタボロミクスの展開, 六車 宜央, 赤津 裕康, 井之上 浩一, JSBMS Letters, 44, (Suppl.) 50 - 50,   2019年08月
  • 誘導体化LC-MS法による低分子代謝物分析の現在, 高山 卓大, 柳 浩由紀, 水野 初, 豊岡 利正, 井之上 浩一, 赤津 裕康, 轟木 堅一郎, JSBMS Letters, 44, (Suppl.) 84 - 84,   2019年08月
  • CTガイド下腸腰筋膿瘍穿刺で診断した結核性脊椎炎・粟粒結核の1例, 田中 創始, 本間 静佳, 和知野 千春, 荒川 和幸, 正木 克由規, 兼松 孝好, 赤津 裕康, 中村 敦, 大原 弘隆, 日本病院総合診療医学会雑誌, 15, (4) 395 - 396,   2019年07月, 87歳女。周期的な弛張熱があり、近医からのレボフロキサシン投与による解熱と投与中止による再燃を繰り返していた。既往歴として陳旧性結核性胸膜炎と変形性腰椎症を有していた。発熱と腰痛を主訴に当院へ紹介となり、CTガイド下腸腰筋膿瘍穿刺による抗酸菌培養検査で結核性脊椎炎・粟粒結核の診断に至ったが、診断には難渋した。その要因として、レボフロキサシン投与により結核がマスキングされていたこと、腰痛の原因となりうる変形性腰椎症の既往があったこと、急性腎盂腎炎の症状(発熱・腰痛・膿尿)を認めたことなどが挙げられ、結核性脊椎炎診断における膿瘍穿刺・培養検査の重要性を認識させられた症例であった。
  • アルツハイマー病のバイオマーカー研究と疾患修飾薬開発研究の現在 認知症のプレシジョン医療実現に向けて 疾患再分類、層別化マーカーと血液コアマーカー, 森原 剛史, 永田 健一, 赤津 裕康, Paillard Luc, 池田 学, 老年精神医学雑誌, 30, (増刊II) 131 - 131,   2019年06月
  • 地域在住高齢者の身体フレイルに及ぼす影響因子の検討, 赤津 裕康, 間辺 利江, 川出 義浩, 正木 克由規, 田中 創始, 荒川 和幸, 兼松 孝好, 早川 富博, 大原 弘隆, 日本老年医学会雑誌, 56, (Suppl.) 117 - 117,   2019年05月
  • 介護・認知症予防の為の介入プログラムの有用性についての検証, 川出 義浩, 間辺 利江, 馬場 隆幸, 植屋 節子, 田村 清美, 森 圭子, 山下 英美, 山田 和政, 島田 裕之, 赤津 裕康, 日本老年医学会雑誌, 56, (Suppl.) 136 - 136,   2019年05月
  • 健康測定会がフレイルに及ぼす影響(身体無介入期間前後比較による行動変容)の検討, 赤津 裕康, 川出 義浩, 間辺 利江, 正木 克由規, 田中 創始, 荒川 和幸, 成瀬 兼人, 兼松 孝好, 山本 憲一, 大原 弘隆, 日本老年医学会雑誌, 56, (Suppl.) 146 - 146,   2019年05月
  • 神経病理学診断による認知症高齢者の生命予後期間に関するBPSDの影響について, 松岡 珠実, 間辺 利江, 赤津 裕康, 橋詰 良夫, 水上 勝義, 日本老年医学会雑誌, 56, (Suppl.) 171 - 171,   2019年05月
  • 神経病理学診断による認知症高齢者の生命予後期間に関するBPSDの影響について, 松岡 珠実, 間辺 利江, 赤津 裕康, 橋詰 良夫, 水上 勝義, 日本老年医学会雑誌, 56, (Suppl.) 171 - 171,   2019年05月
  • 介護・認知症予防の為の介入プログラムの有用性についての検証, 川出 義浩, 間辺 利江, 馬場 隆幸, 植屋 節子, 田村 清美, 森 圭子, 山下 英美, 山田 和政, 島田 裕之, 赤津 裕康, 日本老年医学会雑誌, 56, (Suppl.) 136 - 136,   2019年05月
  • 地域在住高齢者の身体フレイルに及ぼす影響因子の検討, 赤津 裕康, 間辺 利江, 川出 義浩, 正木 克由規, 田中 創始, 荒川 和幸, 兼松 孝好, 早川 富博, 大原 弘隆, 日本老年医学会雑誌, 56, (Suppl.) 117 - 117,   2019年05月
  • 健康測定会がフレイルに及ぼす影響(身体無介入期間前後比較による行動変容)の検討, 赤津 裕康, 川出 義浩, 間辺 利江, 正木 克由規, 田中 創始, 荒川 和幸, 成瀬 兼人, 兼松 孝好, 山本 憲一, 大原 弘隆, 日本老年医学会雑誌, 56, (Suppl.) 146 - 146,   2019年05月
  • 認知症患者への薬物治療が生命予後に及ぼす影響についての検討, 間辺 利江, 水上 勝義, 松岡 珠実, 小川 倫弘, 兼坂 岳志, 谷口 知恵, 山本 左近, 橋詰 良夫, 大原 弘隆, 山本 孝之, 赤津 裕康, 日本老年医学会雑誌, 56, (2) 171 - 180,   2019年04月
  • 2-ピコリルアミン誘導体化UHPLC-ESI-MS/MS法を用いた短鎖脂肪酸のマウス臓器分布解析, 長友 涼介, 福田 敦子, 市村 真祐子, 赤津 裕康, 常山 幸一, 井之上 浩一, 日本薬学会年会要旨集, 139年会, (2) 245 - 245,   2019年03月
  • キラルメタボローム研究の効率化のためのデータ解析ソフトウェアの開発, 高山 卓大, 水野 初, 豊岡 利正, 井之上 浩一, 赤津 裕康, 轟木 堅一郎, 日本薬学会年会要旨集, 139年会, (2) 273 - 273,   2019年03月
  • 誘導体化LC-MS/MS法によるアルツハイマー診断を目指した神経作動性ジペプチドの網羅解析の開発, 内田 和希, 六車 宜央, 筒井 陽仁, 赤津 裕康, 井之上 浩一, 日本薬学会年会要旨集, 139年会, (2) 245 - 245,   2019年03月
  • 診断が遷延した播種性クリプトコックス症の一例, 田中 創始, 和知野 千春, 赤津 裕康, 鈴木 幹三, 中村 敦, 感染症学雑誌, 93, (臨増) 412 - 412,   2019年03月
  • CTガイド下腸腰筋膿瘍穿刺で診断した結核性脊椎炎・粟粒結核の一例, 田中 創始, 和知野 千春, 赤津 裕康, 鈴木 幹三, 中村 敦, 感染症学雑誌, 93, (臨増) 397 - 397,   2019年03月
  • CAA症例のアクアポリン4発現異常に関する病理学的検討, 村賀 香名子, 新堂 晃大, 松尾 皇, 丹羽 篤, 赤津 裕康, 橋詰 良夫, 木村 和美, 冨本 秀和, 臨床神経学, 58, (Suppl.) S207 - S207,   2018年12月
  • CAA症例のアクアポリン4発現異常に関する病理学的検討, 村賀 香名子, 新堂 晃大, 松尾 皇, 丹羽 篤, 赤津 裕康, 橋詰 良夫, 木村 和美, 冨本 秀和, 臨床神経学, 58, (Suppl.) S207 - S207,   2018年12月
  • 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,   2018年09月15日
  • アルツハイマー病の新規発症メカニズム:Aβを制御するリスク遺伝子と分子パスウエイ, 森原剛史, 永田健一, PAILLARD Luc, 赤津裕康, 橋詰良夫, 吉山顕次, 池田学, Dementia Japan, 32,   2018年09月15日
  • リーリンシグナルがアルツハイマー病発症に与える影響, 大嶋智葉, 山影祐子, 河野孝夫, 斎藤貴志, 西道隆臣, 赤津裕康, 松川則之, 服部光治, 次世代を担う若手ファーマ・バイオフォーラム講演要旨集, 17th,   2018年09月
  • アルツハイマー病の新規発症メカニズム Aβを制御するリスク遺伝子と分子パスウエイ, 森原 剛史, 永田 健一, Paillard Luc, 赤津 裕康, 橋詰 良夫, 吉山 顕次, 池田 学, Dementia Japan, 32, (3) 425 - 425,   2018年09月
  • APOE遺伝型はAPPの遺伝子発現量に影響を及ぼすか? ヒト死後脳における検証, 村上 涼太, 朱 斌, 原 範和, 菊地 正隆, 月江 珠緒, 春日 健作, 宮下 哲典, 中谷 明弘, 赤津 裕康, 柿田 明美, 村山 繁雄, 池内 健, Dementia Japan, 32, (3) 429 - 429,   2018年09月
  • アルツハイマー型認知症の病理診断に基づく脳脊髄液・血液ペアのワイドターゲットメタボロミクス解析, 六車宜央, 筒井陽仁, 筒井陽仁, 赤津裕康, 赤津裕康, 井之上浩一, バイオメディカル分析科学シンポジウム講演要旨集, 31st,   2018年08月28日
  • Fmoc誘導体化LC‐MS/MSによる興奮性Glu/抑制性Gly受容体作動性ジペプチドの網羅解析, 内田和希, 六車宜央, 筒井陽仁, 筒井陽仁, 赤津裕康, 赤津裕康, 井之上浩一, バイオメディカル分析科学シンポジウム講演要旨集, 31st,   2018年08月28日
  • ワイドターゲットLC‐MS/MSメタボロミクス解析によるアルツハイマー型およびレビー小体型認知症の識別バイオマーカー探索, 六車宜央, 筒井陽仁, 筒井陽仁, 赤津裕康, 赤津裕康, 井之上浩一, JSBMS Letters, 43,   2018年08月25日
  • 長期経静脈鉄剤投与剖検症例での肝臓鉄沈着,死後血液鉄関連因子の関連性の検討, 赤津裕康, 赤津裕康, 川出義浩, 間辺利江, 間辺利江, 井上風吹, 井村尚斗, 日比英志, 荒川和幸, 正木克由規, 田中創始, 兼松孝好, 橋詰良夫, 常山幸一, 大原弘隆, 日本鉄バイオサイエンス学会学術集会プログラム・抄録集, 42nd,   2018年08月
  • ワイドターゲットLC-MS/MSメタボロミクス解析によるアルツハイマー型およびレビー小体型認知症の識別バイオマーカー探索, 六車 宜央, 筒井 陽仁, 赤津 裕康, 井之上 浩一, JSBMS Letters, 43, (Suppl.) 78 - 78,   2018年08月
  • 死亡患者からみた名市大病院における総合内科・総合診療科の現状と役割, 荒川和幸, 兼松孝好, 田中創始, 正木克由規, 藤原かおる, 赤津裕康, 赤津裕康, 吉田篤博, 大原弘隆, 日本病院総合診療医学会雑誌, 14,   2018年07月31日
  • Advance Care Planningに関するホームページ作成による地域医療教育実習の試み, 兼松孝好, 正木克由規, 赤津裕康, 田中創始, 荒川和幸, 大原弘隆, 医学教育, 49,   2018年07月01日
  • 死亡患者からみた名市大病院における総合内科・総合診療科の現状と役割, 荒川 和幸, 兼松 孝好, 田中 創始, 正木 克由規, 藤原 かおる, 赤津 裕康, 吉田 篤博, 大原 弘隆, 日本病院総合診療医学会雑誌, 14, (4) 393 - 393,   2018年07月
  • Advance Care Planningに関するホームページ作成による地域医療教育実習の試み, 兼松 孝好, 正木 克由規, 赤津 裕康, 田中 創始, 荒川 和幸, 大原 弘隆, 医学教育, 49, (Suppl.) 122 - 122,   2018年07月
  • 脂質過酸化物修飾タンパク質に着目した免疫化学的評価法の開発, 日坂真輔, 山川晴香, 近藤芳皓, 赤津裕康, 赤津裕康, 能勢充彦, 日本酸化ストレス学会学術集会プログラム・抄録集, 71st,   2018年04月19日
  • ヒト組織におけるABCA1,ABCA7蛋白の作用機構の解析, 戸田好信, 本庄原, 林田雅彦, 岡田光貴, 植田和光, 赤津裕康, 天理医療大学紀要, 6,   2018年03月
  • 認知症種別の病理診断に基づく脳脊髄液・血液ペアのワイドターゲットメタボロミクス解析, 六車 宜央, 筒井 陽仁, 赤津 裕康, 井之上 浩一, 日本薬学会年会要旨集, 138年会, (2) 285 - 285,   2018年03月
  • 誘導体化LC-MS/MS法によるマウス便中の分岐鎖短鎖脂肪酸のパターン解析, 岡田 泰毅, 長友 涼介, 赤津 裕康, 丸山 光生, 井之上 浩一, 日本薬学会年会要旨集, 138年会, (2) 285 - 285,   2018年03月
  • 脂質過酸化物修飾タンパク質の免疫化学的解析, 日坂 真輔, 山川 晴香, 近藤 芳皓, 赤津 裕康, 能勢 充彦, 日本薬学会年会要旨集, 138年会, (3) 75 - 75,   2018年03月
  • 地域高齢者住民に対する人工栄養に対する意識調査, 赤津 裕康, 正木 克由規, 田中 創始, 川出 義浩, 竹尾 淳, 兼松 孝好, 大原 弘隆, 日本静脈経腸栄養学会雑誌, 33, (Suppl.) 444 - 444,   2018年01月
  • 脂質過酸化物修飾タンパク質の免疫化学的解析, 日坂真輔, 山川晴香, 近藤芳皓, 赤津裕康, 赤津裕康, 能勢充彦, 日本薬学会年会要旨集(CD-ROM), 138th,   2018年
  • 認知症種別の病理診断に基づく脳脊髄液・血液ペアのワイドターゲットメタボロミクス解析, 六車宜央, 筒井陽仁, 筒井陽仁, 赤津裕康, 赤津裕康, 井之上浩一, 日本薬学会年会要旨集(CD-ROM), 138th,   2018年
  • ペクチン含有濃厚消化態流動食(ハイネイーゲル)の長期投与が栄養状態および消化管に及ぼす影響, 川出 義浩, 赤津 裕康, 丸山 光生, 大原 弘隆, 日本静脈経腸栄養学会雑誌, 33, (Suppl.) 507 - 507,   2018年01月
  • 誘導体化LC‐MS/MS法によるマウス便中の分岐鎖短鎖脂肪酸のパターン解析, 岡田泰毅, 長友涼介, 赤津裕康, 丸山光生, 井之上浩一, 日本薬学会年会要旨集(CD-ROM), 138th,   2018年
  • アルツハイマー病患者における脳ニューロン特異的なα1‐chimaerinの発現, 加藤智子, 小西吉裕, 下濱俊, BEACH T. G, 赤津裕康, 遠山育夫, 日本解剖学会総会・全国学術集会講演プログラム・抄録集, 123rd,   2018年
  • シナプス、軸索の変調から神経変性疾患を理解する FTLDモデルにおけるTDP-43とDISC1の共凝集による樹状突起での局所翻訳異常と精神障害の発現, 遠藤 良, 高嶋 紀子, 猫沖 陽子[町田], 小見 悠介, Hui Kelvin Kai-Wan, 高尾 昌樹, 赤津 裕康, 村山 繁雄, 澤 明, 田中 元雅, 生命科学系学会合同年次大会, 2017年度,   2017年12月
  • リーリン機能低下がアルツハイマー病に与える影響の解明, 大嶋 智葉, 山影 祐子, 赤津 裕康, 松川 則之, 服部 光治, 生命科学系学会合同年次大会, 2017年度,   2017年12月
  • ATBF1はAPP濃度に影響を及ぼす新規APP結合タンパク質である(ATBF1 is a novel APP binding protein that affects APP level), 鄭 且均, 川口 誠, 赤津 裕康, 道川 誠, Dementia Japan, 31, (4) 561 - 561,   2017年10月
  • アルツハイマー病に関する新規診断マーカー(A novel diagnostic marker for Alzheimer's disease), アブドラ・モハンマド, 木村 成志, 赤津 裕康, 橋詰 良夫, フェルドス・タスリマ, 松原 悦朗, 道川 誠, Dementia Japan, 31, (4) 612 - 612,   2017年10月
  • MCIとアルツハイマー病の血液バイオマーカーとしての補体タンパク質プロファイル, 劉 珊, 鈴木 秀昭, 目野 浩二, 赤津 裕康, 松川 則之, 新井 哲明, 朝田 隆, 内田 和彦, Dementia Japan, 31, (4) 610 - 610,   2017年10月
  • アルツハイマー病モデルマウスにおける脳特異的タンパク質α1-chimaerinの発現, 加藤 智子, 小西 吉裕, 下濱 俊, Beach T.G., 赤津 裕康, 椎野 顕彦, 遠山 育夫, Dementia Japan, 31, (4) 571 - 571,   2017年10月
  • ヒト、マウス組織におけるABCA1、ABCA7蛋白の作用機構の解析, 戸田 好信, 赤津 裕康, 植田 和光, 臨床病理, 65, (補冊) 183 - 183,   2017年10月
  • 安定同位体誘導体化を基盤とする高精度キラルメタボロミクスの開発とアルツハイマー病患者CSF解析, 高山卓大, 高山卓大, 水野初, 豊岡利正, 井之上浩一, 赤津裕康, 赤津裕康, 轟木堅一郎, バイオメディカル分析科学シンポジウム講演要旨集, 30th,   2017年08月28日
  • Fmoc誘導体化LC‐MS/MSを用いたヒト脳脊髄液中のアミノ酸骨格代謝系の網羅的定量分析, 六車宜央, 筒井陽仁, 筒井陽仁, 赤津裕康, 赤津裕康, 井之上浩一, バイオメディカル分析科学シンポジウム講演要旨集, 30th,   2017年08月28日
  • ピコリルアミン誘導体化法による短鎖脂肪酸のLC‐ESI‐MS/MS分析法の開発:腸内細菌叢解析への応用, 長友涼介, 岡田泰毅, 筒井陽仁, 筒井陽仁, 赤津裕康, 常山幸一, 井之上浩一, バイオメディカル分析科学シンポジウム講演要旨集, 30th,   2017年08月28日
  • 医療系学生による高齢者家庭訪問実習 2年目における意義の検証と課題の探索, 小嶋 雅代, 明石 惠子, 赤津 裕康, 浅井 清文, 大原 弘隆, 川出 義浩, 木村 和哲, 酒々井 眞澄, 鈴木 匡, 坡下 真大, 村上 里奈, 名古屋市立大学医療系学部・研究科連携教育委員会研究グループ, 医学教育, 48, (Suppl.) 142 - 142,   2017年08月
  • LC-HR/MSによるアルツハイマー病患者脳脊髄液のキラルメタボロミクス, 高山 卓大, 水野 初, 井之上 浩一, 赤津 裕康, 豊岡 利正, 轟木 堅一郎, JSBMS Letters, 42, (Suppl.) 106 - 106,   2017年08月
  • LC-MS/MSを用いたヒト脳脊髄液中におけるアルツハイマー病の新規バイオマーカー探索, 野田 巧, 六車 宜央, 筒井 陽仁, 赤津 裕康, 井之上 浩一, JSBMS Letters, 42, (Suppl.) 76 - 76,   2017年08月
  • ピコリルアミン誘導体化LC-MS/MSを用いた腸内細菌叢解析を目指した短鎖脂肪酸の網羅的分析法の開発, 長友 涼介, 岡田 泰毅, 筒井 陽仁, 赤津 裕康, 丸山 光生, 井之上 浩一, JSBMS Letters, 42, (Suppl.) 83 - 83,   2017年08月
  • 「高齢者家庭訪問実習」の意義の検証と課題の探索 なごやかモデルにおける試み, 小嶋 雅代, 浅井 大策, 石川 大貴, 木村 侑樹, 明石 惠子, 赤津 裕康, 大原 弘隆, 川出 義浩, 木村 和哲, 酒々井 眞澄, 鈴木 匡, 坡下 真大, 早野 順一郎, 村上 里奈, 山本 美由紀, 浅井 清文, 医学教育, 48, (4) 221 - 235,   2017年08月, 背景:医療系学生による高齢者家庭訪問実習の初年度の教育効果の検証。方法:実習に参加した医学部3年生5名、高齢者5名によるフォーカスグループインタビューを基に自記式調査用紙を作成し、医学部3年生、高齢者の全参加者に調査協力を依頼した。結果:学生84人と高齢者30人が協力に同意した。学生の74%が「高齢者の暮らしぶりが分かった」と回答し、高齢者の57%が「良い変化があった」と回答した。93%の高齢者が本実習に満足だったのに対し、学生の肯定的な意見は半数であった。考察:学生が本実習に積極的に取り組むためには、各自が明確な訪問への目的意識を持てるよう、入念な事前準備の必要性が示された。(著者抄録)
  • 感染を契機に急速に増大したが、緊急手術で救命し得た腹部大動脈瘤切迫破裂の1例, 田中 創始, 林 紘太郎, 荒川 和幸, 兼松 孝好, 赤津 裕康, 大原 弘隆, 須田 久雄, 日本病院総合診療医学会雑誌, 13, (1) 163 - 163,   2017年07月
  • 地域と育む未来医療人「なごやかモデル」~名古屋市立大学の取り組み~, 川出義浩, 赤津裕康, 鈴木匡, 土井愛美, 山口知香枝, 坡下真大, 村上里奈, 小嶋雅代, 明石惠子, 酒々井眞澄, 大原弘隆, 浅井清文, 木村和哲, 木村和哲, 人類働態学会会報(Web),   2017年06月16日
  • 地域再生と教育 地域で展開するIPE IPW 「なごやかモデル」を通した大学教育におけるIPEの取り組み, 小嶋 雅代, 赤津 裕康, 浅井 清文, 大原 弘隆, 木村 和哲, 酒々井 眞澄, 村上 里奈, 川出 義浩, 鈴木 匡, 坡下 真大, 山本 美由紀, 明石 惠子, 日本在宅医学会大会, 19回,   2017年06月
  • ビフィズス菌Bifidobacterium longum BB536の臨床効果, 赤津 裕康, 基礎老化研究, 41, (Suppl.) 67 - 67,   2017年06月
  • 高精度キラルメタボロミクスの開発とアルツハイマー患者分析への応用, 高山 卓大, 水野 初, 豊岡 利正, 井之上 浩一, 赤津 裕康, 轟木 堅一郎, JSBMS Letters, 42, (2) 39 - 40,   2017年06月
  • 認知症患者の肺炎による死亡の検討 システマティックレビュー&メタアナリシス, 間辺 利江, 水上 勝義, 赤津 裕康, 工藤 宏一郎, 日本老年医学会雑誌, 54, (Suppl.) 206 - 206,   2017年05月
  • 地域高齢者に対する死後も視野に入れたアドバンスケアプランニング(ACP)の意識調査, 赤津 裕康, 正木 克由規, 田中 創始, 近藤 麻央, 野崎 耀志郎, 長野 弘季, 伊藤 禎芳, 兼松 孝好, 大原 弘隆, 日本老年医学会雑誌, 54, (Suppl.) 166 - 167,   2017年05月
