2021/08/04 更新

写真a

フクイ ユウスケ
福井 裕介
Fukui Yusuke
所属
岡山大学病院 助教(特任)
職名
助教(特任)
外部リンク

研究分野

  • ライフサイエンス / 神経科学一般

経歴

  • 岡山大学大学院医歯薬学総合研究科   脳神経内科学   助教

    2021年4月 - 現在

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  • 四国こどもとおとなの医療センター   流動研究員

    2019年4月 - 2021年3月

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  • 国立長寿医療研究センター   流動研究員

    2018年4月 - 2019年3月

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所属学協会

 

論文

  • Neuroprotective effects of Scallop-derived plasmalogen in a mouse model of ischemic stroke. 査読 国際誌

    Tian Feng, Xinran Hu, Yusuke Fukui, Koh Tadokoro, Zhihong Bian, Ryuta Morihara, Toru Yamashita, Koji Abe

    Brain research   1766   147516 - 147516   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Scallop-derived plasmalogen (sPlas) has both anti-oxidative and anti-inflammation activities, but its efficacy has not been investigated in ischemic stroke models where oxidative stress, inflammation, and neurovascular unit (NVU) damage accelerates pathophysiological progression. Therefore, in the present study, we aimed to assess the neuroprotective effects of sPlas in ischemic stroke by using a transient middle cerebral artery occlusion (tMCAO) mouse model. After the pretreatment of vehicle or sPlas (10 mg/kg/day) for 14 days, adult male mice were subjected to tMCAO for 60 min, then continuously treated with vehicle or sPlas during reperfusion and for an additional 5 days. The administration of sPlas significantly improved motor deficits (corner and rotarod tests, *p < 0.05 vs vehicle), enhanced serum antioxidative activity (OXY-adsorbent and d-ROMs tests, *p < 0.05 vs vehicle), reduced infarction volume (*p < 0.05 vs vehicle), decreased the expression of two oxidative stress markers, 4-HNE (*p < 0.05 vs vehicle) and 8-OHdG (*p < 0.05 vs vehicle), decreased the expression of pro-inflammatory markers Iba-1 (**p < 0.01 vs vehicle), IL-1β (**p < 0.01 vs vehicle), and TNF-α (**p < 0.01 vs vehicle), and alleviated NVU damage (collagen IV, MMP9, and GFAP/collagen IV, *p < 0.05 vs vehicle). Our present findings are the first to demonstrate the neuroprotective effects of sPlas on acute ischemic stroke mice at 5 d after tMCAO via anti-oxidative stress, anti-inflammation, and improvement of NVU damage, suggesting the potential of sPlas in preventing and treating ischemic stroke.

    DOI: 10.1016/j.brainres.2021.147516

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  • Early detection of cognitive decline in mild cognitive impairment and Alzheimer's disease with a novel eye tracking test. 査読 国際誌

    Koh Tadokoro, Toru Yamashita, Yusuke Fukui, Emi Nomura, Yasuyuki Ohta, Setsuko Ueno, Saya Nishina, Keiichiro Tsunoda, Yosuke Wakutani, Yoshiki Takao, Takahiro Miyoshi, Yasuto Higashi, Yosuke Osakada, Ryo Sasaki, Namiko Matsumoto, Yuko Kawahara, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Ryuta Morihara, Koji Abe

    Journal of the neurological sciences   427   117529 - 117529   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Due to an increasing number of dementia patients, the development of a rapid and sensitive method for cognitive assessment is awaited. Here, we examined the usefulness of a novel and short (3 min) eye tracking device to evaluate the cognitive function of normal control (NC, n = 52), mild cognitive impairment (MCI, n = 52), and Alzheimer's disease (AD, n = 70) subjects. Eye tracking total score declined significantly in MCI (**p < 0.01 vs NC) and AD (**p < 0.01 vs NC, ##p < 0.01 vs MCI), and correlated well with the mini-mental state examination (MMSE) score (r = 0.57, *p < 0.05). Furthermore, the eye tracking test, especially memory and deductive reasoning tasks, effectively discriminated NC, MCI and AD. The present novel eye tracking test clearly discriminated cognitive functions among NC, MCI, and AD subjects, thereby providing an advantage for the early detection of MCI and AD in screening.