  • Fmoc誘導体化LC-MS/MS法による簡便なターゲットメタボロミクスの開発, 六車 宜央, 筒井 陽仁, 赤津 裕康, 井之上 浩一, 日本薬学会年会要旨集, 137年会, (2) 283 - 283,   2017年03月
  • ヒトアルツハイマー病、アルツハイマー病モデルマウスにおける神経細胞、グリア細胞の動態、ABCA7蛋白発現に関する研究, 戸田 好信, 末長 敏彦, 林田 雅彦, 岡田 光喜, 池本 正生, 植田 和光, 赤津 裕康, 天理医療大学紀要, 5, (1) 61 - 62,   2017年03月
  • 死後脳内において高頻度にコピー数多型(CNV)が観察された統合失調症3症例の臨床的特徴について, 長岡敦子, 國井泰人, 松本純弥, 和田明, 和田明, 日野瑞城, 丹羽真一, 那波宏之, 高橋均, 柿田明美, 赤津裕康, 赤津裕康, 赤津裕康, 赤津裕康, 橋詰良夫, 橋詰良夫, 山本左近, 山本左近, 尾関祐二, 矢部博興, 統合失調症研究, 7,   2017年03月01日
  • アルツハイマー病モデルマウス脳とβ‐amyloid添加時の海馬培養細胞におけるα1‐chimaerinの発現と局在について, 加藤智子, JAM Faidruz Azura, 小西吉裕, 椎野顯彦, 赤津裕康, 遠山育夫, 日本解剖学会総会・全国学術集会講演プログラム・抄録集, 122nd,   2017年
  • 3T MRIによる皮質微小梗塞の描出 CAAにおけるex vivo MRIと病理所見の直接比較, 丹羽 篤, 伊井 裕一郎, 松尾 皇, 伊藤 愛, 高瀬 伸一, 前田 正幸, 赤津 裕康, 橋詰 良夫, 冨本 秀和, 臨床神経学, 56, (Suppl.) S473 - S473,   2016年12月
  • 脳内Aβ蓄積規定因子Kinesin Light Chain-1 variant E(KLC1vE), 森原 剛史, 佐藤 真広, 赤津 裕康, Paillard Luc, 木村 展之, 鈴木 利治, 数井 裕光, 橋本 亮太, 武田 雅俊, 池田 学, Dementia Japan, 30, (4) 562 - 562,   2016年10月
  • Aβ産生抑制タンパク質ILEI/FAM3Cの脳内発現様式と加齢に伴う発現減少, 渡邊 直希, 劉 磊, 赤津 裕康, 西村 正樹, Dementia Japan, 30, (4) 564 - 564,   2016年10月
  • ALS患者脳に蓄積するTDP-43のプロテオミクス解析, 亀谷 富由樹, 小尾 智一, 宍戸 丈郎, 赤津 裕康, 村山 繁雄, 齊藤 祐子, 長谷川 成人, Dementia Japan, 30, (4) 596 - 596,   2016年10月
  • 培養細胞を用いた脳特異的に発現するα1-chimaerinとβ-amyloidの相互作用の検討, 加藤 智子, 小西 吉裕, 下濱 俊, Beach Thomas G., 赤津 裕康, 遠山 育夫, Dementia Japan, 30, (4) 563 - 563,   2016年10月
  • オルニチン回路/ポリアミン代謝経路を標的とした誘導体化LC‐MS/MS法の開発:アルツハイマー病理診断に基づくヒト脳脊髄液への応用, 六車宜央, 筒井陽仁, 筒井陽仁, 赤津裕康, 赤津裕康, 橋詰良夫, 井之上浩一, バイオメディカル分析科学シンポジウム講演要旨集, 29th,   2016年09月02日
  • アルツハイマー病モデルマウス脳の神経細胞、グリア細胞におけるABCA7蛋白発現に関する研究, 戸田 好信, 岡田 光貴, 赤津 裕康, 池本 正生, 植田 和光, 臨床病理, 64, (補冊) 5 - 6,   2016年09月
  • 培養細胞を用いたベータアミロイドと脳ニューロン特異的なα1-chimaerinの相互作用に関する検討, 加藤 智子, 小西 吉裕, 赤津 裕康, 山本 孝之, 河原 早苗, 遠山 育夫, 日本組織細胞化学会総会・学術集会講演プログラム・予稿集, 57回,   2016年09月
  • 脂質過酸化物由来の翻訳後修飾タンパク質の免疫化学的解析, 山川晴香, 日坂真輔, 近藤芳晧, 吉村知優里, 田嶋翔一, 赤津裕康, 赤津裕康, 大澤俊彦, 能勢充彦, 日本酸化ストレス学会学術集会プログラム・抄録集, 69th,   2016年08月30日
  • アルツハイマー病モデルマウス脳におけるABCA7蛋白発現に対するニコチンに関する研究, 戸田好信, 富岡麻衣子, 岡田光貴, 赤津裕康, 植田和光, 天理医療大学紀要, 4,   2016年08月
  • アルツハイマー病モデルマウス脳におけるABCA7蛋白発現に対するニコチンに関する研究, 戸田 好信, 富岡 麻衣子, 岡田 光貴, 赤津 裕康, 植田 和光, 天理医療大学紀要, 4, (1) 21 - 25,   2016年08月, [目的]ABCタンパク質はATP依存トランスポーターファミリーで、それらの異常はさまざまな疾病を引き起こすと考えられている。近年、ABCA7蛋白の一塩基多型とアルツハイマー病との関連を示唆することが報告された(Paul Hollingworth et al,Nature Gen.2011)。今年度においては、アルツハイマー病モデルマウスを用いて、46週齢まで飼育し、アルツハイマー病発症後、投与したニコチンの効果と神経細胞、グリア細胞、脳血管におけるABCA7、アミロイド前駆体蛋白質、βアミロイド、タウ蛋白質発現とアルツハイマー病発症との関わりを検討した。[方法]APP Tgマウス、老化促進マウス、および正常マウスに24週齢から46週齢までニコチン水溶液を、0.2mg/kg/マウスの割合で1週に1回皮下投与した。アルツハイマー病の発症後、46週齢でマウスを解剖して脳組織を摘出し、病理組織標本を作製しパラフィン標本を作製した。このスライドを用いてrabbit anti-GFAP、rabbit anti-Iba 1、mouse anti-Phospho PHF tau pSer 202/Thr 205、mouse anti-βAmyloid、rabbit anti-ssDNA、rabbit anti-LC3抗体を用いて免疫組織化学染色を行い検討した。[結果]1例15ヶ所の皮質部分においてニコチン投与群、生食投与群間の陽性細胞数を解析した。その結果、ニコチン投与群ではコントロール群に比してNeuN陽性細胞において有意な差が認められた。また、脳重量/解剖時体重においても有意な差が認められた。大脳皮質におけるIbal、GFAP、LC3の陽性細胞数においてはニコチン投与群において陽性細胞数は少ない傾向が見られた。[結論]APPTgマウス脳ではニコチン投与群で神経細胞の数が少なく、なおかつ脳の萎縮も進行していること、また、神経細胞質内にβアミロイド陽性所見の違いがあることから、発症初期からニコチン投与の関連が考えられるが、神経細胞障害との関連は今後の検討課題である。(著者抄録)
  • 多視点ビデオ撮影を用いた診療シミュレーション教育の効果, 兼松 孝好, 林 紘太郎, 荒川 和幸, 赤津 裕康, 正木 克由規, 大原 弘隆, 医学教育, 47, (Suppl.) 110 - 110,   2016年07月
  • tangle-predominant dementia(神経原線維変化型老年期認知症)の精神症状に関する多施設共同研究, 河上 緒, 新井 哲明, 新里 和弘, 大島 健一, 勝瀬 大海, 赤津 裕康, 橋詰 良夫, 池田 研二, 秋山 治彦, 精神神経学雑誌, 112th, (2016特別号) S532 - S532,   2016年06月
  • 認知症の自律神経障害 レビー小体型認知症の病理, 菱川 望, 橋詰 良夫, 赤津 裕康, 阿部 康二, 自律神経, 53, (2) 107 - 112,   2016年06月
  • 補体関連疾患の新局面 アルツハイマー病と補体とのかかわり―あらたな診断的アプローチと抗補体療法の可能性, 赤津裕康, 医学のあゆみ, 257,   2016年05月21日
  • 神経病理的に診断された認知症患者の肺炎合併の実態と予後の検討, 間辺 利江, 寺本 信嗣, 工藤 宏一郎, 赤津 裕康, 感染症学雑誌, 90, (3) 402 - 402,   2016年05月
  • 病理診断による認知症患者の肺炎死亡のリスク因子の検討, 間辺 利江, 水上 勝義, 赤津 裕康, 寺本 信嗣, 中村 誠司, 大久保 孝義, 工藤 宏一郎, 檜澤 伸之, 日本老年医学会雑誌, 53, (Suppl.) 143 - 144,   2016年05月
  • Aβ脳蓄積の鍵の一つとなる遺伝子産物の同定とアルツハイマー病血中バイオマーカーの開発, 森原 剛史, 佐藤 真広, 赤津 裕康, 林 紀行, Silverman Michael, Paillard Luc, 木村 展之, 橋本 亮太, 紙野 晃人, 武田 雅俊, 日本老年医学会雑誌, 53, (Suppl.) 127 - 128,   2016年05月
  • 【補体関連疾患の新局面】アルツハイマー病と補体とのかかわり あらたな診断的アプローチと抗補体療法の可能性, 赤津 裕康, 医学のあゆみ, 257, (8) 849 - 853,   2016年05月, 認知症のなかではアルツハイマー病(AD)の占める割合がもっとも多いが、発症前診断や根治薬開発には至っておらず、病因論的には大枠はとらえられつつあるものの、その本質はまだみえてこない。ADの原因物質とされるアミロイドβ(Aβ)の発見とほぼ時を同じくして老人斑に補体の沈着が報告されたことで、ADは一種の慢性炎症というとらえ方もされるようになった。その後、抗炎症薬での臨床トライアルが開始され、CR1の遺伝子多型がADリスク因子であるとの報告もなされ、ますます補体はAD病態に深くかかわっていると考えられている。さらに著者らは、おもに肝で産生されていると思われていたC3がADでの血液補助診断に使える可能性を報告した。また最近の報告では、C3aがAD脳障害の本質に深く絡み、C5aワクチンが治療に応用できる可能性がモデルマウスで報告されている。(著者抄録)
  • 薬学実務実習生の高齢者イメージに関する研究, 川出 義浩, 山本 美由紀, 江崎 哲夫, 坡下 真大, 岩尾 岳洋, 赤津 裕康, 早野 順一郎, 鈴木 匡, 木村 和哲, 日本薬学会年会要旨集, 136年会, (4) 211 - 211,   2016年03月
  • 脂質過酸化由来の翻訳後修飾タンパク質の解析, 日坂 真輔, 鶴見 沙樹, 澤野 亜矢, 近藤 芳皓, 吉村 知優里, 田嶋 翔一, 赤津 裕康, 大澤 俊彦, 能勢 充彦, 日本薬学会年会要旨集, 136年会, (3) 92 - 92,   2016年03月
  • 統合失調症患者死後脳前頭前皮質におけるAktシグナル伝達系蛋白質群の多項目同時測定, 日野瑞城, 國井泰人, 松本純弥, 和田明, 長岡敦子, 丹羽真一, 丹羽真一, 高橋均, 柿田明美, 赤津裕康, 赤津裕康, 橋詰良夫, 山本孝之, 矢部博興, 統合失調症研究, 6,   2016年03月01日
  • Amyloid‐β蓄積を抑制するILEI/FAM3Cのニューロンにおける発現とアルツハイマー病脳における発現低下, 渡邊直希, 劉磊, 赤津裕康, 西村正樹, 日本分子生物学会年会プログラム・要旨集(Web), 39th,   2016年
  • 3T MRIにおける皮質微小梗塞のin vivo検出 病理所見との比較(In Vivo Detection of Cortical Microinfarcts on 3T MRI: Compared with Pathology), 丹羽 篤, 伊井 裕一郎, 松尾 皇, 高瀬 伸一, 前田 正幸, 赤津 裕康, 橋詰 良夫, 冨本 秀和, 臨床神経学, 55, (Suppl.) S249 - S249,   2015年12月
  • Rac1 GTPase activating protein(GAP)であるalpha 1-chimaerinのアルツハイマー病患者における発現, 加藤 智子, 小西 吉裕, 下濱 俊, Beach T.G., 赤津 裕康, 遠山 育夫, 日本脳科学会プログラム・抄録集, 42回,   2015年11月
  • アルツハイマー病患者におけるヒト脳ニューロン特異的なα1‐chimaerinのmRNAとタンパク質の発現, 加藤智子, 小西吉裕, 赤津裕康, 山本孝之, 遠山育夫, 日本組織細胞化学会総会・学術集会講演プログラム・予稿集, 56th,   2015年10月03日
  • 最先端質量分析 マスプロファイリングからマスイメージングへ タウリンのイメージング質量分析, 松下 祥子, 正木 紀隆, 近藤 豪, 武井 史郎, 赤津 裕康, 秋田 天平, 杉山 栄二, 橋詰 良夫, 福田 敦夫, 瀬藤 光利, 臨床化学, 44, (Suppl.1) 167 - 167,   2015年10月
  • アルツハイマー病脳の神経細胞、グリア細胞におけるABCA7蛋白発現に関する研究, 戸田 好信, 岡田 光貴, 赤津 裕康, 池本 正生, 植田 和光, 臨床病理, 63, (補冊) 130 - 130,   2015年10月
  • アルツハイマー病患者におけるヒト脳ニューロン特異的なα1-chimaerinのmRNAとタンパク質の発現, 加藤 智子, 小西 吉裕, 赤津 裕康, 山本 孝之, 遠山 育夫, 日本組織細胞化学会総会・学術集会講演プログラム・予稿集, 56回, (56) 69 - 69,   2015年10月
  • ALS患者脳に異常蓄積したTDP-43の解析, 亀谷 富由樹, 小尾 智一, 宍戸 丈郎, 赤津 裕康, 村山 繁雄, 齊藤 祐子, 長谷川 成人, Dementia Japan, 29, (3) 422 - 422,   2015年09月
  • 軽度認知障害(MCI)の血液バイオマーカーとしてのAβ sequesterタンパク質, 劉 珊, 内田 和彦, 鈴木 秀昭, 田伏 洋, 西村 吉典, 広川 慶裕, 水上 勝義, 赤津 裕康, 目野 浩二, 朝田 隆, Dementia Japan, 29, (3) 389 - 389,   2015年09月
  • 脳内Aβ蓄積量を規定する遺伝子産物KLC1vEの同定とその機能解析, 森原 剛史, 佐藤 真広, 赤津 裕康, Paillard Luc, 林 紀行, 木村 展之, 鈴木 利治, 橋本 亮太, 柳田 寛太, 武田 雅俊, Dementia Japan, 29, (3) 337 - 337,   2015年09月
  • アルツハイマー病患者由来脳組織ならびに血清中の補体タンパク質の解析, 内田 和彦, 目野 浩二, 鈴木 秀昭, 是永 龍巳, 赤津 裕康, 朝田 隆, Dementia Japan, 29, (3) 390 - 390,   2015年09月
  • tangle-predominant dementiaの精神医学的特徴, 河上 緒, 新井 哲明, 新里 和弘, 大島 健一, 勝瀬 大海, 赤津 裕康, 橋詰 良夫, 池田 研二, 秋山 治彦, 東京都医学総合研究所認知症プロジェクト, Dementia Japan, 29, (3) 340 - 340,   2015年09月
  • 前頭側頭葉変性症患者脳内におけるタウリンの濃度および分布解析, 松下 祥子, 正木 紀隆, 近藤 豪, 武井 史郎, 赤津 裕康, 秋田 天平, 杉山 栄二, 福田 敦夫, 矢尾 育子, 瀬藤 光利, JSBMS Letters, 40, (Suppl.) 101 - 101,   2015年08月
  • アルツハイマー病脳における補体C3の発現解析, 赤津 裕康, 鈴木 秀昭, 小川 倫弘, 兼坂 岳志, 橋詰 良夫, 松川 則之, 大原 弘隆, 朝田 隆, 内田 和彦, 補体, 52, (1) 58 - 58,   2015年08月
  • なごやかモデルの紹介と超高齢社会における人工栄養のあり方, 赤津裕康, 日本在宅医療学会学術集会プログラム・抄録集, 26th,   2015年06月
  • 在宅医療・地域包括体制構築に向けた行政、地域、大学連携による調査, 赤津 裕康, 姜 き鎬, 笹野 弘美, 大原 弘隆, 日本老年医学会雑誌, 52, (Suppl.) 63 - 63,   2015年05月
  • 乳酸菌発酵成分配合流動食およびプレバイオティクスが経管栄養患者のインフルエンザワクチン抗体価に及ぼす影響, 永渕 真也, 栗原 リナ, 奥田 研爾, 高杉 諭, 山地 健人, 高見 正雄, 山本 孝之, 丸山 光生, 赤津 裕康, 腸内細菌学雑誌, 29, (2) 110 - 110,   2015年04月
  • アルツハイマー病モデルマウスの神経細胞、グリア細胞におけるニコチンの効果に関する研究, 戸田 好信, 竹田 真由, 岡田 光貴, 赤津 裕康, 池本 正生, 植田 和光, 日本病理学会会誌, 104, (1) 388 - 388,   2015年03月
  • 神経病理的に診断された認知症患者の肺炎合併の実態と予後の検討, 間辺利江, 間辺利江, 間辺利江, 寺本信嗣, 寺本信嗣, 工藤宏一郎, 赤津裕康, 赤津裕康, 日本感染症学会東日本地方会学術集会・日本化学療法学会東日本支部総会合同学会プログラム・抄録集, 64th-62nd,   2015年
  • マウス疾患感受性の2段階トランスクリプトミクス解析からアルツハイマー病修飾遺伝子KLC1vEの同定, 森原剛史, 佐藤真広, 赤津裕康, PAILLARD Luc, 林紀行, 橋本亮太, 柳田寛太, 山口由美, 角田達彦, 武田雅俊, 日本人類遺伝学会大会プログラム・抄録集, 60th,   2015年
  • 認知症から観たAIP, 赤津裕康, 日本生体医工学会大会プログラム・論文集(CD-ROM), 54th,   2015年
  • 在宅医療・高齢者医療における人工栄養の実態調査, 赤津裕康, 川出義浩, 正木克由規, 兼松孝好, 岩田彰, 早野順一郎, 大原弘隆, 日本在宅静脈経腸栄養研究会学術集会プログラム・抄録集, 12th,   2015年
  • 「なごやかモデル」の紹介と在宅医療・高齢者医療での人工栄養の実態調査, 赤津裕康, 川出義浩, 正木克由規, 兼松孝好, 岩田彰, 早野順一郎, 大原弘隆, 日本静脈経腸栄養学会雑誌, 30,   2015年
  • 認知症から観たAIP, 赤津 裕康, 生体医工学, 53, (0) S104_03 - S104_03,   2015年, 認知症の有病率は加齢とともに増加する。超高齢社会を迎え、今後、認知症患者は増加の一途をたどる。認知症はアルツハイマー病を中心とした神経変性疾患を主体とする症候であるが、社会的には行動心理症状(BPSD)が大きな問題となる。しかしBPSDは薬物療法よりも環境整備が重要であり家族、介護者のみならず地域全体で見守っていく体制が構築することが求められている。本年1月に厚生労働省より新オレンジプランが公表された。これは認知症の方も住みなれた場所で最後まで暮らせる事を目指した地域包括ケアの新たな提言である。認知症の予防、診断、治療を推し進めるとともに地域で認知症患者を支えていくためには見守りシステムや介護者支援をも含めた認知症への理解が医療職以外へも浸透させるのみならず学校教育でも展開されることが期待されている。当セッションでは医工学が認知症のあらゆる場面で重要であるかを概観したい。
  • 鳴子地区在住高齢者の健康状態・生活機能・認知機能の把握調査, 加藤 昇平, 赤津 裕康, 渕田 英津子, 生体医工学, 53, (0) S242_03 - S242_03,   2015年, With the goal of promoting a fruitful and healthy longevity society, we have conducted a field survey on health and life style of elderlies in Naruko Community in Nagoya, Japan. In addition, we have designed a verbally-based cognitive tasks to check the cognitive function and collected speech records and cerebral blood flow activation on frontal lobe from elderly participants during the tasks. We used portable near-infrared spectroscopy (NIRS) OEG-SpO2 (Spectratech Inc, Japan) to measure cerebral blood flow activation. Conducting this observational study longitudinally, we challenge to make a database which can contribute to the prospective cohort study of cognitive decline. In this survey, we have collect elderly's answers for three categorized questionnaires: 1) daily living environment and health condition, 2) nutritional status (including MNA-SF), 3) activities of daily living, and then we have conducted simultaneous voice-NIRS measurement during five cognitive tasks: 4) time orientation, 5) three or four digits backward, 6) daily conversation (season, travel, gourmet, and daily life) 7) category recall (animals and vegetables) 8) letter-number sequencing (working memory index from WAIS-III).