    DOI: 10.1016/j.jns.2021.117529

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  • Hypoxic stress visualized in the cervical spinal cord of ALS patients. 査読 国際誌

    Toru Yamashita, Tetsuhiro Hatakeyama, Kota Sato, Yusuke Fukui, Nozomi Hishikawa, Mami Takemoto, Yasuyuki Ohta, Yoshihiro Nishiyama, Nobuyuki Kawai, Takashi Tamiya, Koji Abe

    Neurological research   43 ( 6 )   429 - 433   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objective: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease. Hypoxic stress is suspected as the pathogenesis of ALS, however, no positron emission tomography (PET) study for hypoxic stress has been conducted in the spinal cord of ALS patients.Methods: In the present study, we examined cervical spinal hypoxic stress of nineALS patients with upper extremity (U/E) atrophy by18F-fluoromisonidazole (FMISO) PET.Results: On the ipsilateral side of C1 and C5 levels, 18F-FMISO uptake increased significantly compared with the contralateral side (*p < 0.05) and the control subject (**p < 0.01). In addition, a strong correlation was found between 18F-FMISO uptake of the C5 level and the rate of progression of the ALS FRS-R score (R = 0.781, *p = 0.013).Conclusion: These results indicate that hypoxic stress increased in the spinal cord of ALS patients with a close link to ALS progression. Both hypoxic stress and a compromised response to hypoxia, which may lead to subsequent motor neuron death, could be a potential therapeutic target for ALS.

    DOI: 10.1080/01616412.2020.1866383

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  • Antioxidative and neuroprotective effects of ascidiacea-derived plasmalogen in a mouse stroke model 査読

    Yusuke Fukui, Tian Feng, Koh Tadokoro, Yoshio Omote, Mami Takemoto, Ryuta Morihara, Toru Yamashita, Koji Abe

    Brain Supplement   3   8 - 17   2021年4月

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    担当区分:筆頭著者   掲載種別:研究論文(学術雑誌)  

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  • Bone Marrow Stromal Cell Transplantation Drives Molecular Switch from Autophagy to the Ubiquitin-Proteasome System in Ischemic Stroke Mice. 査読 国際誌

    Koh Tadokoro, Yusuke Fukui, Toru Yamashita, Xia Liu, Keiichiro Tsunoda, Jingwei Shang, Ryuta Morihara, Yumiko Nakano, Feng Tian, Ryo Sasaki, Namiko Matsumoto, Emi Nomura, Xiaowen Shi, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   29 ( 5 )   104743 - 104743   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Bone marrow stromal cell (BMSC) transplantation is a promising therapeutic approach for cerebral ischemia, as it elicits multiple neuroprotective effects. However, it remains unclear how BMSC transplantation modulates the ubiquitin-proteasome system (UPS) and autophagy under cerebral ischemia. METHODS: In the present study, an intermediate level of cerebral ischemia (30 minutes) was chosen to examine the effect of BMSC transplantation on the molecular switch regulating UPS and autophagy. BMSC or vehicle was stereotactically injected into the penumbra 15 minutes after sham operation or transient middle cerebral artery occlusion (tMCAO). RESULTS: Thirty minutes of tMCAO artery occlusion significantly increased TUNEL-, ubiquitin-, and p62-positive cells (which peaked at 72 hours, 2 hours, and 2 hours after reperfusion, respectively) and ratios of both BAG3/BAG1 and LC3-II/LC3-I at 24 hours after reperfusion. However, intracerebral injection of BMSCs significantly reduced infarct volume and numbers of TUNEL- and p62-positive cells, and improved BAG3/BAG1 and LC3-II/LC3-I ratios. In addition, observed increases in ubiquitin-positive cells 2 hours after reperfusion were slightly suppressed by BMSC transplantation. CONCLUSIONS: These data suggest a protective role of BMSC transplantation, which drove the molecular switch from autophagy to UPS in a murine model of ischemic stroke.