  • アルツハイマー型およびレビー小体型の病理所見を併せ持つ認知症例の臨床的特徴, 岩井 克成, 杉浦 実咲, 瀧田 亘, 杢野 謙次, 橋詰 良夫, 赤津 裕康, 臨床神経学, 54, (Suppl.) S136 - S136,   2014年12月
  • 剖検脳ex vivo MRの至適撮像条件 温度と組織コントラストの関連, 丹羽 篤, 伊井 裕一郎, 高瀬 伸一, 前田 正幸, 赤津 裕康, 橋詰 良夫, 冨本 秀和, 臨床神経学, 54, (Suppl.) S178 - S178,   2014年12月
  • 脳脊髄液中のアミロイドベーター40及び42(Aβ40 and 42)並びに蛋白質抱合アクロレイン(PC-Acro)による認知症重症度診断, 溝井 睦美, 吉田 円, 斎木 遼太郎, 藁谷 正明, 植村 研一, 赤津 裕康, 柏木 敬子, 五十嵐 一衛, 日本生化学会大会プログラム・講演要旨集, 87回,   2014年10月
  • ヒト剖検脳を用いたアルツハイマー病関連マイクロRNAの解析, 原 範和, 菊地 正隆, 宮下 哲典, 初田 裕幸, 齊藤 祐子, 村山 繁雄, 赤津 裕康, 池内 健, 桑野 良三, Dementia Japan, 28, (4) 476 - 476,   2014年10月
  • 質量分析法を基盤とする認知症患者病理試料のノンターゲット多変量解析, 井之上 浩一, 赤津 裕康, 山本 誠, 土屋 浩史, 宮崎 康人, 松川 則之, 橋詰 良夫, 道川 誠, 山本 孝之, 豊岡 利正, Dementia Japan, 28, (4) 482 - 482,   2014年10月
  • 認知症研究におけるCell Biology II 細胞内輸送 遺伝子研究からみえてきたこと アルツハイマー病理形成の原因としての細胞内輸送障害, 森原 剛史, 赤津 裕康, 佐藤 真広, 鈴木 利治, 木村 展之, 林 紀行, 柳田 寛太, 西道 隆臣, 紙野 晃人, 武田 雅俊, Dementia Japan, 28, (4) 432 - 432,   2014年10月
  • 喫煙者、非喫煙者アルツハイマー病脳の神経細胞、グリア細胞におけるABCA7蛋白発現に関する研究, 戸田 好信, 竹田 真由, 岡田 光喜, 赤津 裕康, 池本 正生, 植田 和光, 臨床病理, 62, (補冊) 160 - 160,   2014年10月
  • アルツハイマー病脳・血液のターゲットメタボロミクス解析, 井之上 浩一, 赤津 裕康, 土屋 浩史, 高山 卓大, 松川 則之, 橋詰 良夫, 山本 孝之, 豊岡 利正, JSBMS Letters, 39, (Suppl.) 72 - 72,   2014年09月
  • UHPLC‐MSを用いたアルツハイマー病の標的プロテオミクス/メタボロミクス統合解析, 山本誠, 井之上浩一, 赤津裕康, 松川則之, 橋詰良夫, 山本孝之, 豊岡利正, バイオメディカル分析科学シンポジウム講演要旨集, 27th,   2014年08月16日
  • アルツハイマー型認知症を対象としたメタボロミクス解析の応用, 井之上浩一, 赤津裕康, 土屋浩史, 高山卓大, 松川則之, 橋詰良夫, 山本孝之, 豊岡利正, バイオメディカル分析科学シンポジウム講演要旨集, 27th,   2014年08月16日
  • アルツハイマー病とアンギオテンシン変換酵素遺伝子多型の関連 連続病理解剖症例を用いて, 赤津 裕康, 山本 孝之, 大原 弘隆, 日本老年医学会雑誌, 51, (Suppl.) 50 - 51,   2014年05月
  • メタボロミクス的ターゲット解析によるアルツハイマー型認知症のバイオマーカー探索研究, 筒井 陽仁, 井之上 浩一, 赤津 裕康, 橋詰 良夫, 松川 則之, 道川 誠, 山本 孝之, 豊岡 利正, 日本薬学会年会要旨集, 134年会, (2) 272 - 272,   2014年03月
  • 統合失調症死後脳内タンパク質発現解析および発現量が変動した蛋白質の局在解析;質量分析法による網羅的及び標的指向的な二種の定量解析を用いて, 國井泰人, 大槻純男, 瀧澤陽平, 日野瑞城, 松本純弥, 和田明, 赤津裕康, 橋詰良夫, 山本孝之, 瀬藤光利, 寺崎哲也, 丹羽真一, 矢部博興, 統合失調症研究, 4,   2014年03月
  • 喫煙者、非喫煙者アルツハイマー病脳組織におけるABCA7蛋白発現及びグリア細胞に関する研究, 戸田 好信, 竹田 真由, 赤津 裕康, 池本 正生, 植田 和光, 日本病理学会会誌, 103, (1) 212 - 212,   2014年03月
  • 異常タンパク伝播仮説に基づく神経疾患の画期的治療法の開発 患者脳に蓄積した不溶化TDP‐43はプリオン様の性質を有する, 野中隆, 赤津裕康, 小尾智一, 吉田眞理, 村山繁雄, MANN David, 長谷川成人, 異常タンパク伝播仮説に基づく神経疾患の画期的治療法の開発 平成25年度 総括・分担研究報告書,   2014年
  • 疾患感受性のマウス系統間差をトランスクリプトーム解析:アルツハイマー病のAβ蓄積量を規定する遺伝子KLC1Eの同定, 森原嗣史, 佐藤真広, 角田達彦, 山口由美, 赤津裕康, 橋本亮太, 紙野晃人, 武田雅俊, 日本遺伝子診療学会大会プログラム・抄録集, 21st,   2014年
  • 病態に根ざしたALSの新規治療法開発 ALS,FTLD患者脳に存在する異常TDP‐43のプリオン様特性, 長谷川成人, 野中隆, 赤津裕康, 吉田眞理, 村山繁雄, MANN David, 秋山治彦, 神経変性疾患に関する調査研究班 分科班「病態に根ざしたALSの新規治療法開発」 平成25年度 研究報告書,   2014年
  • 異常タンパク伝播仮説に基づく神経疾患の画期的治療法の開発 αシヌクレインのプリオン様伝播, 長谷川成人, 鈴掛雅美, 久保真城, 野中隆, 赤津裕康, 吉田眞理, 村山繁雄, MANN David, 秋山治彦, 異常タンパク伝播仮説に基づく神経疾患の画期的治療法の開発 平成25年度 総括・分担研究報告書,   2014年
  • 乳酸菌(殺菌)配合ゼリー摂取が高齢者のインフルエンザワクチン接種に及ぼす影響, 赤津 裕康, 下野 智弘, 山本 孝之, 大原 弘隆, 丸山 光生, 静脈経腸栄養, 29, (1) 307 - 307,   2014年01月
  • IgG4関連全身硬化性疾患の1例, 清水 周哉, 宮部 勝之, 兼松 孝好, 荒川 和幸, 赤津 裕康, 大原 弘隆, 日本病院総合診療医学会雑誌, 5, (2) 121 - 122,   2013年12月
  • 高トリグリセライド血症で急性膵炎を発症した1例, 宮部 勝之, 大原 弘隆, 清水 周哉, 兼松 孝好, 荒川 和幸, 赤津 裕康, 大和 俊信, 中沢 貴弘, 林 香月, 内藤 格, 近藤 啓, 吉田 道弘, 山下 宏章, 梅村 修一郎, 堀 寧, 日本病院総合診療医学会雑誌, 5, (2) 111 - 112,   2013年12月
  • アルツハイマー病脳におけるオルニチン代謝産物関連因子の免疫組織化学的検討, 赤津 裕康, 筒井 陽仁, 井之上 浩一, 兼松 孝好, 豊岡 利正, 松川 則之, 橋詰 良夫, 大原 弘隆, 山本 孝之, Dementia Japan, 27, (4) 482 - 482,   2013年10月
  • 質量分析装置によるアルツハイマー病患者脳中におけるリン酸化HCNPの微量解析, 松川 則之, 保坂 大樹, 井之上 浩一, 赤津 裕康, 豊岡 利正, 小鹿 幸生, Dementia Japan, 27, (4) 482 - 482,   2013年10月
  • 晩期発症型アルツハイマー病とTREM2の関連解析, 宮下 哲典, 温 雅楠, 初田 裕幸, 村山 繁雄, 山口 晴保, 赤津 裕康, 柿田 明美, 高橋 均, 井原 康夫, 池内 健, 桑野 良三, JGSCAD(The Japanese Genetic Study Consortium for Alzheimer's Disease), Dementia Japan, 27, (4) 483 - 483,   2013年10月
  • ヒト脳メタボローム解析によるアルツハイマー病低分子バイオマーカー探索研究, 井之上 浩一, 筒井 陽仁, 赤津 裕康, 橋詰 良夫, 松川 則之, 山本 孝之, 豊岡 利正, Dementia Japan, 27, (4) 480 - 480,   2013年10月
  • 微細構造修飾アミロイドβのUPLC‐MS/MS分析法:アルツハイマー患者の脳組織への応用, 井之上浩一, 保坂大樹, 望月奈々, 土屋浩史, 赤津裕康, 松川則之, 橋詰良夫, 山本孝之, 豊岡利正, バイオメディカル分析科学シンポジウム講演要旨集, 26th,   2013年08月02日
  • アルツハイマー病脳のLC‐MSによるメタボローム解析, 筒井陽仁, 井之上浩一, 赤津裕康, 槁爪良夫, 松川則之, 山本孝之, 豊岡利正, バイオメディカル分析科学シンポジウム講演要旨集, 26th,   2013年08月02日
  • キラル誘導体化UPLC-MS/MSによるアルツハイマー病脳中の翻訳語修飾N-末端アミロイドβの解析, 保坂 大樹, 井之上 浩一, 赤津 裕康, 松川 則之, 橋詰 良夫, 山本 孝之, 豊岡 利正, JSBMS Letters, 38, (Suppl.) 79 - 79,   2013年08月
  • 【高齢者の栄養管理】高齢者の栄養障害 慢性期病棟における栄養状態とその管理, 赤津 裕康, 栄養-評価と治療, 30, (3) 202 - 205,   2013年08月, 医療法人さわらび会福祉村病院では、栄養サポートチーム(NST)の立ち上げ以前より経皮内視鏡的胃瘻造設(PEG)の導入を行っており、導入当初は経鼻胃管(NG)の相当数の症例がPEGに移行したが、現在では点滴栄養を希望される家族も多い状況を反映し、中心静脈からの高カロリー輸液法(CV/TPN)症例が増えた。しかし、CV/TPNはより高度な医療であり、その平均維持期間も10ヵ月に及ぶ。昨今、胃瘻は敬遠される風潮にあるが、その後の漫然とした継続を避ければ有用な場合もあり、適応となる時期も存在している。腸管を使用することはより自然であり、また新バイオティクスなどの介入により免疫能への働きかけも可能であるため、正しい知識に基づき患者、家族の意思を尊重した総合的な栄養管理が望まれる。(著者抄録)
  • 学習成果基盤型教育(CBME)に基づいた、診断推論に関するチーム基盤型学習(TBL)の導入と効果, 兼松 孝好, 赤津 裕康, 大原 弘隆, 早野 順一郎, 飯塚 成志, 吉田 篤博, 医学教育, 44, (Suppl.) 109 - 109,   2013年07月
  • 高度の全身浮腫と意識消失により発見された、反復性Systemic capillary leak syndromeの1例, 兼松 孝好, 荒川 和幸, 赤津 裕康, 友斉 達也, 村井 俊介, 豊田 剛成, 千田 勝博, 大原 弘隆, 日本病院総合診療医学会雑誌, 4, (2) 102 - 103,   2013年06月
  • 高齢者サルコペニアの栄養管理 基礎と臨床 高齢者への栄養介入の効果 最近の知見, 赤津 裕康, 日本老年医学会雑誌, 50, (Suppl.) 138 - 138,   2013年05月
  • 認知症の分析科学的アプローチ, 井之上浩一, 赤津裕康, 豊岡利正, ぶんせき, (3) 132 - 139,   2013年03月05日
  • ヒト脳メタボライトプロファイリングによるアルツハイマー病新規低分子バイオマーカー探索研究, 筒井 陽仁, 井之上 浩一, 赤津 裕康, 山本 孝之, 豊岡 利正, 日本薬学会年会要旨集, 133年会, (2) 295 - 295,   2013年03月
  • アルツハイマー病患者の脳組織中の不溶性アミロイドβに関する抽出法の検討, 望月 奈々, 井之上 浩一, 赤津 裕康, 山本 孝之, 豊岡 利正, 日本薬学会年会要旨集, 133年会, (2) 303 - 303,   2013年03月
  • キラル誘導体化UPLC-ESI-MS/MSによるアルツハイマー病脳中のN-末端光学異性アミロイドβの検出, 保坂 大樹, 望月 奈々, 井之上 浩一, 赤津 裕康, 山本 孝之, 豊岡 利正, 日本薬学会年会要旨集, 133年会, (2) 300 - 300,   2013年03月
  • 認知症の分析科学的アプローチ, 井之上 浩一, 赤津 裕康, 豊岡 利正, ぶんせき, (459) 132 - 139,   2013年03月
  • アルツハイマー病診療のスキルアップを考える この症例をどう診るか, 繁田 雅弘, 角 徳文, 井藤 佳恵, 和田 民樹, 赤津 裕康, 浦上 克哉, 老年精神医学雑誌, 24, (増刊I) 7 - 23,   2013年02月, 認知症医療の実践におけるコンセンサスを得る目的で、アルツハイマー病研究会に参加した医師を対象として症例を提示し、認知症医療の実地判断について尋ねた。診断や治療、マネジメント等にかかわる種々の判断についてトータライザーを通して回答を得、そのつどリアルタイムで表示して議論した。(著者抄録)
  • 死後脳の多施設共同研究に使用可能なリサーチリソースネットワークの構築に関する研究 確保されたリサーチリソースを用いた死後脳の多施設共同研究―本邦アルツハイマー病および統合失調症脳におけるβ‐secretase(BACE)の変化―, 小西吉裕, 三浦由真子, 吉田衣智子, 森本香織, 山田光則, 今野秀彦, 原口俊, 女屋光基, 藤村晴俊, 本田和弘, 村山繁雄, 赤津裕康, 國井泰人, 丹羽真一, 有馬邦正, SHEN Yong, 死後脳の多施設共同研究に使用可能なリサーチリソースネットワークの構築に関する研究 平成22-24年度 総括研究報告書,   2013年
  • 病態に根ざしたALSの新規治療法開発 シード依存的な細胞内TDP‐43蓄積細胞モデルの構築, 長谷川成人, 野中隆, 赤津裕康, 吉田眞理, 村山繁雄, DAVID Mann, 秋山治彦, 神経変性疾患に関する調査研究班分科班「病態に根ざしたALSの新規治療法開発」 平成24年度 研究報告書,   2013年
  • 末期高齢者の栄養アクセス, 赤津裕康, 山本佳代子, 岩橋有香, 河邊美名子, 中下洋子, 中神利恵子, 今川恵, 静脈経腸栄養, 28,   2013年
  • 筋萎縮性側索硬化症の分子病態解明と新規治療法創出に関する研究 患者脳に蓄積したTDP‐43のプリオン様性質, 野中隆, 赤津裕康, 小尾智一, 吉田眞理, 村山繁雄, MANN David, 長谷川成人, 筋萎縮性側索硬化症の分子病態解明と新規治療法創出に関する研究 平成24年度 総括・分担研究報告書,   2013年
  • 患者脳に蓄積したTDP‐43のプリオン様性質, 野中隆, 鈴掛(増田, 雅美, 新井哲明, 赤津裕康, 吉田眞理, 村山繁雄, 秋山治彦, 長谷川成人, 日本分子生物学会年会プログラム・要旨集(Web), 36th,   2013年
  • 筋萎縮性側索硬化症の分子病態解明と新規治療法創出に関する研究 ALS患者脳に蓄積するTDP‐43のプロテオミクス解析, 亀谷富由樹, 小尾智一, 宍戸丈郎, 赤津裕康, 村山繁雄, 齊藤祐子, 吉田眞理, 長谷川成人, 筋萎縮性側索硬化症の分子病態解明と新規治療法創出に関する研究 平成24年度 総括・分担研究報告書,   2013年
  • プレバイオティスク強化乳酸菌発酵成分配合流動食で経管栄養を行った老齢胃瘻モデルラットの腸内菌叢の変化, 芦田 欣也, 小川 沙織, 山地 健人, 高橋 毅, 赤津 裕康, 丸山 光生, 静脈経腸栄養, 28, (1) 401 - 401,   2013年01月
  • 長期療養型病院での終末期栄養管理の現状, 赤津 裕康, 山本 孝之, 静脈経腸栄養, 28, (1) 323 - 323,   2013年01月
  • 長期TPN管理高齢者での血中微量元素の検討, 赤津 裕康, 山本 孝之, 丸山 光生, 静脈経腸栄養, 28, (1) 450 - 450,   2013年01月
  • 経腸栄養患者および健常高齢者における腸内のビフィズス菌種構成, 小田巻 俊孝, 高橋 幸子, 清水 金忠, 安部 文明, 赤津 裕康, 丸山 光生, 近藤 順子, 大澤 朗, 静脈経腸栄養, 28, (1) 401 - 401,   2013年01月
  • 日本神経科学ブレインバンクネットワークの構築, 村山 繁雄, 齊藤 祐子, 高尾 昌樹, 赤津 裕康, 臨床神経学, 52, (12) 1581 - 1581,   2012年12月
  • アミロイドβタンパク質における脂質過酸化に由来する翻訳後修飾の解析, 日坂 真輔, 林 佳美, 赤津 裕康, 永井 雅代[社本], 加藤 陽二, 能勢 充彦, 丸山 和佳子, 大澤 俊彦, 日本生化学会大会プログラム・講演要旨集, 85回,   2012年12月
  • ヒト脳組織中アミロイドβを対象としたC‐末端フラグメントターゲットの超高感度UPLC‐MS/MSの開発, 井之上浩一, 望月奈々, 筒井陽仁, 赤津裕康, MIN Jun Zhe, 轟木堅一郎, 山本孝之, 豊岡利正, Chromatography, 33, (Supplement 2) 53 - 54,   2012年11月07日
  • 多価不飽和脂肪酸は酸化ストレスを介して神経変性疾患を惹起しうるか, 日坂真輔, 林佳美, 赤津裕康, 永井(社本)雅代, 加藤陽二, 能勢充彦, 丸山和佳子, 大澤俊彦, 衛生薬学・環境トキシコロジー講演要旨集, 2012,   2012年10月13日
  • 脳脊髄液・血液診断マーカーとしてのp3-Alcの解析, 羽田 沙緒里, 大森 智織, 浦上 克哉, 池内 健, 赤津 裕康, 朝田 隆, 鈴木 利治, Dementia Japan, 26, (4) 508 - 508,   2012年10月
  • ヒト鼻粘膜・嗅球におけるAβ解析と診断の可能性, 赤津 裕康, 井之上 浩一, 望月 奈々, 福原 崇臣, 山本 孝之, 橋詰 良夫, 豊岡 利正, 遠山 育夫, Dementia Japan, 26, (4) 509 - 509,   2012年10月
  • ABCA7の脳特異的発現および細胞内局在の免疫組織化学的解析, 戸田 好信, 國領 久美子, 富岡 麻衣子, 橋詰 良夫, 赤津 裕康, 植田 和光, 臨床病理, 60, (補冊) 218 - 218,   2012年10月
  • アルツハイマー病患者の鼻腔で検出されるアミロイドβの意義について, 清水志乃, 福原崇臣, 亀島直子, 南條俊文, 赤津裕康, 遠山育夫, 清水猛史, 日本鼻科学会会誌(Web), 51,   2012年09月25日
  • 嗅覚とその関連 アルツハイマー病患者の鼻腔で検出されるアミロイドβの意義について, 清水 志乃, 福原 崇臣, 亀島 直子, 南條 俊文, 赤津 裕康, 遠山 育夫, 清水 猛史, 日本鼻科学会会誌, 51, (3) 325 - 325,   2012年09月
  • Mass Microscopeを用いたヒト網膜組織の脂質イメージング解析, 早坂 孝宏, 井上 菜穂子, 正木 紀隆, 小川 倫弘, 兼坂 岳志, 堀 映, 赤津 裕康, 瀬藤 光利, JSBMS Letters, 37, (Suppl.) 79 - 79,   2012年09月
  • 半固形栄養材の物性による注入後カテーテル内残留量の比較, 蟹江 治郎, 赤津 裕康, 静脈経腸栄養, 27, (3) 923 - 928,   2012年05月, 【目的】半固形栄養材を胃瘻カテーテルへの注入後、その物性によりカテーテル内の残留量の差違を検証する。【方法】寒天により半固形状とした栄養材と粘度増強により半固形状とした栄養材を、各々胃瘻カテーテル内に注入した後にフラッシュを行い、カテーテル内の残留量を測定する。【結果】同じ半固形栄養材においても、その物性の差によって、注入後のカテーテルへの付着量に差違を認めた。【結論】寒天による半固形栄養材においては、その付着性が低いことから、注入後の注水によりカテーテル内の汚染が最小限に抑えられるものと考える。(著者抄録)
  • 高齢者における腸内のビフィズス菌種構成, 高橋 幸子, 小田巻 俊孝, 清水 金忠[肖], 岩附 慧二, 赤津 裕康, 近藤 順子, 大澤 朗, 腸内細菌学雑誌, 26, (2) 108 - 108,   2012年04月
  • 質量顕微鏡法による統合失調症死後脳の脂質解析, 松本純弥, 杉浦悠毅, 由木大, 國井泰人, 堤弘次, 和田明, 日野瑞城, 赤津裕康, 橋詰良夫, 山本孝之, 佐藤慎二, 池本桂子, 瀬藤光利, 丹羽真一, 統合失調症研究, 2,   2012年03月
  • 日本神経科学ブレインバンクネットワークの構築, 村山繁雄, 齊藤祐子, 高尾昌樹, 赤津裕康, 日本神経学会学術大会プログラム・抄録集, 53rd,   2012年
  • 半固形栄養材の物性による注入後カテーテル内残留量の比較, 蟹江治郎, 赤津裕康, 静脈経腸栄養, 27,   2012年
  • EPAをめぐって 経管栄養管理高齢者におけるEPA・DHA配合流動食介入によるアディポサイトカインへの影響, 赤津 裕康, 遠山 友紀子, 丸山 光生, 山本 孝之, 静脈経腸栄養, 27, (1) 279 - 279,   2012年01月
  • シンバイオティックス 高齢経腸栄養患者へのビフィズス菌長期投与による腸内細菌叢の検討, 赤津 裕康, 栗原 リナ, 奥田 研爾, 山本 孝之, 丸山 光生, 静脈経腸栄養, 27, (1) 269 - 269,   2012年01月
  • 医療圏の中で一貫した栄養評価・治療を行なう「東三河地域連携栄養カンファランス」の構築, 柴田 佳久, 平松 和洋, 酒井 秀樹, 高田 幸児, 竹内 勝彦, 金子 猛, 赤津 裕康, 岩間 克氏, 平岩 善喜, 下郷 宏, 小野沢 雄彦, 静脈経腸栄養, 27, (1) 479 - 479,   2012年01月
  • 機能性食品の発展性 乳酸菌発酵成分およびプレバイオティクス配合流動食が経腸栄養患者の腸内菌叢および獲得免疫に及ぼす影響, 赤津 裕康, 永渕 真也, 山地 健人, 川島 昭浩, 遠山 友紀子, 高橋 毅, 山本 孝之, 丸山 光生, 静脈経腸栄養, 27, (1) 243 - 243,   2012年01月
  • 老化に伴う脳神経の膜脂質過酸化は構造異常タンパク質の生成を介して神経変性に関与する, 丸山 和佳子, 山岡 朗子, 日坂 真輔, 大澤 俊彦, 赤津 裕康, 直井 信, 臨床神経学, 51, (12) 1406 - 1406,   2011年12月
  • 背景遺伝子が異なるAPP Tgマウスの網羅的解析により同定されたAbeta蓄積修飾遺伝子KLC1 splicing variantの同定 ヒトの脳、末梢リンパ球での発現解析, 横小路 美貴子, 森原 剛史, 林 紀行, 木村 展之, 赤津 裕康, 高村 明孝, 片山 泰一, 斎藤 有紀, 鈴木 利治, 加藤 希世子, 辰巳 真一, 柳田 寛太, 児玉 高志, 田中 稔久, 武田 雅俊, Dementia Japan, 25, (3) 418 - 418,   2011年10月
  • 多系統萎縮症患者脳ではγ-tubulinが減少しており、人工的γ-tubulin 2減少モデル動物は多系統萎縮症様の神経変性と運動失調を発症する(γ-Tubulins are decreased in the MSA patient brains and γ-tubulin 2-deficient mouse displays MSA-like neurodegeneration and ataxia), 堤 弘次, 久保 亜紀子, 高木 博, 赤津 裕康, 紺野 在, 宮本 裕子, 矢尾 育子, 江川 潔, 佐藤 尚武, 久保 亮治, 安武 かおり, 諸根 信弘, 山内 大輔, 堀尾 哲也, 木村 芳滋, 宮川 剛, 福田 敦夫, 塚田 秀夫, 吉田 眞理, 橋詰 良夫, 峰雪 芳宣, 小西 慶幸, 池上 浩司, 瀬藤 光利, 神経化学, 50, (2-3) 163 - 163,   2011年09月