    DOI: 10.1016/j.jstrokecerebrovasdis.2020.104743

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  • Yoga-plus exercise mix promotes cognitive, affective, and physical functions in elderly people. 査読 国際誌

    Nozomi Hishikawa, Yoriko Takahashi, Yusuke Fukui, Ryo Tokuchi, Junichi Furusawa, Mami Takemoto, Kota Sato, Toru Yamashita, Yasuyuki Ohta, Koji Abe

    Neurological research   41 ( 11 )   1001 - 1007   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objectives: Increased attention is being paid to Asian medicine in balanced total health care. We investigated the effects of mixed exercise including yoga ('Yoga-plus') among elderly individuals. Methods: A total of 385 subjects (72 males and 313 females, 75.5 ± 8.7 years old) participated in a 12-month (M) exercise program at a health and welfare center, a day service center, and a nursing home. Cognitive, affective, and physical functions, and activities of daily living (ADL), were compared at baseline (0M), 6M and 12M of exercise intervention. Results: Mean scores on the frontal assessment battery, clock drawing test, cube copying test, letter fluency, and category fluency significantly improved after the Yoga-plus intervention, while mini-mental state examination, Hasegawa dementia score-revised, and trail-making test performance were relatively stable. Affective scores on the geriatric depression scale (GDS), apathy scale (AS) and Abe's behavioral and psychological symptoms of dementia were not significantly affected by exercise therapy, but subgroups with higher baseline GDS (GDS ≥ 5) and AS (AS ≥ 16) scores showed a significant improvement after intervention. One-leg standing time and 3-m timed up and go test performance significantly improved after 12M intervention. Discussion: Yoga-plus improved cognitive, affective, ADL, and physical functions in a local elderly population, particularly among below-baseline individuals, indicating the benefits of dementia prevention among elderly individuals.

    DOI: 10.1080/01616412.2019.1672380

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  • Serine Phosphorylation of IRS1 Correlates with Aβ-Unrelated Memory Deficits and Elevation in Aβ Level Prior to the Onset of Memory Decline in AD. 査読

    Wang W, Tanokashira D, Fukui Y, Maruyama M, Kuroiwa C, Saito T, Saido TC, Taguchi A

    Nutrients   11 ( 8 )   2019年8月

  • Neuroprotective effects of SMTP-44D in mice stroke model in relation to neurovascular unit and trophic coupling. 査読 国際誌

    Xiaowen Shi, Yasuyuki Ohta, Jingwei Shang, Ryuta Morihara, Yumiko Nakano, Yusuke Fukui, Xia Liu, Tian Feng, Yong Huang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Eriko Suzuki, Keiji Hasumi, Koji Abe

    Journal of neuroscience research   96 ( 12 )   1887 - 1899   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Stachybotrys microspora triprenyl phenol (SMTP)-44D has both anti-oxidative and anti-inflammatory activities, but its efficacy has not been proved in relation to the pathological changes of neurovascular unit (NVU) and neurovascular trophic coupling (NVTC) in ischemic stroke. Here, the present study was designed to assess the efficacies of SMTP-44D, moreover, compared with the standard neuroprotective reagent edaravone in ischemic brains. ICR mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min, SMTP-44D (10 mg/kg) or edaravone (3 mg/kg) was intravenously administrated through subclavian vein just after the reperfusion, and these mice were examined at 1, 3, and 7 d after reperfusion. Compared with the vehicle group, SMTP-44D treatment revealed obvious ameliorations in clinical scores and infarct volume, meanwhile, markedly suppressed the accumulations of 4-HNE, 8-OHdG, nitrotyrosine, RAGE, TNF-α, Iba-1, and cleaved caspase-3 after tMCAO. In addition, SMTP-44D significantly prevented the dissociation of NVU and improved the intensity of NAGO/BDNF and the number of BDNF/TrkB and BDNF/NeuN double positive cells. These effects of SMTP-44D in reducing oxidative and inflammatory stresses were similar to or stronger than those of edaravone. The present study demonstrated that SMTP-44D showed strong anti-oxidative, anti-inflammatory, and anti-apoptotic effects, moreover, the drug also significantly improved the NVU damage and NVTC in the ischemic brain.