  • 神経変性疾患関連タンパク質における脂質過酸化に由来する翻訳後修飾の解析, 日坂 真輔, 林 佳美, 赤津 裕康, 永井 雅代[社本], 加藤 陽二, 能勢 充彦, 丸山 和佳子, 大澤 俊彦, 日本生化学会大会プログラム・講演要旨集, 84回,   2011年09月
  • Clinical Nutrition Week 2011(A.S.P.E.N) に参加して, 赤津 裕康, 静脈経腸栄養 : 日本静脈経腸栄養学会機関誌 = The journal of Japanese Society for Parenteral and Enteral Nutrition, 26, (4) 1147 - 1148,   2011年07月25日
  • 経腸栄養成分が高齢者の獲得免疫/インフルエンザ抗体価に及ぼす影響, 赤津 裕康, 永渕 真也, 栗原 リナ, 奥田 研爾, 高杉 諭, 山地 健人, 高見 正雄, 山本 孝之, 丸山 光生, 静脈経腸栄養, 26, (4) 1149 - 1149,   2011年07月
  • アルツハイマー病とSORL1遺伝子多型との関連について, 木村 亮, 山本 美都子, 森原 剛史, 赤津 裕康, 工藤 喬, 紙野 晃人, 武田 雅俊, 日本老年医学会雑誌, 48, (4) 412 - 413,   2011年07月
  • 経管栄養管理高齢者へのDHA・EPA配合流動食介入による炎症指標および脂質・鉄代謝への影響, 赤津 裕康, 遠山 友紀子, 丸山 光生, 山本 孝之, 日本老年医学会雑誌, 48, (Suppl.) 81 - 81,   2011年05月
  • 栄養投与経路別にみたインフルエンザワクチン接種後の抗体価の動き, 赤津 裕康, 永渕 真也, 山本 孝之, 日本老年医学会雑誌, 48, (Suppl.) 67 - 67,   2011年05月
  • 全経過10年以上の確定アルツハイマー病の経過解析, 赤津 裕康, 山本 孝之, 日本老年医学会雑誌, 48, (Suppl.) 74 - 75,   2011年05月
  • 【病院・施設・在宅を結ぶ高齢者の栄養ケア】(Part 4)高齢者栄養ケアの実際 高齢者における胃瘻管理, 赤津 裕康, 臨床栄養, 118, (6) 658 - 669,   2011年05月
  • 高齢者における完全静脈栄養管理時のビタミンの検討, 赤津 裕康, 瀬藤 光利, 山本 孝之, 静脈経腸栄養, 26, (3) 977 - 983,   2011年05月, 【目的】ビタミン配合高カロリー輸液製剤を用いて高齢者の栄養管理を行った場合のビタミンB1、B6、C、葉酸の過不足を検討した。【方法】完全静脈栄養(total parenteral nutrition;以下、TPNと略)管理を要する必要水分量が1000mL前後の高齢な入院患者を対象とした。TPNは輸液量1000-1500mLを24時間持続点滴で投与した。追跡開始日、28日、56日、84日目に採血し、ビタミンB1、B6、C、葉酸の血中濃度を測定した。【結果】家族の同意が得られた17例の結果を得た。男性6例、女性11例で平均年齢は84.6±6.4歳(70歳-98歳)であった。追跡開始日において、平均血中ビタミンC濃度は平均3.7±1.9μg/mLと基準値(5.5-16.8μg/mL)より低かった。ビタミンC500mg/日を追加投与した6例の平均血中ビタミンC濃度は、基準値内に回復した(最終12.5±3.1μg/mL)。追加投与を行わなかった11例の平均血中ビタミンC濃度は低値のまま推移した(最終3.5±2.4μg/mL)。平均血中ビタミンB1濃度は基準値をやや上回る推移を示した。平均血中ビタミンB6濃度、平均血中葉酸濃度は基準値範囲内で推移した。【考察】TPNが必要な高齢者では、血中ビタミンC濃度が低下している可能性があり、ビタミン配合高カロリー輸液製剤の1000-1500mL/日投与では血中ビタミンC濃度が低値の持続を認めた。TPN管理が必要な高齢者では、定期的にビタミンCの血中濃度を測定し、補充する必要性が示唆された。(著者抄録)
  • 中部山岳国立公園内に開設13年目を迎えた山岳医療の現状, 佐藤 裕也, 黒川 英輝, 浅井 清文, 青木 康博, 赤津 裕康, 酒々井 眞澄, 間渕 則文, 中川 隆, 伊藤 友弥, 早川 純午, 薊 隆文, 藤堂 庫治, 松嶋 麻子, 坪井 謙, 小山 勝志, 菊池 篤志, 矢崎 蓉子, 土肥 名月, 西村 恭子, 野路 久仁子, 河辺 眞由美, 黒野 智恵子, 津田 洋幸, 森山 昭彦, 森田 明理, 三浦 裕, Nagoya Medical Journal, 51, (4) 216 - 217,   2011年03月
  • 死後脳の多施設共同研究に使用可能なリサーチリソースネットワークの構築に関する研究 確保されたリサーチリソースを用いた死後脳の多施設共同研究―本邦アルツハイマー病脳におけるβ‐secretase(BACE)の変化, 小西吉裕, 森本香織, 吉田衣智子, 山田光, 今野秀彦, 原口俊, 女屋光基, 杠岳文, 藤村晴俊, 本田和弘, 村山繁雄, 赤津裕康, BEACH Homas, SHEN Yong, 精神・神経疾患研究開発費による研究報告集(2年度班・初年度班) 平成22年度,   2011年
  • 老化に伴う脳神経の膜脂質過酸化は構造異常タンパク質の生成を介して神経変性に関与する, 丸山和佳子, 山岡朗子, 日坂真輔, 大澤俊彦, 赤津裕康, 直井信, 日本神経学会学術大会プログラム・抄録集, 52nd,   2011年
  • 高齢者における完全静脈栄養管理時のビタミンの検討, 赤津裕康, 瀬藤光利, 山本孝之, 静脈経腸栄養, 26,   2011年
  • 神経変性疾患関連タンパク質における脂質過酸化に由来する翻訳後修飾の解析, 日坂真輔, 林佳美, 赤津裕康, 永井(社本)雅代, 加藤陽二, 能勢充彦, 丸山和佳子, 大澤俊彦, 生化学,   2011年
  • 高齢経腸・静脈栄養管理患者における腸内菌叢及びインフルエンザ抗体価と栄養状態の検討, 赤津 裕康, 山本 孝之, 丸山 光生, 静脈経腸栄養, 26, (1) 384 - 384,   2011年01月
  • 高齢者経管栄養管理におけるフラクトオリゴ糖(FOS)介入による腸管環境改善の試み, 赤津 裕康, 遠山 友紀子, 丸山 光生, 山本 孝之, 静脈経腸栄養, 26, (1) 392 - 392,   2011年01月
  • 経管栄養管理高齢者へのDHA・EPA配合流動食介入による炎症指標および脂質・鉄代謝への影響, 遠山 友紀子, 小橋 修, 山本 孝之, 赤津 裕康, 静脈経腸栄養, 26, (1) 380 - 380,   2011年01月
  • 経腸栄養成分が高齢者の獲得免疫/インフルエンザ抗体価に及ぼす影響, 赤津 裕康, 永渕 真也, 栗原 リナ, 奥田 研爾, 高杉 諭, 山地 健人, 高見 正雄, 山本 孝之, 丸山 光生, 静脈経腸栄養, 26, (1) 182 - 182,   2011年01月
  • プロバイオティクスの経腸栄養管理高齢者への応用 ビフィズス菌長期投与による生体防御改善, 赤津 裕康, 清水 金忠, 松山 善次郎, 栗原 リナ, 小川 康一, 奥田 研爾, 山本 孝之, 丸山 光生, 静脈経腸栄養, 26, (1) 213 - 213,   2011年01月
  • 胃ろう導入17年目 長期療養型病院での胃瘻造設645例の予後解析, 赤津 裕康, 蟹江 治郎, 山本 孝之, 静脈経腸栄養, 26, (1) 479 - 479,   2011年01月
  • Clinical Nutrition Week 2011 (A.S.P.E.N) に参加して, 赤津 裕康, 静脈経腸栄養, 26, (4) 1147 - 1149,   2011年
  • シヌクレイノパチーマウス及び細胞モデルにおけるリソソーム病変と糖脂質の蓄積, 藁谷 正明, 関川 明生, 藤田 雅代, 関山 一成, 赤津 裕康, 魏 建設, 橋本 款, 臨床神経学, 50, (12) 1083 - 1083,   2010年12月
  • アルツハイマー病モデルマウス大脳皮質に発現するヘパラン硫酸グリコサミノグリカンの構造解析, 細野 友美, 新美 しおり[大竹], モタラブ・ホサイン, 菅谷 典子, 赤津 裕康, トニー・ワイスコレイ, 木全 弘治, 道川 誠, 内村 健治, 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, 83回・33回,   2010年12月
  • 【ブレインバンク】療養型病床群を基盤とする福祉村ブレインバンクと内外連携, 赤津 裕康, BRAIN and NERVE: 神経研究の進歩, 62, (10) 1043 - 1052,   2010年10月
  • 異なる背景遺伝子を持つAPP Tgマウスの解析によるアミロイド蓄積量修飾遺伝子KLC1の同定, 横小路 美貴子, 林 紀行, 赤津 裕康, 辰巳 真一, 加藤 希世子, 柳田 寛太, 児玉 高志, 森 康治, 田上 真次, 大河内 正康, 田中 稔久, 工藤 喬, 森原 剛史, 武田 雅俊, Dementia Japan, 24, (3) 390 - 390,   2010年09月
  • 脳神経の膜脂質過酸化は構造異常タンパク質の生成を介して神経変性に関与する, 丸山 和佳子, 日坂 真輔, 永井 雅代, 能勢 弓, 加藤 陽二, 大澤 俊彦, 赤津 裕康, 直井 信, Dementia Japan, 24, (3) 306 - 306,   2010年09月
  • Alcadeinのγセクレターゼ代謝産物p3-Alcの血中からの抽出と定量, 今野 禎子, 羽田 沙緒里, 中矢 正, 濱田 由紀子, 前田 雅弘, 桑野 良三, 赤津 裕康, 鈴木 利治, Dementia Japan, 24, (3) 388 - 388,   2010年09月
  • アルツハイマー病患者における髄液、血液、尿中Alcadein断片測定の検討, 赤津 裕康, 今野 禎子, 羽田 沙緒里, 小川 倫弘, 兼坂 岳志, 山本 孝之, 鈴木 利治, Dementia Japan, 24, (3) 310 - 310,   2010年09月
  • アルツハイマー病モデルマウス脳内に発現するヘパラン硫酸糖鎖の内部ドメイン構造の解析, 細野 友美, 新美 しおり, Hossain Md. Motarab, Britschgi Markus, 赤津 裕康, 木全 弘治, 道川 誠, Wyss-Coray Tony, 内村 健治, Dementia Japan, 24, (3) 393 - 393,   2010年09月
  • APP代謝及びAβ産生におけるATBF1(AT-motif binding factor 1)の機能解析, 厳 景玉, 赤津 裕康, 三浦 裕, 道川 誠, 鄭 且均, Dementia Japan, 24, (3) 370 - 370,   2010年09月
  • 脳疾患解明に向けた死後脳研究の新展開 脳バンクの重要性 神経科学ブレインバンクネットワークの構築(New trends in the postmortem brain studies of neuropssychietric diseases Establishment of Japanese Brain Bank Network for Neuroscience Research), 村山 繁雄, 齊藤 祐子, 高尾 昌樹, 赤津 裕康, 神経化学, 49, (2-3) 451 - 451,   2010年08月
  • APP代謝及びAβ産生機構におけるホメオティック因子ATBF1の機能解析(The role of ATBF1 in APP processing and β generation), 鄭 且均, 厳 景玉, 三浦 裕, 赤津 裕康, 道川 誠, 神経化学, 49, (2-3) 666 - 666,   2010年08月
  • 質量顕微鏡法によるヒト脳脂質の分子イメージング(Molecular imaging of lipids in the human brain by mass spectrometry), 由木 大, 財満 信宏, 杉浦 悠毅, 赤津 裕康, 橋詰 良夫, 山本 孝之, 藤原 正美, 杉山 圭吉, 瀬藤 光利, 神経化学, 49, (2-3) 689 - 689,   2010年08月
  • Alcadein断片血中測定によるアルツハイマー病血液スクリーニング法の確立, 赤津 裕康, 山本 孝之, 日本老年医学会雑誌, 47, (Suppl.) 66 - 66,   2010年05月
  • (末期)高齢者の栄養管理 経管栄養腸管環境を中心に, 赤津 裕康, 日本老年医学会雑誌, 47, (Suppl.) 126 - 127,   2010年05月
  • 免疫と老化 経腸栄養管理高齢者へのプレバイオティックス介入のインフルエンザ抗体価に及ぼす影響, 赤津 裕康, 山本 孝之, 丸山 光生, 基礎老化研究, 34, (2) 36 - 36,   2010年05月
  • リサーチリソースネットワークを用いた神経・精神疾患の研究資源(剖検脳等)の確保と病態解明を目指した研究 新鮮剖検脳よりの培養細胞バンクの構築へ向け(1)グリア細胞培養 H19年度, 小西吉裕, 赤津裕康, 堀映, 山本孝之, リサーチリソースネットワークを用いた神経・精神疾患の研究資源(剖検脳等)の確保と病態解明を目指した研究 平成19-21年度 総括研究報告書,   2010年
  • シヌクレイノパチーマウス及び細胞モデルにおけるリソソーム病変と糖脂質の蓄積, 藁谷正明, 関川明生, 藤田雅代, 関山一成, 赤津裕康, 魏建設, 橋本款, 日本神経学会総会プログラム・抄録集, 51st,   2010年
  • リサーチリソースネットワークを用いた神経・精神疾患の研究資源(剖検脳等)の確保と病態解明を目指した研究 確保されたリサーチリソースのグリア細胞培養の確立と細胞バンク化への体制作り H21年度, 小西吉裕, 森本香織, 堀尾樹里, 兼坂岳志, LINDHOLM Kiristina, 赤津裕康, 堀映, 奥田研爾, 山本孝之, SHEN Yong, リサーチリソースネットワークを用いた神経・精神疾患の研究資源(剖検脳等)の確保と病態解明を目指した研究 平成19-21年度 総括研究報告書,   2010年
  • 経腸栄養成分が高齢者の獲得免疫/インフルエンザ抗体価に及ぼす影響, 赤津 裕康, 永渕 真也, 栗原 リナ, 奥田 研爾, 高杉 諭, 山地 健人, 高見 正雄, 山本 孝之, 丸山 光生, 静脈経腸栄養, 25, (1) 182 - 182,   2010年01月
  • 高齢者におけるTPN管理時のビタミンの検討, 赤津 裕康, 瀬藤 光利, 山本 孝之, 静脈経腸栄養, 25, (1) 311 - 311,   2010年01月
  • アルツハイマー病新規診断マーカーとしての糖タンパクの解析, 谷口 美也子, 岡山 由佳, 古川 勝敏, 荒井 啓行, 赤津 裕康, 浦上 克哉, 臨床神経学, 49, (12) 1003 - 1003,   2009年12月
  • 高カロリー輸液にて栄養管理している高齢者における栄養・微量元素の推移に関する研究, 赤津 裕康, 伊苅 弘之, 松山 善次郎, 小橋 修, 瀬藤 光利, 山本 孝之, 新薬と臨牀, 58, (11) 1921 - 1930,   2009年11月, 平成20年6〜9月の入院患者(脳血管障害、末期認知症等)で経口摂取及び経管栄養管理が何らかの理由で不可能な中心静脈栄養(TPN)適応症例で65歳以上、文書による同意が得られた除外例を除く18例(男6例、女12例、70〜98歳・平均83.8±6.8歳)を対象に、栄養・微量元素の推移を評価した。84日間(12週)、TPNを実施し、高カロリー輸液用微量元素製剤1管(2mL)を投与し、各微量元素の配合量の妥当性を血中濃度推移から検討した。血清Fe、Zn、Cu、T3、T4濃度、血液Mn濃度の各平均値は試験開始日に比べ維持が可能であった。高カロリー輸液用微量元素製剤を混合調製した総合ビタミン配合型高カロリー輸液製剤は、高齢者においても適切に用いれば微量元素濃度と栄養状態が維持された。
  • 脊髄発育異常の病理学 脊髄神経根の走行異常, 堀 映, 赤津 裕康, 脊椎脊髄ジャーナル, 22, (10) 1095 - 1101,   2009年10月
  • 生体内脂質過酸化による神経傷害機構の化学的解明, 日坂 真輔, 林 佳美, 加藤 陽二, 赤津 裕康, 丸山 和佳子, 大澤 俊彦, 日本生化学会大会プログラム・講演要旨集, 82回,   2009年09月
  • アルツハイマー病脳アミロイド沈着におけるRB4CD12抗体認識ヘパラン硫酸鎖内部ドメインの蓄積, 細野 友美, ホサイン・モタラブ, Britschgi Markus, 赤津 裕康, 道川 誠, van Kuppevelt Toin, Wyss-Coray Tony, 内村 健治, 日本生化学会大会プログラム・講演要旨集, 82回,   2009年09月
  • アルツハイマー病態脳におけるヘパラン硫酸鎖内部ドメインの発現解析, 細野友美, HOSSAIN Motarab, BRITSCHGI Markus, 赤津裕康, 道川誠, VAN KUPPEVELT Toin, WYSS‐CORAY Tony, 内村健治, 日本糖質学会年会要旨集, 29th,   2009年08月10日
  • 富山湾海洋深層水から調整した等張液による創傷治癒促進効果 in vitro study, 常山 幸一, 赤津 裕康, 溝口 訓弘, 藤井 侃, 日本褥瘡学会誌, 11, (3) 369 - 369,   2009年08月
  • 褥瘡洗浄液およびスキンケア(褥瘡予防)としての海洋深層水の有用性について, 赤津 裕康, 溝口 訓弘, 小橋 修, 山本 孝之, 藤井 侃, 常山 幸一, 日本褥瘡学会誌, 11, (3) 402 - 402,   2009年08月
  • 血清ペプチドミクスによるアルツハイマー病・MCIの血液診断マーカーの同定, 内田 和彦, 石井 俊, 目野 浩二, 鈴木 秀昭, 永島 廉平, 浅島 誠, 赤津 裕康, 水上 勝義, 朝田 隆, Dementia Japan, 23, (2) 185 - 185,   2009年08月
  • アルツハイマー病態脳におけるヘパラン硫酸糖鎖多硫酸化ドメインの発現解析, 細野 友美, ホサイン・モタラブ, Britschgi Markus, 赤津 裕康, 道川 誠, van Kuppevelt Toin, Wyss-Coray Tony, 内村 健治, Dementia Japan, 23, (2) 209 - 209,   2009年08月
  • 褥瘡洗浄液としての海洋深層水試用経験, 赤津 裕康, 伊苅 弘之, 小橋 修, 山本 孝之, 藤井 侃, 常山 幸一, 日本老年医学会雑誌, 46, (Suppl.) 80 - 80,   2009年05月
  • 生体内脂質過酸化による酸化傷害機構の化学的解明, 日坂真輔, 林佳美, 加藤陽二, 赤津裕康, 丸山和佳子, 大澤俊彦, 日本農芸化学会大会講演要旨集, 2009,   2009年03月05日
  • 【アルツハイマー病診療のスキルアップを考える】アルツハイマー病診療のスキルアップを考える この症例をどうみるか, 浦上 克哉, 田北 昌史, 繁田 雅弘, 中川 正法, 清水 秀明, 根本 清貴, 赤津 裕康, 老年精神医学雑誌, 20, (増刊I) 7 - 24,   2009年02月, アルツハイマー病研究会はわが国の認知症の専門医が参加する会である。プレナリーセッション1は参加者にトータライザーを用いて回答をしていただき、コンセンサスを知り議論を深めるものである。今回は、「高度アルツハイマー病とドネペジル10mgによる治療」「著明な語想起障害と理解の障害がみられたアルツハイマー病」「軽度認知機能障害の診断とアルツハイマー病への移行について」「多系統萎縮症とアルツハイマー病の合併と考えられた剖検例」の4症例が提示され、問題点が議論された。(著者抄録)
  • 政策的に対応を要する疾患等の予防診断・治療法等の開発に関する研究 経口脂肪酸摂取によるアルツハイマー病の発症予防法開発に関する研究, 道川誠, 河島洋, 紺谷昌仙, 赤津裕康, 政策創薬総合研究研究報告書 平成20年度,   2009年
  • レビー小体型痴呆症(DLB)患者脳の海馬・前頭葉・側頭葉を用いた比較定量プロテオミクス解析, 横銭 拓, 石井 俊, 赤津 裕康, 朝田 隆, 内田 和彦, 日本プロテオーム学会大会要旨集, 2009, (0) 36 - 36,   2009年, The dementia with Lewy bodies (DLB) shows the important associations with the Parkinson disease and the Alzheimer disease (AD). In this study, quantitative proteome analysis of DLB brains was performed using fluorescent two-dimensional difference gel electrophoresis (2-D DIGE) to identify disease-specific changes in protein expression. We compared signals corresponding to individual proteins between post mortem brain tissues from DLB patients and those from age-matched nondemented controls (NDC). In order to provide a more complete picture of pathogenesis in DLB, we investigated proteins from three brain tissues such as hippocampus, frontal cortex and occipital cortex. We detected 30 spots as differentially expressed proteins in hippocampus, 41 spots in frontal cortex and 73 spots in occipital cortex. Among them we identified 33 proteins and found that most of proteins are related to oxidative stress or mitochondrial glycolysis. As noted, we found that septin 8, a member of family proteins whose functions are involved in cell polarity, cytoskeletal remodeling, vesicle transport and cell cycle progression, was increased in all tissues from DLB. Taken together, our findings support the hypothesis that both mitochondrial dysfunction and oxidative stress are involved in the pathogenesis of neurodegenerative disease and in addition, propose septin 8 as a novel protein possibly involved in the pathogenesis of DLB.
  • 福祉村病院における栄養サポートチーム(NST)の介入が及ぼした影響について, 赤津裕康, 宮本圭子, 山本淑子, 堀映, 小橋修, 小阪憲司, 山本孝之, 鳥取臨床科学研究会誌, 1, (1) 47 - 53,   2008年12月
  • 福祉村病院における栄養サポートチーム(NST)の介入が及ぼした影響について, 赤津 裕康, 宮本 圭子, 山本 淑子, 堀 映, 小橋 修, 小阪 憲司, 山本 孝之, 鳥取臨床科学研究会誌, 1, (1) 47 - 53,   2008年12月, 福祉村病院で栄養サポートチーム(NST)の稼動が始まって3年が経過した.持ち寄りパーティー方式で栄養士,薬剤師,医師に各看護単位での担当看護師を構成員として,回診,ミーティング,勉強会を軸に活動を行っている.全患者への栄養アセスメントはbody mass index(BMI)を中心とした一般身体観察,主観的包括的評価(subjective global assessment:SGA)と栄養不良者に対しては客観的データ評価(Objective data assessment:ODA)を行い,開始1ヵ月,3ヵ月,6ヵ月,12ヵ月後に経過を追った.今回の解析では目立った成果は見出せなかった.それは1992年より内視鏡的胃瘻造設術(percutaneous endoscopic gastrostomy:PEG)が導入されて間接的に栄養経路の検討,栄養介入の体制が確立されていた点が考えられる.しかし老人病院ゆえの問題点もいくつか浮き彫りにされた.(著者抄録)
  • AβはATBF1の発現を上昇させ神経細胞死を誘導する(Aβ enhance the ATBF1 expression responsible for the neuronal cell death), 鄭 且均, 川口 誠, 三浦 裕, 赤津 裕康, 金 康善, 道川 誠, 神経化学, 47, (2-3) 258 - 258,   2008年08月
  • アルツハイマー病患者での血中Aβとアンギオテンシン変換酵素活性相関解析, 赤津 裕康, 小川 倫弘, 兼坂 岳志, 山本 孝之, 道川 誠, Dementia Japan, 22, (2) 137 - 137,   2008年08月
  • コットンウールプラーク型アルツハイマー病の1剖検例, 山懸 英久, 鎌田 一億, 宮崎 龍彦, 田邉 敬貴, 三木 哲郎, 赤津 裕康, 山本 孝之, 堀 映, 和氣 現人, 渡部 一郎, 木村 尚人, 三室 アヤ, 吉田 眞理, 橋詰 良夫, 臨床神経学, 48, (7) 525 - 525,   2008年07月
  • Dynamin 2 gene is a novel susceptibility gene for late-onset Alzheimer disease in non-APOE-ε4 carriers, Aidaralieva Nuripa Jenishbekovna, Kamino Kouzin, Kimura Ryo, YAMAMOTO Mitsuko, MORIHARA Takeshi, KAZUI Hiroaki, HASHIMOTO Ryota, TANAKA Toshihisa, KUDO Takashi, KIDA Tomoyuki, OKUDA Jun-Ichiro, UEMA Takeshi, YAMAGATA Hidehisa, MIKI Tetsuro, AKATSU Hiroyasu, KOSAKA Kenji, TAKEDA Masatoshi, Journal of human genetics, 53, (4) 296 - 302,   2008年04月01日
  • アルツハイマー病における剖検脳を用いたCa homeostasis異常による神経細胞死機構の解明, 松山 善次郎, 赤津 裕康, 堀 映, 研究結果報告書集, 14,   2008年
  • アルツハイマー病患者の剖検脳におけるプロスタグランジンE2合成酵素の発現, 高橋 三津雄, 秋武 義治, 亀井 大輔, 町田 和之, 赤津 裕康, 小阪 憲司, 小野 和彦, 中島 学, 工藤 一郎, 臨床神経学, 47, (12) 1144 - 1144,   2007年12月
  • トロンビン活性化線溶阻止因子(TAFI)の正常者血漿中濃度解析, 赤津 裕康, 石黒 雅江, 小川 倫弘, 兼坂 岳志, 岡田 則子, 山本 孝之, 岡田 秀親, 日本血栓止血学会誌, 18, (5) 541 - 541,   2007年10月
  • 胃瘻患者への短期間のたんぱく質強化による栄養介入効果とインフルエンザワクチン抗体価に及ぼす影響, 赤津 裕康, 松本 光弘, 宮本 圭子, 山本 淑子, 芦田 欣也, 高見 正雄, 小橋 修, 栄養-評価と治療, 24, (3) 307 - 314,   2007年06月, たんぱく質補給食品を用いて、低栄養を示す胃瘻患者に7週間にわたり28g/日のたんぱく質補給の短期間栄養介入を行い、栄養評価を行った。また、試験開始2週間後にインフルエンザワクチンを接種し、たんぱく質強化による抗体価への影響も検討した。その結果、たんぱく質非強化群では、総蛋白(total protein;TP)および血清アルブミン濃度(albumin;Alb)がそれぞれ6.6±0.5から6.2±0.9g/dl、3.4±0.4から3.2±0.7g/dlと試験開始前よりも低下した。これらに対して、たんぱく質強化群では、TPおよびAlbはそれぞれ6.4±0.7から6.6±0.7g/dl、3.1±0.6から3.3±0.4g/dlと試験開始前よりも増加し、その他の栄養指標値も増加した。インフルエンザワクチンのH1N1,H3N2およびB-1の各抗原に対する抗体価については、たんぱく質強化の効果は認められなかったが、たんぱく質強化および非強化の両群の試験終了時のAlbとB-1,H3N2抗体価には正の相関が認められた。(著者抄録)
  • 赤芽球および赤血球におけるαシヌクレインの発現, 中井 雅晶, 藁谷 正明, 藤田 雅代, 魏 建設, 洲鎌 秀永, 赤津 裕康, 丸山 千秋, 岡戸 晴生, 橋本 款, 日本獣医学会学術集会講演要旨集, 143回,   2007年03月
  • 候補遺伝子アプローチによるアルツハイマー病の発症機序の解明, 山縣 英久, 三木 哲郎, 満田 憲昭, 赤津 裕康, 精神薬療研究年報, (39) 236 - 243,   2007年03月, アルツハイマー病(AD)を含む老年期認知症に関するアポリポ蛋白E(APOE)以外の遺伝的危険因子を多角的に効率よく分子遺伝学的に解明した。対象サンプルは凍結ブレインバンク由来の剖検脳海馬組織23例、cDNA解析遺伝子はCLU(APOJ)、APOER2、IDE、BACE1、NCSTN、PPARα、COL11A1、RELN、UBQLN、TRPM6の10遺伝子である。パーキンソン病原因遺伝子やγセクレターゼ構成成分、βアミロイド関連遺伝子など大半の1塩基多型(SNP)において有意差は認めなかった。スプライス変異種解析では解析した10遺伝子の内、真のアイソフォーム変異種はNCSTN遺伝子のみしか検出できなかった。AD剖検脳海馬由来cDNAをPCR増幅して得た大部分の予想と異なるサイズのバンドは解析すると全く別の遺伝子であることが判明した。APP、SNCAの異数体は検出されず日本における頻度はまれであると考えられた。
  • アルツハイマー病患者の剖検脳におけるプロスタグランジンE2合成酵素の発現, 高橋三津雄, 秋武義治, 亀井大輔, 町田和之, 赤津裕康, 小阪憲司, 小野和彦, 中島学, 工藤一郎, 日本神経学会総会プログラム・抄録集, 48th,   2007年
  • モノアミン系の加齢変化とうつ病の解明・予防に関する研究 高齢者および血管障害後のうつ病・認知症とモノアミンとの関連の解析, 赤津裕康, モノアミン系の加齢変化とうつ病の解明・予防に関する研究 平成18年度 総括・分担研究報告書,   2007年
  • X連鎖ジストニア・パーキンソニズムのゲノム解析, 田宮元, 牧野悟士, 梶龍兒, 安野勝史, 後藤惠, 松本慎一, TABUENA Daisy, MARANON Elma, DANTES Marita, LEE Lillian V, 遠山育夫, 小笠原一誠, 赤津裕康, 西村公考, 日本人類遺伝学会大会プログラム・抄録集, 52nd,   2007年
  • 生体の持つストレス応答機能を利用した老化制御,予防研究 免疫制御による脳変性疾患の予防, 赤津裕康, 生体の持つストレス応答機能を利用した老化制御、予防研究 平成16-18年度 総合研究報告書,   2007年
  • モノアミン系の加齢変化とうつ病の解明・予防に関する研究 高齢者および血管障害後のうつ病・認知症とモノアミンとの関連の解析, 赤津裕康, モノアミン系の加齢変化とうつ病の解明・予防に関する研究 平成17-18年度 総合研究報告書,   2007年
  • アルツハイマー病発症の危険因子であるコレステロール代謝関連遺伝子の機能解析に関する研究 アルツハイマー病脳および髄液サンプルを用いた脂質関連因子の解析, 赤津裕康, アルツハイマー病発症の危険因子であるコレステロール代謝関連遺伝子の機能解析に関する研究 平成18年度 総括・分担研究年度終了報告書,   2007年
  • 生体の持つストレス応答機能を利用した老化制御,予防研究 免疫制御による脳変性疾患の予防, 赤津裕康, 生体の持つストレス応答機能を利用した老化制御、予防研究 平成18年度 総括研究報告書,   2007年
  • アルツハイマー病のアミロイドを検出する新規PETプローブ, 伊藤 啓, 岡村 信行, 加藤 元久, 古本 祥三, 赤津 裕康, 山本 孝之, 稲田 義行, 荒井 啓行, 工藤 幸司, 谷内 一彦, 日本薬理学雑誌, 129, (1) 7P - 7P,   2007年01月
  • アルツハイマー病患者における脈絡叢のプロテオーム解析, 赤津 裕康, 朝田 隆, 小川 倫弘, 水上 勝義, 石井 俊, 鈴木 秀昭, 片桐 拓也, 山本 孝之, 小阪 憲司, 内田 和彦, 日本臨床プロテオーム研究会要旨集, 2007, (0) 7 - 7,   2007年, 目的:アルツハイマー病(AD)はアミロイドβ(Aβ)の蓄積が原因であると考えられている。Aβワクチン療法はヒトの剖検脳所見でAβ沈着が抑制されていた現象が認められた。これはAβが免疫作用で排出・分解されている事を示している。脈絡叢は脳脊髄液産生を担っていると同時に、脈絡叢上皮細胞は血液脳脊髄液関門の実体である。脈絡叢にAβが存在することも免疫染色法により示され、AD患者脈絡叢では形態異常が報告されている。脳脊髄液中Aβ42の濃度がADで減少する知見は、Aβの排出機構と脈絡叢との関係を示唆し、脈絡叢タンパク質が新たな創薬ターゲットとなる可能性がある。方法:Aβ排出での脈絡叢システムに注目し脈絡叢とADの関係をタンパク質レベルで解明するため、複数例のAD患者と性・年齢を一致させたコントロール(CN)との差異解析を行った。神経病理学的にADと診断された症例及びNCの剖検脳脈絡叢からタンパク質を抽出し、二次元電気泳動ディファレンシャル解析(2D-DIGE)を行った。2D-DIGEには、タンパク質を蛍光色素CyDyesで多重標識するEttanDIGE法を用いた。症例は全て書面にて遺伝子・蛋白解析等の研究に凍結脳を用いる事が明記された承諾書を遺族より得ており、福祉村病院倫理委員会の承認を得ている。結果:解析ソフトによる統計解析の結果、AD群とNC群間で蛋白質発現量の変化が認められる複数のスポットを検出した。考察:AD脈絡叢で正常群と比べて発現蛋白の違いを認めた。今後、髄液成分・血液成分の解析とその混入の可能性を否定できれば脈絡叢が病態に関与している可能性が示唆される。これらの蛋白質について、ペプチドマスフィンガープリント法を用いて同定し、ADとの関連およびAβ排出機構における脈絡叢システムの役割を検討する予定である。
  • アルツハイマー病患者における脈絡叢のプロテオーム解析, 赤津 裕康, 朝田 隆, 小川 倫弘, 水上 勝義, 石井 俊, 鈴木 秀昭, 片桐 拓也, 山本 孝之, 小阪 憲司, 内田 和彦, 日本プロテオーム学会大会要旨集, 2007, (0) 127 - 127,   2007年, 目的:アルツハイマー病(AD)は老人斑形成の中核であるアミロイドβ(Aβ)の蓄積が主たる原因であると考えられている。Aβワクチン療法はヒトの剖検脳所見でAβ沈着が抑制されていた現象が認められた。これはAβが免疫作用で排出・分解されている事を示している。脈絡叢は脳脊髄液産生を担っていると同時に、脈絡叢上皮細胞は血液脳脊髄液関門の実体でもある。脈絡叢にAβが存在することも免疫染色法により示され、AD患者脈絡叢では形態異常が報告されている。脳脊髄液中Aβ42の濃度がADで減少する知見は、Aβの排出機構と脈絡叢との関係を示唆し、脈絡叢タンパク質が新たな創薬ターゲットとなる可能性がある。方法:Aβ排出での脈絡叢システムに注目し脈絡叢とADの関係をタンパク質レベルで解明するため、複数例のAD患者と性・年齢を一致させたコントロール(CN)との差異解析を行った。神経病理学的にADと診断された症例及びNCの剖検脳脈絡叢からタンパク質を抽出し、二次元電気泳動ディファレンシャル解析(2D-DIGE)を行った。2D-DIGEには、タンパク質を蛍光色素CyDyesで多重標識するEttanDIGE法を用いた。症例は全て書面にて遺伝子・蛋白解析等の研究に凍結脳を用いる事が明記された承諾書を遺族より得ており、福祉村病院倫理委員会の承認を得ている。結果:解析ソフトによる統計解析の結果、AD群とNC群間で蛋白質発現量の変化が認められる複数のスポットを検出した。考察:AD脈絡叢で正常群と比べて15個の減少スポットと34個の増加スポットの発現蛋白の違いを認めた。今後、髄液成分・血液成分の解析とその混入の可能性を否定できれば脈絡叢が病態に関与している可能性が示唆される。本会までにはこれらの蛋白質について、ペプチドマスフィンガープリント法を用いて同定し報告する予定である。
  • リンパ球特異的蛋白チロシンキナーゼはアルツハイマー病の新規リスク遺伝子である, 山縣 英久, 鐘 望涛, 田口 敬子, 赤津 裕康, 紙野 晃人, 川尻 真和, 武田 雅俊, 三木 哲郎, 臨床神経学, 46, (12) 1132 - 1132,   2006年12月
  • ニカストリン遺伝子スプライス変異と確実例アルツハイマー病の関連, 三木 哲郎, 山縣 英久, 満田 憲昭, 鐘 望涛, 青戸 守, 赤津 裕康, 紙野 晃人, 武田 雅俊, 小原 克彦, 小阪 憲司, 臨床神経学, 46, (12) 1132 - 1132,   2006年12月
  • 栄養療法にて肝性脳症をコントロールし得た末期肝癌例, 赤津裕康, 宮本圭子, 平尾美保, 谷水清美, 石田美穂, 山本淑子, 宮脇優子, 小橋修, 山本孝之, 静脈経腸栄養, 21,   2006年09月25日
  • 栄養療法にて肝性脳症をコントロールし得た末期肝癌例, 赤津 裕康, 宮本 圭子, 平尾 美保, 谷水 清美, 石田 美穂, 山本 淑子, 宮脇 優子, 小橋 修, 山本 孝之, 静脈経腸栄養, 21, (3) 139 - 139,   2006年09月
  • APOBEC1遺伝子Met80Ile多型は血漿HDLコレステロールに影響し、男性アルツハイマー病の遺伝的リスクとして発症年齢に関係する, 紙野 晃人, 木村 亮, 数井 裕光, 田中 稔久, 工藤 喬, 武田 雅俊, 山縣 英久, 三木 哲郎, 赤津 裕康, 服部 英幸, 上間 武, 中島 健二, 和田 健二, 浦上 克哉, 川上 秀史, 米田 博, Dementia Japan, 20, (2) 177 - 177,   2006年08月
  • アルツハイマー病,レビー小体型痴呆症および統合失調症患者剖検脳を用いたディファレンシャルプロテオーム解析, 石井 俊, 水上 勝義, 片桐 拓也, 赤津 裕康, 朝田 隆, 内田 和彦, 精神神経学雑誌, 102nd, (2006特別) S224 - S224,   2006年05月
  • アルツハイマー病患者における脈絡叢のプロテオーム解析, 赤津 裕康, 水上 勝義, 石井 俊, 山本 孝之, 小阪 憲司, 片桐 拓也, 内田 和彦, 朝田 隆, 精神神経学雑誌, 102nd, (2006特別) S223 - S223,   2006年05月
  • APOEとは独立したアルツハイマー病疾患感受性遺伝子LCKの同定, 山縣 英久, 田口 敬子, 赤津 裕康, 紙野 晃人, 三木 哲郎, 日本老年医学会雑誌, 43, (Suppl.) 115 - 115,   2006年05月
  • 候補遺伝子アプローチによるアルツハイマー病関連遺伝子の探索, 山縣 英久, 鐘 望濤, 田口 敬子, 名倉 潤, 川尻 真和, 秦 龍二, 赤津 裕康, 紙野 晃人, 武田 雅俊, 三木 哲郎, 日本内科学会雑誌, 95, (Suppl.) 253 - 253,   2006年02月
  • 胃瘻造設患者へのタンパク質補給食品(メイプロテイン)の栄養介入による栄養改善効果, 赤津 裕康, 松本 光弘, 宮本 圭子, 山本 淑子, 芦田 欣也, 高見 正雄, 小橋 修, 静脈経腸栄養, 21, (増刊) 244 - 244,   2006年01月
  • 生体の持つストレス応答機能を利用した老化制御,予防研究 免疫制御による脳変性疾患の予防, 赤津裕康, 生体の持つストレス応答機能を利用した老化制御、予防研究 平成17年度 総括研究報告書,   2006年
  • リンパ球特異的蛋白チロシンキナーゼはアルツハイマー病の新規リスク遺伝子である, 山県英久, 鐘望涛, 田口敬子, 赤津裕康, 紙野晃人, 川尻真和, 武田雅俊, 三木哲郎, 日本神経学会総会プログラム・抄録集, 47th,   2006年
  • アルツハイマー病脳組織におけるα1‐chimaerinタンパク質の発現について, 加藤智子, 小西吉裕, 下濱俊, 辻輝之, 赤津裕康, 遠山育夫, 日本脳科学会プログラム・講演抄録集, 33rd,   2006年
  • ニカストリン遺伝子スプライス変異と確実例アルツハイマー病の関連, 三木哲郎, 山県英久, 満田憲昭, 鐘望涛, 青戸守, 赤津裕康, 紙野晃人, 武田雅俊, 小原克彦, 小阪憲司, 日本神経学会総会プログラム・抄録集, 47th,   2006年
  • アルツハイマー病発症の危険因子であるコレステロール代謝関連遺伝子の機能解析に関する研究 アルツハイマー病脳および髄液サンプルを用いた脂質関連因子の解析, 赤津裕康, アルツハイマー病発症の危険因子であるコレステロール代謝関連遺伝子の機能解析に関する研究 平成17年度 総括研究報告書,   2006年
  • FGF1プロモーター遺伝子多型は確実例アルツハイマー病のリスクとなる, 山縣 英久, 田口 敬子, 赤津 裕康, 紙野 晃人, 武田 雅俊, 伊藤 仁一, 横山 信二, 川尻 真和, 山本 孝之, 小阪 憲司, 三木 哲郎, 近藤 郁子, 臨床神経学, 45, (12) 1096 - 1096,   2005年12月
  • 海馬発現関連解析によるアルツハイマー病リスク遺伝子多型の同定, 田口 敬子, 山縣 英久, 鐘 望濤, 紙野 晃人, 田原 康玄, 赤津 裕康, 名倉 潤, 小原 克彦, 武田 雅俊, 近藤 郁子, 三木 哲郎, 臨床神経学, 45, (12) 1096 - 1096,   2005年12月
  • α1-chimerinの発現は,アルツハイマー病脳で減少している, 遠山 育夫, 加藤 智子, 下濱 俊, 辻 輝之, 赤津 裕康, 臨床神経学, 45, (12) 1097 - 1097,   2005年12月
  • 左右差のある脳萎縮を呈する痴呆患者の臨床病理学的検討, 芹川 佳代子, 宮崎 昭徳, 中川 龍治, 赤津 裕康, 山本 孝之, 小阪 憲司, 高橋 三津雄, 臨床神経学, 45, (12) 1097 - 1097,   2005年12月
  • アルツハイマー病患者における脈絡叢のプロテオーム解析, 梅津正博, 石井俊, 水上勝義, 片桐拓也, 内田和彦, 朝田隆, 小坂憲司, 赤津裕康, 日本分子生物学会年会講演要旨集, 28th,   2005年11月25日
  • アルツハイマー病,レビー小体型痴呆症および統合失調症患者剖検脳を用いたプロテオーム比較解析, 石井俊, 片桐拓也, 水上勝義, 赤津裕康, 小阪憲司, 朝田隆, 内田和彦, 日本分子生物学会年会講演要旨集, 28th,   2005年11月25日
  • 胃瘻チューブ交換時に生じた腹腔内誤挿入に対し外来処置のみで対処が可能であった1例, 蟹江 治郎, 赤津 裕康, 鈴木 裕介, 日本老年医学会雑誌, 42, (6) 698 - 701,   2005年11月, 53歳男.患者は胃瘻による経管栄養管を受けて在宅診療を行っていた.経皮内視鏡的胃瘻造設術(PEG)チューブは定期的に在宅医によって交換され,状態は安定していた.しかし今回,胃内容物の吸引不能の主訴によりチューブ腹腔内誤挿入が疑われ受診となった.緊急内視鏡検査を施行し,生検鉗子を誤挿入によって穿破した瘻孔を経由して体外へ誘導し,その生検鉗子で胃瘻造設用のループワイヤーを把持して内視鏡を抜去し,Pull式胃瘻造設法に準じて胃瘻造設用チューブを経口的に挿入し留置した.その結果,チューブの留置により穿孔部はチューブによって被覆され,胃内固定板による胃壁と腹壁の密着により穿孔部の閉鎖が得られた.また,PEGチューブによる胃内減圧も行なえ,胃内容物の腹腔への流出を回避して,汎発性腹膜炎の発生を防止することもできた.以後,内視鏡終了と同時に帰宅となり,診療所間の連携により在宅診療の継続となった