    DOI: 10.1002/jnr.24326

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  • Antineuroinflammatory Effect of SMTP-7 in Ischemic Mice. 査読 国際誌

    Yong Huang, Yasuyuki Ohta, Jingwei Shang, Ryuta Morihara, Yumiko Nakano, Yusuke Fukui, Xia Liu, Xiaowen Shi, Tian Feng, Toru Yamashita, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Eriko Suzuki, Keiji Hasumi, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   27 ( 11 )   3084 - 3094   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Stachybotrys microspora triprenyl phenol-7 (SMTP-7) has both potentials of thrombolytic and neuroprotective effects, but its detailed neuroprotective mechanisms in ischemic stroke are still unclear. Here, we assessed the neuroprotective effects of SMTP-7 for anti-inflammatory and antiapoptosis mechanisms after 60 minutes of transient middle cerebral artery occlusion (tMCAO) in mice. METHODS: After 60minutes of tMCAO, 0.9% NaCl, tissue-type plasminogen activator (tPA), SMTP-7 or tPA+SMTP-7 was intravenously administrated through subclavian vein just before the reperfusion, and these mice were examined at 24hours after reperfusion. We histologically assessed the antineuroinflammatory effect of SMTP-7 on the expressive changes of inflammatory markers in ischemic mouse brains. RESULTS: Compared with the vehicle and tPA groups, SMTP-7 treatment significantly improved clinical scores and decreased the infarct volume and the numbers of TNF-α, nuclear factor-κB (NF-κB), nucleotide oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), and cleaved caspase-3-positive cells in the brain of mice at 24hours after tMCAO but not p62-positive cells. However, tPA+SMTP-7 treatment did not show such effects. CONCLUSIONS: The present study suggested that SMTP-7 provides a therapeutic benefit for ischemic stroke mice through anti-inflammatory and antiapoptotic effects but not antiautophagic effect.

    DOI: 10.1016/j.jstrokecerebrovasdis.2018.06.039

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  • Chronic cerebral hypoperfusion accelerates Alzheimer's disease pathology with the change of mitochondrial fission and fusion proteins expression in a novel mouse model. 査読 国際誌

    Tian Feng, Toru Yamashita, Yun Zhai, Jingwei Shang, Yumiko Nakano, Ryuta Morihara, Yusuke Fukui, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Brain research   1696   63 - 70   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mitochondrial dynamically undergo massive fusion and fission events to continuously maintain their function in cells. Although an impaired balance of mitochondrial fission and fusion was reported in in-vitro and in-vivo Alzheimer's disease (AD) model, changes of mitochondrial fission and fusion proteins have not been reported in AD with chronic cerebral hypoperfusion (HP) as an etiological factor related to the development of elder AD. To clarify the impacts of HP on mitochondrial fission and fusion, related oxidative stress in the pathogenesis of AD, and protective effect of galantamine, the novel AD with HP mouse model (APP23 + HP) was applied in this project. Compared with APP23 mice, APP23 + HP mice greatly enhanced the number of Aβ oligomer-positive/phosphorylated tau (pTau) cells, the expression of mitochondrial fission proteins (Drp1 and Fis1), and decreased the expression of mitochondrial fusion proteins (Opa1 and Mfn1) in the cerebral cortex (CTX) and thalamus (TH) at 12 month (M) of age. Moreover, the expression of peroxidation products (4-HNE and 8-OHdG) showed a significant increase in CTX and TH of APP23 + HP mice at 12 M. However, above neuropathological characteristics were retrieved by galantamine (Gal) treatment, detected through immunohistochemical analyses. The present study demonstrates that cerebral HP shifted the balance in mitochondrial morphology from fusion to fission with increasing Aβ oligomer/pTau accumulations in APP23 mice, and such neuropathologic processes were strongly attenuated by Gal treatment.

    DOI: 10.1016/j.brainres.2018.06.003

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  • Protective effect of a novel sigma-1 receptor agonist is associated with reduced endoplasmic reticulum stress in stroke male mice. 査読 国際誌

    Ryuta Morihara, Toru Yamashita, Xia Liu, Yumiko Nakano, Yusuke Fukui, Kota Sato, Yasuyuki Ohta, Nozomi Hishikawa, Jingwei Shang, Koji Abe