  • コドン105点変異を認めた小脳失調型のGerstman-Strausller-Scheinker症候群の1例, 木澤 麻由紀, 堀 紀夫, 岩崎 靖, 川合 圭成, 祖父江 元, 杢野 謙次, 小阪 憲司, 赤津 裕康, 中澤 秀嘉, 臨床神経学, 45, (10) 782 - 782,   2005年10月
  • 固形化経腸栄養剤の投与により血糖管理が容易になった1例, 赤津 裕康, 山本 孝之, 鈴木 裕介, 蟹江 治郎, 日本老年医学会雑誌, 42, (5) 564 - 566,   2005年09月25日
  • Machado‐Joseph病(MJD)におけるMRI所見の経時的変化の検討, 堀本佳彦, 松本光弘, 赤津裕康, 小島章弘, 片田栄一, 野倉一也, 山本紘子, 湯浅浩之, 三竹重久, 日本神経学会総会プログラム・抄録集, 12,   2005年09月
  • 新規アミロイドイメージング剤[11C]BF227の合成と評価, 古本 祥三, 岡村 信行, 岩田 錬, 石川 洋一, 丸山 将浩, 赤津 裕康, 澤田 徹, 伊藤 正敏, 谷内 一彦, 荒井 啓行, 工藤 幸司, 核医学, 42, (3) 342 - 342,   2005年09月
  • 固形化経腸栄養剤の投与により血糖管理が容易になった1例, 赤津 裕康, 山本 孝之, 鈴木 裕介, 蟹江 治郎, 日本老年医学会雑誌, 42, (5) 564 - 566,   2005年09月, 60歳男.脳梗塞により長期経管栄養の適応となり,約1年前に経皮内視鏡的胃瘻造設術(PEG)が行われた.来院時には,食後高血糖,難治性下痢,胃瘻周囲の栄養剤リーク,喀痰増加がみられた.原因精査を行うも下痢の原因は不明で,液状経腸栄養剤による合併症と考えポリカルボフィルカルシウム 1.2gおよび塩酸ロペラミドによる対症療法を行ったが,症状の改善はみられなかった.各症状および問題点に対する対策として,粉末寒天による経腸栄養剤の固形化を導入したところ,変更後3日目より下痢症状の改善を認め,胃瘻周囲の栄養剤漏出や,頻回の喀痰排泄も,変更後約1週間で消失した.また液状経腸栄養剤注入時に比較して,固形化経腸栄養剤注入時には食後血糖値の最高値は低下し,IRI値も低値となった
  • アルツハイマー病を中心とした髄液中コレステロールの解析, 赤津 裕康, 道川 誠, 山田 達夫, 岡田 秀親, 山本 孝之, 伊藤 仁一, 横山 信治, Dementia Japan, 19, (2) 142 - 142,   2005年08月
  • アミロイドイメージング用PETプローブBF-227の開発, 岡村 信行, 古本 祥三, 加藤 元久, 丸山 将浩, 荒井 啓行, 赤津 裕康, 山本 孝之, 澤田 徹, 谷内 一彦, 工藤 幸司, Dementia Japan, 19, (2) 155 - 155,   2005年08月
  • Machado-Joseph病におけるMRI像と病理所見の対比, 堀本 佳彦, 松本 光弘, 赤津 裕康, 小阪 憲司, 山本 孝之, 小島 章弘, 吉田 眞理, 橋詰 良夫, 臨床神経学, 45, (7) 557 - 557,   2005年07月
  • 脳水腫と脳梗塞を併発し非特異的老人斑を伴ったアルツハイマー病の1例, 赤津裕康, 磯島大輔, 桑野良三, 山本孝之, 小阪憲司, Neuropathology, 25,   2005年05月
  • レビー小体型痴呆における中隔核の免疫組織学的検討, 藤城弘樹, 梅垣宏行, 赤津裕康, 磯島大輔, 井口昭久, 小阪憲司, Neuropathology, 25,   2005年05月
  • 4‐repeat tauopathiesにおけるpretanglesの検討, 都甲崇, 勝瀬大海, 塩崎一昌, 井関栄三, 秋山治彦, 土谷邦秋, 磯島大輔, 赤津裕康, 鈴木京子, DE SILVA Rohan, LEES Andrew, 小阪憲司, 平安良雄, Neuropathology, 25,   2005年05月
  • Machado‐Joseph病におけるMRI所見と病理所見の対比, 堀本佳彦, 松本光弘, 赤津裕康, 小阪憲司, 山本孝之, 小島章弘, 吉田真理, 橋詰良夫, Neuropathology, 25,   2005年05月
  • α1‐chimaerinの発現は,アルツハイマー病脳で減少している, 加藤智子, 小西吉裕, 下濱俊, 辻輝之, 赤津裕康, 遠山育夫, 日本脳科学会プログラム・講演抄録集, 32nd,   2005年
  • 左右差のある脳萎縮を呈する痴呆患者の臨床病理学的検討, 芹川佳代子, 宮崎昭徳, 中川龍治, 赤津裕康, 山本孝之, 小阪憲司, 高橋三津雄, 日本神経学会総会プログラム・抄録集, 46th,   2005年
  • アポリポ蛋白A2遺伝子による高齢発症型アルツハイマー病の発症促進効果, 紙野晃人, 山本美都子, 田中稔久, 赤津裕康, 上間武, 小林敏子, 服部英幸, 山県英久, 三木哲郎, 米田博, 今川正樹, 井原康夫, 太田茂男, 日本生物学的精神医学会プログラム・講演抄録, 27th,   2005年
  • FGF1プロモーター遺伝子多型は確実例アルツハイマー病のリスクとなる, 山県英久, 田口敬子, 赤津裕康, 紙野晃人, 武田雅俊, 伊藤仁一, 川尻真和, 山本孝之, 近藤郁子, 日本神経学会総会プログラム・抄録集, 46th,   2005年
  • アルブミン遺伝子とアルツハイマー病との遺伝的関連について, 木村亮, 紙野晃人, 山本美都子, 上間武, 数井裕光, 池尻義隆, 赤津裕康, 田中稔久, 工藤喬, 武田雅俊, 日本生物学的精神医学会プログラム・講演抄録, 27th,   2005年
  • α1‐chimerinの発現は,アルツハイマー病脳で減少している, 遠山育夫, 加藤智子, 下浜俊, 辻輝之, 赤津裕康, 日本神経学会総会プログラム・抄録集, 46th,   2005年
  • 海馬発現関連解析によるアルツハイマー病リスク遺伝子多型の同定, 田口敬子, 山県英久, 鐘望涛, 紙野晃人, 田原康玄, 赤津裕康, 名倉潤, 武田雅俊, 近藤郁子, 日本神経学会総会プログラム・抄録集, 46th,   2005年
  • 胃ろうチューブ交換時に生じた腹腔内誤挿入に対し外来処置のみで対処が可能であった1例, 蟹江 治郎, 赤津 裕康, 鈴木 裕介, 日本老年医学会雑誌, 42, (6) 698 - 701,   2005年, 症例は53歳男性. 脊髄小脳変性症による寝たきり状態で, 胃瘻による経管栄養管理を受け在宅診療を行っていた. 胃瘻チューブは, かかりつけ医により在宅で定期的に交換がされていたが, 定期交換時にチューブが腹腔内に誤って挿入されたため当院へ来院した. 当院来院後は緊急内視鏡を行い, 生検鉗子を誤挿入により穿破した瘻孔を経由して体外へ誘導し, その生検鉗子で胃瘻造設用のループワイヤーを把持して内視鏡を抜去し, Pull 式胃瘻造設法に準じて胃瘻造設用チューブを経口的に挿入し留置を行った. この手技により瘻孔穿孔部は胃瘻チューブにより被覆され, 胃瘻チューブによる胃内減圧も行えるため, 胃内容物の腹腔への流出を回避して汎発性腹膜炎の発生を防止し得た. 本例はこの処置により診療所間の連携により入院治療を行うことなく在宅診療の継続が可能であった.
  • アルツハイマー病患者のデイケアでの臨床経過分類, 芹川 佳代子, 高橋 三津雄, 宮崎 昭徳, 中川 龍治, 赤津 裕康, 小阪 憲司, 臨床神経学, 44, (12) 1172 - 1172,   2004年12月
  • アルツハイマー病患者由来ヒト脳のプロテオーム・トランスクリプトーム解析, 石井俊, 片桐拓也, 水上勝義, 飯島鮎子, 赤津裕康, 小坂憲司, 朝田隆, 内田和彦, 日本分子生物学会年会プログラム・講演要旨集, 27th,   2004年11月25日
  • 胎児肝由来多能性前駆細胞の神経様細胞への分化, 小松文成, 赤津裕康, 小島清秀, 山本孝之, 岡田秀親, 福島武雄, 日本脳神経外科学会総会抄録集, 63rd,   2004年10月06日
  • 固形化経腸栄養剤の投与を実現するための取り組みについて, 蟹江 治郎, 各務 千鶴子, 赤津 裕康, 鈴木 裕介, 在宅医療と内視鏡治療, 8, (1) 88 - 88,   2004年09月
  • Benzoxazole誘導体のアミロイドイメージング用プローブとしての有用性の検討, 岡村 信行, 加藤 元久, 谷内 一彦, 古本 祥三, 工藤 幸司, 船木 善仁, 岩田 錬, 島津 浩, 澤田 徹, 赤津 裕康, 山本 孝之, 核医学, 41, (3) 380 - 380,   2004年09月
  • BDNF遺伝子(Val66Met)多型と確定痴呆性疾患との関連, 赤津 裕康, 山縣 英久, 川又 純, 紙野 晃人, 武田 雅俊, 山本 孝之, 三木 哲郎, 遠山 育夫, 下濱 俊, 小阪 憲司, Dementia Japan, 18, (2) 133 - 133,   2004年08月
  • レビー小体型痴呆症におけるアポリポ蛋白E4型の関与, 赤津 裕康, KAMINO Kouzin, YAMAGATA Hidehisa, ISOJIMA Daisuke, KONDO Ikuko, YAMAMOTO Takayuki, KIDA Tomoyuki, TAKEDA Masatoshi, MIKI Tetsuro, KOSAKA Kenji, Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society, 4, (2) 24 - 32,   2004年06月01日
  • レビー小体型痴呆における黒質線条体路と黒質へん桃核路は異なる変性過程を示す?, 丸井和美, 井関栄三, 赤津裕康, 小阪憲司, 加藤雅紀, Neuropathology, 24,   2004年05月
  • レビー小体型痴呆における血管病変の検討, 磯島大輔, 赤津裕康, 都崇, 内門大丈, 藤城弘樹, 井関栄三, 平安良雄, 小阪憲司, Neuropathology, 24,   2004年05月
  • 非特異的老人斑を呈した混合型痴呆症例, 赤津裕康, 磯島大輔, 山本孝之, 小阪憲司, Neuropathology, 24,   2004年05月
  • レビー小体型痴呆におけるレビー病理変化の脳内進展様式は一律ではない?, 井関栄三, 丸井和美, 赤津裕康, 小阪憲司, 加藤雅紀, Neuropathology, 24,   2004年05月
  • Argyrophilic grain diseaseの臨床的特徴, 都甲崇, 磯島大輔, 鈴木京子, 内門大丈, 赤津裕康, 井関栄三, 小阪憲司, 平安良雄, Neuropathology, 24,   2004年05月
  • アルツハイマー病の病因遺伝子探索のための候補遺伝子アプローチ, 田口 敬子, 山縣 英久, 紙野 晃人, 田原 康玄, 赤津 裕康, 名倉 潤, 小原 克彦, 近藤 郁子, 三木 哲郎, 日本老年医学会雑誌, 41, (Suppl.) 143 - 143,   2004年05月
  • アルツハイマー病患者のデイケアでの臨床経過分類, 芹川佳代子, 高橋三津雄, 宮崎昭徳, 中川龍治, 赤津裕康, 小阪憲司, 日本神経学会総会プログラム・抄録集, 45th,   2004年04月01日
  • 固形化経腸栄養剤の実施における栄養剤の安定性と安全性の評価 : 調理によるビタミンの変化と細菌学的変化, 蟹江 治郎, 鈴木 裕介, 赤津 裕康, 各務 千鶴子, 静脈経腸栄養, 19, (1) 65 - 69,   2004年03月25日
  • 固形化経腸栄養剤の実施における栄養剤の安定性と安全性の評価 調理によるビタミンの変化と細菌学的変化, 蟹江 治郎, 鈴木 裕介, 赤津 裕康, 各務 千鶴子, 静脈経腸栄養, 19, (1) 65 - 69,   2004年03月, 市販の経腸栄養剤を用い,ゲル化を行う固定化経腸栄養剤について,調理によるビタミン含有量の変化と,調理後の細菌的変化細菌的を検討し,固形化経腸栄養剤の安定性と安全性について評価を行った.60℃に加熱した検体において,加熱開始前,加熱6時間後,加熱24時間後のいずれの検体においても,ビタミンの変化は認めなかった.80℃に加熱した検体においては,レチノール,リボフラビン,総アスコルビン酸については変化を認めなかったが,サイアミンについては加熱6時間後で,加熱前の88.2%に,加熱24時間後,加熱前の60.1%に減少した.固形化経腸栄養剤の調理に伴うビタミンの減少は,調理後72時間以内において認められなかった.5℃冷蔵庫で保存した検体においては,2検体とも調理後72時間以内の細菌増加は認めなかった
  • アミロイド斑の生体画像化を目的とした新規PET薬剤の開発, 岡村 信行, 谷内 一彦, 末元 隆寛, 島津 浩, 鈴木 雅子, 塩満 剛, 赤津 裕康, 山本 孝之, 工藤 幸司, 澤田 徹, 日本薬理学雑誌, 123, (1) 10P - 10P,   2004年01月
  • 255剖検例におけるAPOEゲノタイプと痴呆性疾患との相関, 赤津 裕康, 紙野 晃人, 山縣 英久, 近藤 郁子, 武田 雅俊, 山本 孝之, 三木 哲郎, 小阪 憲司, Dementia Japan, 17, (2) 179 - 179,   2003年08月
  • アミロイドアンギオパチーと血管周囲のタウ病変の関係について アミロイドアンギオパチーを伴う老年痴呆の2剖検例の神経病理学的検討, 内門 大丈, 日野 博昭, 都甲 崇, 赤津 裕康, 小阪 憲司, 井関 栄三, Dementia Japan, 17, (2) 201 - 201,   2003年08月
  • 脳アミロイドの画像化を目的とした新しいPETプローブの開発 プローブ候補であるBF-177,-178,-179の老人斑結合性とマウスにおける脳移行性の検討, 末元 隆寛, 岡村 信行, 鈴木 雅子, 塩満 剛, 島津 浩, 赤津 裕康, 山本 孝之, 工藤 幸司, 澤田 徹, Dementia Japan, 17, (2) 167 - 167,   2003年08月
  • 経皮内視鏡的胃ろう造設術(PEG)とケアの実際 知っておきたい知識 経腸栄養剤固形化によるPEG後期合併症への対策, 蟹江治郎, 赤津裕康, 各務千鶴子, 臨床看護, 29, (5) 664 - 670,   2003年05月15日
  • 【経皮内視鏡的胃瘻造設術(PEG)とケアの実際】知っておきたい知識 経腸栄養剤固形化によるPEG後期合併症への対策, 蟹江 治郎, 赤津 裕康, 各務 千鶴子, 臨床看護, 29, (5) 664 - 670,   2003年05月, 現在,経管栄養患者の経腸栄養剤は,経管的投与を簡便に行うために液体の形状となっている.著者等は食品用の粉末寒天を利用して経腸栄養剤を固形化し,胃瘻チューブを利用して投与を行うことにより,液体経腸栄養剤により発生する胃食道逆流,瘻孔からの栄養剤リーク,下痢などの合併症に対応を行っている.そこで,この固形化経腸栄養剤の効果,調理法,投与法について解説し,あわせて,著者等が実験した症例についても紹介した
  • レビー小体型痴呆の病理学的拡がりとアルツハイマー病との境界, 丸井 和美, 丸井 和美, 井関 栄三, 加藤 雅紀, 赤津 裕康, 小阪 憲司, Neuropathology : official journal the Japanese Society of Neuropathology, 23,   2003年05月01日
  • 【ここまで解った神経変性疾患の最先端研究-アルツハイマー,パーキンソン病を中心に】アルツハイマー病 ADの画像診断:生体における脳アミロイドイメージング技術の開発, 岡村 信行, 末元 隆寛, 工藤 幸司, 澤田 徹, 荒井 啓行, 佐々木 英忠, 赤津 裕康, 山本 孝之, 遺伝子医学, 7, (1) 39 - 43,   2003年03月
  • 抗核抗体応答は自己免疫疾患患者と高齢者痴呆症患者で異なる 自己修飾抗原を用いた解析, 金井 芳之, 飯塚 秀樹, 赤津 裕康, リウマチ, 43, (2) 365 - 365,   2003年03月
  • レビー小体病剖検例の臨床像, 堀本 佳彦, 松本 光弘, 赤津 裕康, 伊苅 弘之, 山本 孝之, 大塚 康史, 上田 龍三, 小鹿 幸生, 小阪 憲司, 臨床神経学, 42, (12) 1232 - 1232,   2002年12月
  • 特発性正常圧水頭症の臨床病理学的研究, 松本 光弘, 小阪 憲司, 堀本 佳彦, 赤津 裕康, 山本 孝之, 松川 則之, 上田 龍三, 小鹿 幸生, Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society, 2, (4) 289 - 294,   2002年12月
  • アルツハイマー病(AD)におけるHippocampal Cholinergic Neurostimulating Peptide(HCNP)前駆体蛋白mRNA発現の検討, 牧 美奈, 松川 則之, 湯浅 浩之, 山本 孝之, 赤津 裕康, 岡本 尚, 小鹿 幸生, 上田 龍三, 名古屋市立大学医学会雑誌, 53, (2〜3) 233 - 234,   2002年08月
  • 脳アミロイドの画像化を目的とした新しいPETプローブの開発 老人斑との結合性の検討, 岡村 信行, 末元 隆寛, 鈴木 雅子, 塩満 剛, 島津 浩, 赤津 裕康, 山本 孝之, 荒井 啓行, 佐々木 英忠, 工藤 幸司, 澤田 徹, Dementia Japan, 16, (2) 118 - 118,   2002年08月
  • 脳アミロイドの画像化を目的とした新しいPETプローブの開発 in vivoにおけるアミロイドとの結合性と脳移行性の検討, 末元 隆寛, 岡村 信行, 鈴木 雅子, 塩満 剛, 島津 浩, 赤津 裕康, 山本 孝之, 工藤 幸司, 澤田 徹, Dementia Japan, 16, (2) 118 - 118,   2002年08月
  • 固形化経腸栄養剤の投与により胃ろう栄養の慢性期合併症を改善し得た1例, 蟹江治郎, 各務千鶴子, 山本孝之, 赤津裕康, 鈴木裕介, 葛谷雅文, 井口昭久, 日本老年医学会雑誌, 39, (4) 448 - 451,   2002年07月25日
  • カルボキシペプチダーゼRのSandwich ELISA法の再検討, 赤津 裕康, 石川 泰成, Campbell William, 谷 さゆり, 岡田 則子, 岡田 秀親, 補体シンポジウム講演集, 39,   2002年07月
  • 胞状軟部肉腫肺転移症例に対する自己活性化リンパ球療法, 石黒 雅江, 赤津 裕康, 瀬戸 正史, 内田 淳正, 山本 孝之, 岡田 秀親, 補体シンポジウム講演集, 39,   2002年07月
  • Human C1q受容体の再検討, 赤津 裕康, McGreal Eamon P., 池脇 信直, Morgan B.Paul, Gasque Philippe, 補体シンポジウム講演集, 39,   2002年07月
  • 固形化経腸栄養剤の投与により胃瘻栄養の慢性期合併症を改善し得た1例, 蟹江 治郎, 各務 千鶴子, 山本 孝之, 赤津 裕康, 鈴木 裕介, 葛谷 雅文, 井口 昭久, 日本老年医学会雑誌, 39, (4) 448 - 451,   2002年07月, 85歳女.介護老人保健施設にて胃瘻による経管栄養管理を受けていた.経腸栄養剤の流涎,胃瘻部からの経腸栄養剤リーク,嘔吐,発熱,栄養剤注入時の呼吸困難症状,肺炎等の症状を繰り返した.各症状の緩和の為に粉末寒天により固形化した経腸栄養剤投与開始したところ,その直後に発熱以外の症状が消失し発熱も2週間後に消失した.又,投与も楽で介護者の労働的負担の軽減にも寄与し得た
  • 高齢者に対する内視鏡的胃瘻造設術の経験 経腸栄養剤固形化による胃食道逆流の予防効果に対する検討, 蟹江 治郎, 各務 千鶴子, 赤津 裕康, 山本 孝之, 葛谷 雅文, 井口 昭久, 日本老年医学会雑誌, 39, (Suppl.) 79 - 79,   2002年05月
  • 固形化経腸栄養剤の投与により胃ろう栄養の慢性期合併症を改善し得た1例, 蟹江 治郎, 各務 千鶴子, 山本 孝之, 赤津 裕康, 鈴木 裕介, 葛谷 雅文, 井口 昭久, 日本老年医学会雑誌, 39, (4) 448 - 451,   2002年, 症例は85歳女性. 介護老人保健施設にて胃瘻による経管栄養管理を受けていた. 来所時は状態が安定していたが, その後, 経腸栄養剤の流涎, 胃瘻挿入部からの経腸栄養剤リーク, 嘔吐, 発熱, 栄養剤注入時の呼吸困難様症状, 肺炎などの症状を反復して認めた. そのため, 各症状の緩和のために, 粉末寒天により固形化した経腸栄養剤投与を開始したところ, 投与直後より発熱以外の症状が消失し, 発熱に関しても開始後2週間で消失し, 良好な経過が得られた. また投与手技も簡略化され, 介護者の労働的負担の軽減にも寄与し得た.
  • アルツハイマー病初期患者の海馬における遺伝子発現変化 Microarrayによる検討, 秦 龍二, 升村 誠, 赤津 裕康, 山本 孝之, 阪中 雅広, 小阪 憲司, 澤田 徹, 臨床神経学, 41, (11) 969 - 969,   2001年11月
  • アルツハイマー病(AD)におけるHippocampal Cholinergic Neurostimulating Peptide(HCNP)前駆体蛋白mRNA発現の検討, 牧 美奈, 松川 則之, 大塚 康史, 湯浅 浩之, 山本 孝之, 赤津 裕康, 小鹿 幸生, 上田 龍三, 臨床神経学, 41, (11) 984 - 984,   2001年11月
  • レビー小体病剖検例の臨床像, 堀本 佳彦, 松本 光弘, 赤津 裕康, 伊苅 弘之, 山本 孝之, 小阪 憲司, 大塚 康史, 上田 龍三, 小鹿 幸生, 臨床神経学, 41, (10) 723 - 723,   2001年10月
  • 福祉村病院での10年間にわたる237剖検例の臨床神経病理学的検討, 赤津 裕康, 高橋 三津雄, 松川 則之, 石川 泰成, 近藤 直樹, 佐藤 知雄, 中澤 秀嘉, 山田 達夫, 岡田 秀親, 山本 孝之, Dementia Japan, 15, (2) 117 - 117,   2001年08月
  • アレルギー性喘息病態における補体の関与, 阿部 正義, 清水 直美, 早志 友里, 坂田 則行, 赤津 裕康, 柴田 和彦, 桂木 猛, 岡田 秀親, 補体シンポジウム講演集, 38,   2001年08月
  • ラットC5a受容体の組織分布解析, 赤津 裕康, 阿部 正義, 三輪 隆史, 立山 尚, 前田 誠司, 岡田 則子, 小島 清秀, 山本 孝之, 岡田 秀親, 補体シンポジウム講演集, 38,   2001年08月
  • 病理学的に正常であった高齢者の生前画像における脳萎縮についての検討, 堀本 佳彦, 松本 光弘, 中澤 秀嘉, 赤津 裕康, 佐藤 知雄, 藤本 勝洋, 高橋 三津雄, 日野 博昭, 伊苅 弘之, 山本 孝之, 臨床神経学, 40, (12) 1367 - 1367,   2000年12月
  • 自己免疫性肝炎類似の病像を呈したサイトメガロウイルス感染性急性肝炎の1例, 澤田 武, 河村 攻, 中田 滋, 赤津 晋太郎, 兒玉 達樹, 眞田 治人, 嶋崎 正晃, 大原 裕康, 松下 和彦, 共済医報, 49, (4) 343 - 348,   2000年11月, 50歳女.食欲不振,黄疸,肝機能障害を主訴とし,経過中サイトメガロウイルス(CMV)抗体価の急上昇を認めCMVによる急性肝炎と診断された.副腎皮質ステロイドを投与し,改善したため漸減,中止したが肝逸脱酵素の再上昇を認め,抗平滑筋抗体陽性であったため肝生検を施行した.肝組織像ではCMV急性肝炎に特徴的な核内封入体はなく,免疫組織染色も陰性であり,急性肝炎回復期の像も呈していなかった.門脈域の拡大,削り取り壊死,小葉内の虚脱を認め,自己免疫性肝炎(AIH)に合致した像であった.肝組織像と併せてAIHの国際診断基準にてscore13点であり,probableAIHと診断された.ウイルス感染により何らかの自己免疫学的機序が働き,AIH類似の病像を呈したと考えられた
  • ラットProcarboxypeptidase RとCarboxypeptidase N active subunitのクローニングと機能解析, 加藤 朋美, 赤津 裕康, 松尾 清一, 山本 孝之, 岡田 則子, 岡田 秀親, 日本免疫学会総会・学術集会記録, 30,   2000年11月
  • ラットprocarboxypeptidase R及びcarboxypeptidase N active subunitのクローニングと機能解析, 加藤 朋美, 赤津 裕康, 佐藤 知雄, 松尾 清一, 山本 孝之, Campbell William, 岡田 則子, 岡田 秀親, 補体シンポジウム講演集, 37,   2000年08月
  • 気管支喘息病態におけるアナフィラトキシンC5aの関与, 阿部 正義, 清水 直美, 坂田 則行, 赤津 裕康, 柴田 和彦, 桂木 猛, 岡田 秀親, 補体シンポジウム講演集, 37,   2000年08月
  • 高齢者に対する内視鏡的胃瘻造設術の経験 胃瘻造設後,胃潰瘍を発生した症例に対しての検討, 蟹江 治郎, 河野 勤, 大澤 雅子, 赤津 裕康, 山本 孝之, 下方 浩史, 安藤 富士子, 井口 昭久, 日本老年医学会雑誌, 37, (Suppl.) 179 - 179,   2000年05月
  • 高齢者に対する経皮内視鏡的胃ろう造設術における合併症 創部感染症と呼吸器感染症の検討, 蟹江治郎, 河野和彦, 河野勤, 大沢雅子, 山本孝之, 赤津裕康, 下方浩史, 井口昭久, 日本老年医学会雑誌, 37, (2) 143 - 148,   2000年02月25日
  • 高齢者に対する経皮内視鏡的胃瘻造設術における合併症:創部感染症と呼吸器感染症の検討, 蟹江 治郎, 河野 和彦, 河野 勤, 大澤 雅子, 山本 孝之, 赤津 裕康, 下方 浩史, 井口 昭久, 日本老年医学会雑誌, 37, (2) 143 - 148,   2000年02月, 症例は65歳以上で内視鏡的胃瘻造設術(PEG)を受けた計341名で,その術後経過を経腸栄養剤投与方法と抗生剤投与方法により分類し検討した.術後の経腸栄養剤投与方法は,術後5日間,経腸栄養剤を注入しない群(group I),術後24時間以内に無菌状態の経腸栄養剤(点滴用乳酸加リンゲル液)を無菌状態の点滴用キットを利用して開始し,5日間継続した群(group II),そして術後24時間以内から通常の経腸栄養剤を注入し5日間継続した群(group III)の3群に分けた.各々を抗生剤の予防投与を行った群(AB(+))と行わなかった群(以下AB(-))の2群に分けて合計6群とした.そして,それらの6群間における,急性呼吸器感染症及び局所皮膚感染症の発生率をカイ2乗検定を用いて比較検討し,PEGの術式(Pull/Push法とIntroducer法)による差異についても検討した.創部感染の発生頻度は,group I及びgroup IIに対して,group IIIは有意に高頻度.造設手技間では,Push/Pull法は,Introducer法に比して有意に高頻度.呼吸器感染の発症頻度は,AB(+)群がAB(-)群に比して有意に低かった.以上より,高齢者に対するPEG術後における呼吸器感染の予防には,術後の抗生剤投与が有効である
  • 高齢者に対する経皮内視鏡的胃ろう造設術における合併症 創部感染症と呼吸器感染症の検討:創部感染症と呼吸器感染症の検討, 蟹江 治郎, 河野 和彦, 河野 勤, 大澤 雅子, 山本 孝之, 赤津 裕康, 下方 浩史, 井口 昭久, 日本老年医学会雑誌, 37, (2) 143 - 148,   2000年, 内視鏡的胃瘻造設術 (Percutaneous Endoscopic Gastrostomy, 以下PEG) の術後急性合併症として, 高頻度に認められる呼吸器感染症と局所皮膚感染症に対し, 有効な術後管理法について検討した.
    症例は65歳以上でPEGを受けた計341名 (男性131名, 女性210名, 平均年齢80.3歳) で, その術後経過を経腸栄養剤投与方法と抗生剤投与方法により分類し検討した. 術後の経腸栄養剤投与方法は, 術後5日間, 経腸栄養剤を注入しない群 (以下 group I), 術後24時間以内に無菌状態の経腸栄養剤 (点滴用乳酸加リンゲル液) を無菌状態の点滴用キットを利用して開始し, 5日間継続した群 (以下 group II), そして術後24時間以内から通常の経腸栄養剤を注入し5日間継続した群 (以下 group III) の三群に分けた. また, それぞれを抗生剤の予防投与を行った群 (以下AB (+)) と行わなかった群 (以下AB (-)) の二群に分けて合計六群とした. そして, それらの六群間における, 急性呼吸器感染症および局所皮膚感染症の発生率をカイ2乗検定を用いて比較検討し, PEGの術式 (Pull/Push 法と Introducer 法) による差異についても検討した.
    その結果, 創部感染の発生頻度は, group Iおよび group IIに対して, group IIIは有意に高頻度であった. 造設手技間では, Push/Pull 法は, Introducer 法に比して有意に高頻度であった. 呼吸器感染の発症頻度は, AB (+) 群がAB (-) 群に比して有意に低かった. 以上より, 高齢者に対するPEG術後における呼吸器感染の予防には, 術後の抗生剤投与が有効である. 一方, 術後の創部感染は, 抗生剤使用との関連は低く, 経腸栄養剤投与法に関連している. 術直後からの点滴用製剤を, 点滴用注入キットを利用して無菌的に開始し, あわせて抗生剤を使用する方法は, 術後の呼吸器感染および創部感染という, PEG術後急性期の二大合併症予防に有効な方法であると考えられる.
  • 自己免疫性肝炎様の病像を呈したサイトメガロウイルス(CMV)感染性急性肝炎の1例, 河村 攻, 真田 治人, 兒玉 達樹, 赤津 晋太郎, 澤田 武, 中田 滋, 嶋崎 正晃, 大原 裕康, 松下 和彦, 共済医報, 48, (Suppl.) 108 - 108,   1999年10月
  • 非痴呆高齢者脳における老人斑と神経原線維変化の分布の定量的検討 : アルツハイマー型老年痴呆およびlimbic neurofibrillary tangle dementiaとの関係, 角田 貞治, 井関 栄三, 鈴木 京子, 小阪 憲司, 赤津 裕康, 山本 孝之, Neuropathology : official journal the Japanese Society of Neuropathology, 19,   1999年06月03日
  • 炎症におけるカルボキシペプチダーゼR(CPR)とカルボキシペプチダーゼN(CPN)の動態, 佐藤 知雄, 三輪 隆史, 赤津 裕康, 松川 則之, 小幡 京子, 岡田 則子, 岡田 秀親, 補体シンポジウム講演集, 36,   1999年06月
  • 敗血症性肺障害並びにアレルギー性肺障害モデルにおけるアナフィラトキシン受容体と誘導型一酸化窒素の関与, 阿部 正義, 岡本 育, 柴田 和彦, 赤津 裕康, 岡田 秀親, 清水 直美, 坂田 則行, 田中 経一, 桂木 猛, 補体シンポジウム講演集, 36,   1999年06月
  • 高齢者に対する内視鏡的胃瘻造設術の経験 胃瘻造設後,経管栄養を離脱できた症例に対しての検討, 蟹江 治郎, 河野 勤, 大澤 雅子, 河野 和彦, 赤津 裕康, 山本 孝之, 下方 浩史, 安藤 富士子, 井口 昭久, 日本老年医学会雑誌, 36, (Suppl.) 93 - 93,   1999年05月
  • アルツハイマー病におけるレプチンの変動, 小川 修, 三浦 久幸, 赤津 裕康, 上田 宗, 玉谷 典華, 中畑 英樹, 梅垣 宏行, 伊苅 弘之, 山本 孝之, 井口 昭久, Dementia Japan, 12, (2) 185 - 185,   1998年09月
  • 病理診断されたDiffuse Lewy body disease 11例の臨床的検討 Dementia with Lewy bodiesの臨床診断基準を用いて, 池田 智昭, 小阪 憲司, 赤津 裕康, 中畑 英樹, 山本 孝之, Dementia Japan, 12, (2) 141 - 141,   1998年09月
  • 老人病院における経皮内視鏡的胃ろう造設術の問題と有用性, 蟹江治郎, 河野和彦, 山本孝之, 赤津裕康, 下方浩史, 井口昭久, 日本老年医学会雑誌, 35, (7) 543 - 547,   1998年07月
  • 老人病院における経皮内視鏡的胃瘻造設術の問題と有用性, 蟹江 治郎, 河野 和彦, 山本 孝之, 赤津 裕康, 下方 浩史, 井口 昭久, 日本老年医学会雑誌, 35, (7) 543 - 547,   1998年07月, 高度の痴呆や寝たきりの患者が中心のいわゆる老人病院において施行し管理された,経皮内視鏡的胃瘻造設術の問題と有用性について検討した.急性期,慢性期とも合併症は稀なものではなかったが,老人病院特有の問題はなかった.また施行前に抑制処理を行っていた症例の65.2%が抑制処置が軽減又は中止し得,55.5%の症例において活動性が改善,胃瘻施行症例の14.0%に経口摂取が可能になるなどQOLの著明な改善が得られた.更に経管栄養チューブ自己抜去の機会の減少や,交換手技が容易になるなど,管理面でも改善が得られた
  • 老人病院における経皮内視鏡的胃ろう造設術の問題と有用性, 蟹江 治郎, 河野 和彦, 山本 孝之, 赤津 裕康, 下方 浩史, 井口 昭久, 日本老年医学会雑誌, 35, (7) 543 - 547,   1998年, 高度の痴呆や寝たきりの患者が中心のいわゆる老人病院において施行し管理された, 経皮内視鏡的胃瘻造設術の問題と有用性について検討した. 検討された項目は, 急性期合併症, 慢性期合併症, 施行前後の抑制処置の有無, 活動性の変化, そして経口摂取の可否である. その結果急性期, 慢性期とも合併症は稀なものではなかったが, 老人病院特有の問題はなかった. また施行前に抑制処置を行っていた症例の65.2%が抑制処置が軽減または中止し得, 55.5%の症例において活動性が改善, 胃瘻施行症例の14.0%に経口摂取が可能になるなどQOLの著明な改善が得られた. さらに経管栄養チューブ自己抜去の機会の減少や, 交換手技が容易になるなど, 管理面でも改善が得られた. よって, 老人病院においても必要な管理を行えば, 胃瘻の施行および管理は十分可能であり, 慢性期における管理の簡便化, そして患者のQOLの改善を考えれば, その実施はきわめて有用な行為である.
  • ラットC5a受容体のクローニングとその解析, 赤津 裕康, 補体シンポジウム講演集, 34,   1997年07月
  • 胃食道逆流のある高齢者に対し TGJ tube(Transgastrostomal Jejunal tube : 経胃瘻的空腸栄養チューブ)を用いた経管栄養管理により在宅管理が可能になった1例, 蟹江 治郎, 河野 和彦, 山本 孝之, 赤津 裕康, 井口 昭久, 日本老年医学会雑誌, 34, (1) 60 - 64,   1997年01月25日
  • 胃食道逆流のある高齢者に対しTGJ tube(Transgastrostomal Jejunal tube:経胃ろう的空腸栄養チューブ)を用いた経管栄養管理により在宅管理が可能になった1例, 蟹江治郎, 河野和彦, 山本孝之, 赤津裕康, 井口昭久, 日本老年医学会雑誌, 34, (1) 60 - 64,   1997年01月
  • 胃食道逆流のある高齢者に対しTGJ tube(Transgastrostomal Jejunal tube:経胃ろう的空腸栄養チューブ)を用いた経管栄養管理により在宅管理が可能になった1例, 蟹江 治郎, 河野 和彦, 山本 孝之, 赤津 裕康, 井口 昭久, 日本老年医学会雑誌, 34, (1) 60 - 64,   1997年, 経鼻胃管栄養および胃瘻栄養管理では, 胃食道逆流により, 逆流性食道炎による吐血と嚥下性肺炎を繰り返していた82歳の男性に, 経胃瘻的空腸栄養チューブによる管理を行った. その結果, 経腸栄養剤が空腸内に直接投与されることにより胃食道逆流が減少し, 逆流性食道炎および嚥下性肺炎の反復がみられなくなった. さらに, 嘔吐, 痴呆による自己抜去そして不穏等も認められなくなり管理が非常に容易となり在宅管理へ移行し得た.
  • ヒト老年正常脳組織における膜性補体制御因子の発現, 赤津裕康, 山田達夫, 岡田則子, 山階学, 山本孝之, 岡田秀親, 日本免疫学会総会・学術集会記録, 25,   1995年10月
  • ヒト老人正常脳組織における補体制御膜因子の発現, 赤津 裕康, 補体シンポジウム講演集, 32,   1995年06月
  • 小柴胡湯及びその有効成分のHIV感染細胞に対するアポトーシス誘導作用, Wu Xiaoshan, 赤津 裕康, 岡田 秀親, Japanese Journal of Medical Science & Biology, 48, (2) 79 - 87,   1995年06月, バイカリンは漢方薬小柴胡湯から抽出された化合物20μg/mlを培養T細胞系CEM細胞と共に24時間培養しても,正常CEM細胞に対する細胞毒性を持たなかったが,HIV感染CEM細胞,特に重感染された細胞に対して細胞毒性を示した.24時間培養HIV感染細胞方にDNAフラグメンテーションが見られアポトーシスを起こさせていることを示す.以上バイカリンはHIV重感染細胞に対して選択的にアポトーシス誘導することにより,HIV感染抑制作用を期待できる
  • アミロイドアンギオパチーを伴い、老人性変化の非定型的分布を示したアルツハイマー型痴呆の1例-神経病理学的・免疫組織化学的検討, 日野 博昭, 井関 栄三, 小阪 憲司, 塩崎 一昌, 赤津 裕康, 山本 孝之, Neuropathology : official journal the Japanese Society of Neuropathology, 15,   1995年06月01日
  • APOPTOSIS OF HIV-INFECTED CELLS FOLLOWING TREATMENT WITH SHO-SAIKO-TO AND ITS COMPONENTS, 呉 笑山, 赤津 裕康, 岡田 秀親, Japanese Journal of Medical Science and Biology, 48, (2) 79 - 87,   1995年, Baicalein and baicalin are components of Sho-saiko-to (SST), a Chinese medical drug which is claimed to be therapeutically effective in treating HIV-infected patients. Although 20 μg/ml of baicalin was not cytotoxic to CEM cells, a cultured T cell line, it proved to be cytotoxic to HIV-infected CEM cells (CEM-HIV) with a higher HIV-releasing capacity and DNA fragmentation was detected within 24 hr of incubation. However, after incubation of CEM-HIV with a lower dose of baicalin (0.1, 0.3 and 2 μg/ml) for 24 and 48 hr, the viable cell number increased by about 25% and the p24 release into the medium was 25% lower than that of the control. After further incubation in the presence of the agent for 6 and 9 days, only cells with a lower HIV-releasing capacity survived. Baicalin might selectively induce apoptosis of CEM-HIV cells which have a high virusreleasing capacity, and stimulate proliferation of CEM-HIV which have a relatively lower capacity of HIV-production.
  • 特集: アポトーシス 機序と病態 自己免疫病とアポトーシス, 赤津裕康, 岡田秀親, 最新医学, 49, (6) 1124 - 1130,   1994年06月
  • 自己免疫病とアポトーシス, 赤津 裕康, 岡田 秀親, 最新医学, 49, (6) 1124 - 1130,   1994年06月

書籍等出版物

  • 特集 アルツハイマー病の早期診療法の現状, 赤津 裕康, 編集, 特集にあたってIntroduction, BIO INDUSTRY,   2018年06月
  • 治療が劇的にうまくいく 高齢者の栄養 はじめの一歩, 赤津 裕康, 分担執筆, 長期療養型病床における高齢者の栄養管理, 羊土社,   2013年
  • 老年期認知症ナビゲーター, 赤津 裕康, 分担執筆, αシヌクレインと認知症, メディカルレビュー社,   2006年

受賞

  •   2012年, 第2回日本認知症予防学会, 浦上賞
  •   2011年02月, 日本静脈経腸栄養学会, フェローシップ賞

競争的資金

  • 高齢者の発話音声・脳血流解析を用いた認知機能障害の疾患・地域多様性の横断的研究, 日本学術振興会, 科学研究費助成事業 基盤研究(A),   2019年04月01日 - 2024年03月31日
  • ラクトフェリンによる炎症性腸疾患の発症予防と寛解維持および発がん予防効果, 日本学術振興会, 科学研究費助成事業 基盤研究(C),   2019年04月01日 - 2022年03月31日
  • ヒト脳内での2段階にわたるアミロイドβ蓄積の機序の解明, 日本学術振興会, 科学研究費助成事業 基盤研究(B),   2018年04月01日 - 2021年03月31日, アルツハイマー病の原因とされるAβが「なぜ」、「どのように」ヒト脳内で蓄積するのか未だ不明である。我々は脳内のAβの特徴的な領域分布に着目し独自に剖検脳を解析することで、①シナプスがまず全長型Aβの蓄積に関与し引き金となり、②ついで何らかの別の因子がN末端の断片化したAβの蓄積を引き起こし臨床病理症状と結びつくこと、を見出し、提唱した(Shinohara et al., Brain 2017)。その分子的実態や臨床的意義をさらに解明するため本研究では、①シナプスがどのような機序で全長型Aβの蓄積に関与するのか、②断片化Aβがどのような機序で蓄積するのか、の分子的な詳細について、これまでの領域分布に着目した剖検脳解析とともに、新規in vivoマイクロダイアリシスを用いた動物モデル解析や、新規結合因子の同定、領域横断的な遺伝子ネットワークの構築、独自のex vivo分解系の導入、高感度ELISAの開発と臨床検体の解析などを通じて明らかにすることを目的とする。当該年度は、研究に必要な動物モデルや臨床検体の導入や倫理申請を進めるととともに、解析系、実験系の立ち上げ、導入などを行った。3年計画の1年目ということもありいくつかの問題にも直面し、十分な成果は得られてはいないが、残り2年で成果が得られるように私が関与している本研究以外の全体の研究内容・時間配分の見直しも行い、本研究に尽力したいと考える。
  • フッ素MR画像法によるAβオリゴマー、Aβフィブリル、リン酸化タウ蛋白の同時解析, 日本学術振興会, 科学研究費助成事業 基盤研究(B),   2017年04月01日 - 2021年03月31日, アルツハイマー病の病態は、ベータアミロイドペプチ(Aβ)オリゴマー形成、老人斑の形成、神経原線維変化の形成と進んでいくと考えられている。しかしながら、それぞれの異常蛋白相互の関連については良く解っていない。これらの異常蛋白相互の関連を明らかにするためには、複数の異常蛋白をin vivoで同時に画像化する技術が不可欠である。我々はこれまで、超高磁場MR画像装置を用い、フッ素MR画像法による画像化技術の開発に取り組み、最近、試薬の出す19F-NMR信号のケミカルシフトの違いを利用して、複数の脳内異常蛋白を同時画像化(多重フッ素MR画像法)することに成功した。本研究では、Aβオリゴマー、老人斑、神経原線維変化、の3つの標的に的を絞り、多重フッ素MR画像法を用いて同時解析を行う。アルツハイマー病の遺伝子改変モデルマウスに対して、経時的に多重フッ素MR画像を試み、Aβオリゴマーや老人斑、神経原線維変化がどのように脳内で形成されて伝搬していくか、in vivoで解析する. アルツハイマー病は、本来、この3つの主要病変が相互作用しながら進展しており、ひとつの病変(たとえばアミロイド病理)を標的にした薬であっても、3病変に対して影響を及ぼしていることは、十分に考えられる。したがって、動物を生かしたまま複数の病変を解析できる技術は、治療薬開発にとっても極めて重要と考える。そこで、多重フッ素MR画像法を治療薬開発研究に応用する。とともに、治療薬の効果を検証することも研究計画に加える。
  • コホート・生体試料支援プラットフォーム, 日本学術振興会, 科学研究費助成事業 新学術領域研究(研究領域提案型)『学術研究支援基盤形成』,   2016年 - 2021年, ①総括支援活動 : 10.2万名の健常人コホートにより、経時的生活情報とともに血清、DNA等のバイオリソースを、また、がん組織、脳疾患や高齢者の脳組織等から、倫理面に十分配慮された、1万件に達する生体試料を、それぞれ収集してきた。これらの研究基盤リソースを提供するとともに、これをさらに全国規模で発展継続させ、生命科学研究者の独創的な基盤的研究に貢献しようとする、この分野における我が国最大規模の支援である。当プラットフォームの支援活動自体は国民一人ひとりとの関わりが強い活動であることから、総括支援活動においては、その支援内容や知見について広く市民の理解を得られるよう、青少年を含む一般市民に向けた公開講座を、シンポジウム等とならんで首都圏以外の各地でも積極的に開催してきた。 ②コホートによるバイオリソース支援活動 : 従来の血清、血漿、DNA、生活習慣・健診データ、ゲノムワイド関連解析(GWAS)用タイピングデータに加え、追跡調査で判明したがん罹患症例についても、GWAS用タイピングを開始し、研究支援準備を進めた。 ③ブレインリソースの整備と活用支援 : ブレインバンク生前ドナー登録を剖検がほぼ零の沖縄に拡大した。RIN、apoE genotypingによるリソース品質管理を生前同意登録全例に拡大した。広島大学ブレインバンク拠点構築に着手した。 ④生体試料による支援活動 : 205課題に生体機能分子の高感度解析・技術支援と連携構築支援を実施した。135課題にがん試料・情報(組織、血液)を提供、5,513試料を収集。解析支援・連携支援・試料支援体制を強化。普及・啓発講演を実施した。
  • 高齢者タウオパチー診断を目指した病態研究, 日本学術振興会, 科学研究費助成事業 基盤研究(C),   2017年04月01日 - 2020年03月31日, a) 年間30例程の病理解剖症例の蓄積は継続して進められている。ただ、神経原線維変化型認知症(SD-NFT)及び嗜銀顆粒型認知症(AGD)の症例は必ずしも多 数ではないため、症例数の点からは当初の計画どうりには増えていない。ただ、これまでに病理解剖が終了し、病理診断まで終了している症例における臨床・病 理解剖記録の臨床 記録のデータ収集は終了している。新たな症例に関しては、今後もサンプル収集、臨床・病理解析を進めていく。 この点における体制は昨年度と変わらず継続している。 b) 病理検索においては、神経病理診断のため一般的形態的組織染色の他老人斑を形成するアミロイド蛋白(Aβ)や、神経原線維変化の原因物質であるリン酸化 タウ蛋白(p-tau)などの 主な免疫染色も新たに追加された症例を除いて終了している。さらに蓄積された症例に関しても臨床神経病理検討会を定期的に行な い、一定ペースで進めている。マーカー候補の探索においては、昨年度の補体の挙動に加え、今年度は鉄代謝関連マーカーの検索も始めている。 c) マイクロアレー解析は既に終了しているデータの見直しをしており、新たな追加は行わない方針とした。 d) メタボローム解析はヒト脳サンプルの前処理条件検討は終了した。 e) 血液診断マーカー探索は新たなコホート体制を構築できた。また、筑波大内田らとともに英国との共同研究体制の構築を開始している。 f) 認知症関連の異常蓄積蛋白が実際の血漿補体などに影響を及ぼすかについて、vitroにおける実験体制を構築しつつある。
  • 医療・介護に関する事前指示書オンライン登録システムの開発と有効性の評価, 日本学術振興会, 科学研究費助成事業 基盤研究(C),   2017年04月01日 - 2020年03月31日, 本研究では,終末期における医療・介護に関する事前指示(アドバンス・ケア・プランニング:以下ACP)をオンライン・クラウド型の事前指示書に記載し,それを多施設で情報共有する為のシステムを試験的に構築し,評価することを目的とするものである.初年度の計画では,これらのシステム構築を図る事を目標とし,第1段階として,ACPに関する事前指示書をオンラインで登録できるよう,Webシステムの開発を目指した.本システムの主たる利用者は一般者であるが,予備的なアンケート調査において,ACP全般についての理解が十分進んでいないことが判明した.このため,本システムを利用する際には,ACPそのものの趣旨や意義についても理解が得られるよう,内容を平易な表現で解説し,追加資料などの閲覧により補助できるようなwebコンテンツが必要と考えられた.初年度は,試験的にwebコンテンツを開発し,複数の医療機関の医療関係者によりチェックを受けた後,その後複数の病院を訪問中の一般者を無作為に選出し,試験的に閲覧した後のアンケート調査を実施した.計43名分のアンケート結果が得られ,解析を行った.2年度についてはこれを元に,改良型のwebシステムを調整中であり,今後これをオンライン・クラウド型のwebシステムに拡張予定であったが,本webシステム利用者の認証確認システムやアクセス制限の管理,さらに保存される個人情報の保管・保全に関する検証などを行ったが,安全性の確立などに時間を要しており,正式なシステム運用開始が遅れている.現在,より安全性の高いクラウド型webシステム構築を行う為にweb製作業者を選定中であり,選定が済み次第,作成を依頼する予定となっている.また,本システムは,医療・福祉関係者による情報利用の共有がテーマであるが,本研究に協力して頂ける医療・福祉施設の選定を勧めており,次年度の試験運用に向けて準備を始めている.
  • 歯周病によるアルツハイマー病病態促進の分子機構解明と治療介入による認知症進行抑止, 日本学術振興会, 科学研究費助成事業 基盤研究(B),   2016年04月01日 - 2019年03月31日, 歯周病を惹起させたADモデルマウスを使った研究から、歯周病における慢性炎症が脳内に波及し、それによって脳内Aβ産生増加、サイトカインレベルの上昇を来たし、AD病態悪化と認知機能障害を誘導することを明らかにした(NPJ Aging Mech Dis, 2017)。 また、認知症患者に対して歯周病治療・口腔ケアの介入によって認知症進行を抑止するかどうかを検証する臨床研究を認知症患者40名を対象に行った(文部科学省基盤研究B-当該研究)。その結果、歯周病治療・口腔ケア介入群では、認知症の進行が予防されることを示唆するデータを得た。
  • マウストランスクリプトミクス新戦略によるアルツハイマー病関連遺伝子同定と機能解析, 日本学術振興会, 科学研究費助成事業 基盤研究(C),   2014年04月01日 - 2018年03月31日, アルツハイマー病は複雑な多因子疾患である。その解明のため現在行われているヒトゲノムワイド関連解析(Genome Wide Association Study: GWAS)は膨大な研究リソースが必要である。また同定された疾患関連遺伝子の機能解析は難航している。 本研究ではヒトの代わりにマウスを、ゲノム解析の代わり独自の発現解析を行った。DBA/2というマウス系統ではアルツハイマー病の中心病理であるAβ脳内蓄積量が低かった。DBA/2のどの遺伝子がAβ蓄積量を抑制している遺伝子産物KLC1vEを独自の2段階トランスクリプトームで同定した。この結果はヒト剖検脳や新競培養細胞でも確認された。
  • コレステロール恒常性の鍵をにぎるABC蛋白質の作用機構解明, 日本学術振興会, 科学研究費助成事業 基盤研究(S),   2013年05月31日 - 2018年03月31日, ABC蛋白質は、共通のATP加水分解ドメインをもつ膜蛋白質の総称で、人の健康維持に重要な役割を果たしている。本研究は、コレステロール恒常性に関わるABC蛋白質の輸送機構と生理的役割の解明を目的とした。その結果、HDL(いわゆる善玉コレステロール)の産生メカニズムに関して、これまで信じられてきた機構とは全く異なる新規機構を提唱するに至った。また、ABCA1が細胞膜中でコレステロールの分布を変化させ増殖シグナルを微調整していることを発見した。さらに、脂溶性化合物排出ポンプABCB1の高分解能での構造解析によって輸送機構を解明し、コレステロール輸送型ABC蛋白質の研究の基盤を構築することに成功した。
  • 鼻粘膜に存在する認知症バイオマーカーの同定と鼻粘膜を用いた低侵襲的診断法の開発, 日本学術振興会, 科学研究費助成事業 挑戦的萌芽研究,   2014年04月01日 - 2016年03月31日, アルツハイマー病(AD)の早期診断法として、PETによるアミロイドイメージングや髄液中のβアミロイドペプチド(Aβ)の測定が提唱されているが、もっと簡便で侵襲が少なく安価な診断法の開発が期待されている。我々は、血液を介さずに脳内との間で物質の移動が行われる鼻腔・鼻粘膜に着目し、鼻粘膜に存在する認知症バイオマーカーの同定と測定技術の確立を目的に本研究を行った。その結果、ヒト鼻粘膜中にAβ、タウ、リン酸化タウが存在することを明らかにした。さらに、ヒト鼻粘膜サンプルをからAβ42を定量測定する方法を開発して学術誌に発表した。開発した方法を用いてAD患者、対照例を対象に臨床研究を実施した。
  • 平野小体・顆粒空胞変性形成過程におけるHCNP前駆体蛋白の働き, 日本学術振興会, 科学研究費助成事業 基盤研究(C),   2013年04月01日 - 2016年03月31日, 孤発アルツハイマー病解明には、加齢変化を念頭に入れた検討が重要である。海馬・海馬傍回の平野小体・顆粒空胞変性は加齢変化の一つで、認知症によって急激に増加する。本研究では、海馬神経機能調節因子である海馬由来コリン作動性神経刺激ペプチドの前駆体タンパクが軽度酸性化された細胞内において平野小体形成に関与する可能性およびそのリン酸化体が顆粒空胞変性の形成過程にp62と共に関連している可能性が示唆された。
  • 包括型脳科学研究推進支援ネットワーク, 日本学術振興会, 科学研究費助成事業 新学術領域研究(研究領域提案型),   2010年04月01日 - 2016年03月31日, 科学研究費助成事業によって推進される個別研究者と、脳の遺伝子、分子、回路、システムから行動、病態、計算理論などの分野の「新学術領域研究」に所属する研究者からの要望に応えて、最先端の研究リソース・技術を提供した。また、異分野の研究者が共同で実施する研究を積極的に支援し、異分野交流ワークショップの開催、若手研究者育成支援を行った。これにより、研究分野を融合する独創的な成果を多数挙げることに貢献した。
  • ヒトサンプルでのアンギオテンシン変換酵素とアルツハイマー病の関連性に関する研究, 日本学術振興会, 科学研究費助成事業 基盤研究(C),   2012年04月01日 - 2015年03月31日, アンギオテンシン変換酵素(ACE)がAβ1-42を1-40に切断する事をヒト、マウスで明らかにした。ACEには遺伝子多型(Isoleucine; I/Aspartic acid; D)が存在しI typeが発症リスクとされている。神経病理診断を行った488例でACE I/D多型とAlzheimer病(AD)との関連を検討した。165例がADと診断されACE多型はAD群DD 25(15%)/ID 73(44%)/II 67(41%)に対しnon AD 群がDD 42(13%)/ID 141(44%)/II 140(43%)となりカイ二乗検定では統計的有意差はなかった。
  • モデル動物など多角的研究方法によるアルツハイマー病関連遺伝子の同定とその機構解明, 日本学術振興会, 科学研究費助成事業 基盤研究(C),   2011年 - 2013年, 我々はアルツハイマー病の中心病理である脳内Aβ蓄積量がマウスストレイン間で大きく異なることを見出した。マウスストレインの差異をトランスクリプトーム解析するというこれまでにない研究戦略を立案実行し、Aβ蓄積修飾因子KLC1 splice variant E(KLC1 E)の同定に成功した。 Klc1とAβ蓄積の関係はマウスのゲノム解析でも確認された。マウスにおいてDBA/2由来のKlc1アレルを持つとKlc1E発現量が低く脳内アミロイドβ蛋白蓄積量も低くなることが解明された.
  • 統合失調症死後脳における異常タンパクの半網羅的定量的プロファイル解析, 日本学術振興会, 科学研究費助成事業 若手研究(B),   2011年 - 2013年, 我々は、統合失調症及び健常対照各10 例の凍結脳サンプルの前頭前野皮質について、質量分析に基づく新規の網羅的及び標的指向的タンパク質解析法を用いてタンパク質発現比較を行った。網羅的解析では8768分子のタンパク質が同定され、そのうち300分子で統合失調症と対照で有意な差が認められた。標的指向的解析では統合失調症病態関連する候補分子108分子についてタンパク質発現量解析を行い、数種のタンパク質で有意な差を得た。これらの分子には既報の因子及び本研究で新規に明らかになった因子が存在した。これらのタンパク質については凍結脳を蛍光免疫組織化学染色し、細胞組織内局在及び発現強度の比較も行った。
  • 脂質輸送に関与するABC蛋白質の生理的基質と機能の解明, 日本学術振興会, 科学研究費助成事業 基盤研究(S),   2008年 - 2012年, ABC 蛋白質は、共通の ATP 加水分解ドメインをもち、さまざまな物質を細胞膜を介して輸送する膜蛋白質の総称である。ヒト染色体上には 48 種の ABC 蛋白質遺伝子が存在し、それらの異常はさまざまな疾病と関係している。本研究は、特に脂質恒常性に関わる ABC 蛋白質の輸送基質の同定と機能の解明をめざし、生化学的・細胞生物学的解析と全反射蛍光顕微鏡を用いた 1分子観察、さらには結晶構造解析を統合して行った。
  • シノビオリンを機軸とした関節リウマチの総合的理解, 日本学術振興会, 科学研究費助成事業 基盤研究(A),   2008年 - 2011年, われわれがリウマチ滑膜細胞より発見した小胞体関連E3ユビキチンリガーゼ シノビオリンは遺伝子改変動物を用いた研究により、少なくともマウスにおいては関節症発症の必要十分因子であることが証明されていた。また、関節リウマチの新薬である抗TNFα製剤の感受性を決定するバイオマーカーの可能性も示されている。一方で、シノビオリンの完全欠損マウスは胎生期において致死であることも明らかとなっていた。したがって、これまで成獣における同分子の生理機能の解析、並びに関節症における分子病態を明らかとすることが不可能であった。そこで、本研究事業により、同分子のコンディショナルノックアウトマウスを作製し、これらの点を明らかにすることを目的とした。 その結果、シノビオリンのコンディショナルノックアウトマウスは胎生致死でのみならず、出生後に同遺伝子をノックアウトした場合でも致死であることを発見した。さらに、その過程で線維化・慢性炎症に非常に密接に関与することが示されている(論文準備中)。現在、その恒常性維持にシノビオリンが必要と考えられる関節などの臓器特異的なコンディショナルノックアウトマウスの解析を行っている。 上記のようにシノビオリンの機能制御は関節リウマチのみならず、線維化・慢性炎症を基盤とする疾患の創薬標的であることは明白であろう。われわれの有するシノビオリン抑制剤がマウスにおける関節炎モデルに有効であることを証明した(論文投稿中)。さらに、本テーマは橋渡し研究として米国のユビキチンに特化した創薬系ベンチャー プロジェンラ社との創薬開発プロジェクトへと進展した。
  • 実験動物における種特異的補体制御膜因子の研究, 日本学術振興会, 科学研究費助成事業 国際学術研究,   1996年 - 1997年, 種特異的補体制御膜因子は自己細胞に対する補体反応を防いで、侵入異物にのみ補体が反応するという、自己・非自己の識別を司る合い言葉の役割を果たすと考えられる。 ヒトの種特異的補体制御膜因子としては、DAF,MCP,HRF20(CD59)などがcDNAのクローニングも含めて同定され、作用機序の解析も進んでいたが、実験動物での研究は立ち遅れていた。 我々は、ラットの512Ag(Crry)の他に、ラットDAF,MCPのcDNAのクローニングやマウスのDAF,MCP,CD59等のcDNAクローニングにも成功した。Morgan教授らもラットのCD59の他に、我々とは別の方法でラットDAFのcDNAをクローニングすると共に、それに対するモノクローナル抗体の作成にも成功した。 我々は更にモルモットのDAFやMCPのcDNAをクローニングすると共に、その遺伝子をハムスター細胞に導入発現させ、補体活性化制抑作用について解析し、Altemative spricingによって多形性を示すDAFの中で鎖長の長いものの方が補体抑制活性が強いことを示した。マウスのDAFについては、CHOに遺伝子導入して発現させたトランスフェクタントをアルメニアハムスターに免疫して、そのリンパ球をマウスミエローマ細胞株と融合させてハイブリドーマをつくり、モノクローナル抗体産生株を樹立した。 我々の作成したモノクローナル抗体やMorgan教授らの作成したモノクローナル抗体を用いて免疫組織染色を行い、ラット、マウス、モルモット等の実験動物における種特異的補体制御膜因子群の生体内における発現動態を明らかにした。更に、消化管等に炎症をおこさせることにより、DAF等の発現増強が起こることも示した。 炎症反応に関わる膜分子としてラットのC5aレセプターの遺伝子をクローニングすると共に、C3aレセプターのcDNAのクローニングについても英国のグループと共同で成果を挙げた。

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