    Journal of neuroscience research   96 ( 10 )   1707 - 1716   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sigma-1 receptor (Sig-1R) is expressed at endoplasmic reticulum (ER) membranes, where it regulates a variety of specific physiological functions. However, the profile and exact roles of ER stress-related molecules after Sig-1R agonist treatment in an in vivo stroke model are largely unknown. The aim of this study is to investigate the effect of a novel Sig-1R agonist, aniline derivative compound (Comp-AD), on the ER stress response following ischemic stroke. Male C57BL/6J mice received transient middle cerebral artery occlusion for 90 min, and were then treated with vehicle saline or Comp-AD at reperfusion. At 3 hr, 1 day, and 7 days after reperfusion, immunohis- tochemistry was performed for Sig-1R and ER stress-related proteins including phospho protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), phospho inositol requiring enzyme 1α (p- IRE1α), and activating transcription factor 6 (ATF6). Neurobehavioral analysis showed improved functional recovery at 1 day and 7 days after reperfusion, and the infarct volume was significantly smaller at 7 days (p < .05), in the Comp-AD group compared with the vehicle group. Comp-AD treatment upregulated Sig-1R immunoreactivity at 3 hr and 1 day (p < .05), and reduced p-PERK and p-IRE1α expression at 1 day (p < .05, respectively), in the peri-ischemic region compared with the vehicle group. Treatment with the novel Sig-1R agonist Comp-AD was neuroprotective after transient middle cerebral artery occlusion, and was associated with upregulation of Sig-1R and a reduction of ER stress.

    DOI: 10.1002/jnr.24270

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  • A Unique Case with Oral Dyskinesia, Chorea, Ataxia, and Mild Cognitive Impairment with Caudate Atrophy and Characteristic Brain Calcifications. 査読

    Nozomi Hishikawa, Yusuke Fukui, Kota Sato, Mami Takemoto, Toru Yamashita, Yasuyuki Ohta, Koji Abe

    Internal medicine (Tokyo, Japan)   57 ( 16 )   2399 - 2402   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The authors report a man who developed oral dyskinesia at 46 years of age, followed by slowly progressive choreic movement and mild cognitive impairment over 20 years. He showed caudate atrophy and four types of intracranial calcification in the hippocampus (dot-like), cerebellar white matter (vague-mass), occipital cortices (laminar), and cerebral white matter (linear). Linear-calcification in the corona radiata seems to be deposition along small veins, which may be related to the white matter changes and to the decreased regional cerebral blood flow in the frontal and parietal lobes. The present case shows a slowly progressive disease with caudate atrophy and characteristic brain calcifications.

    DOI: 10.2169/internalmedicine.9454-17

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  • Therapeutic Effects of Pretreatment with Tocovid on Oxidative Stress in Postischemic Mice Brain. 査読 国際誌

    Jingwei Shang, Hongjing Yan, Yang Jiao, Yasuyuki Ohta, Xia Liu, Xianghong Li, Ryuta Morihara, Yumiko Nakano, Yusuke Fukui, Xiaowen Shi, Yong Huang, Tian Feng, Mami Takemoto, Kota Sato, Nozomi Hishikawa, Toru Yamashita, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   27 ( 8 )   2096 - 2105   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Dietary supplement is an attempt to reduce the risk of ischemic stroke in high-risk population. A new mixed vitamin E-Tocovid that mainly contains tocotrienols other than tocopherol, attenuated the progression of white matter lesions by oral in humans. However, the effect of Tocovid on ischemic stroke has not been examined. In the present study, we assessed the therapeutic effects of Tocovid pretreatment on transient middle cerebral artery occlusion (tMCAO) in mice. MATERIALS AND METHODS: After pretreatment with Tocovid (200 mg/kg/d) or vehicle for 1 month, 60-minute tMCAO was performed, and these mice were examined at 1 day, 3 days, and 7 days after reperfusion. We histologically assessed the effects of Tocovid pretreatment on the expressive changes of oxidative stress markers, cleaved caspase-3, and LC3-II after tMCAO in mice. RESULTS: We observed that Tocovid pretreatment significantly improved the rotarod time, reduced infarct volume, decreased the number of 4-HNE, nitrotyrosine, and 8-OhdG positive cells, inhibited advanced glycation end products biomarkers RAGE, CMA, and CML expressions, and increased Nrf2 and MRP1 levels with GSSG/GSH ratio decrease. Furthermore, Tocovid pretreatment greatly decreased cleaved caspase-3 and LC3-II expressions after tMCAO. CONCLUSIONS: The present study obviously demonstrated that Tocovid pretreatment showed neuroprotective effects against oxidative stress and at least in part by antiapoptotic/autophagic cell death in ischemic mice brain.

    DOI: 10.1016/j.jstrokecerebrovasdis.2018.03.012

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  • Detecting spinal pyramidal tract of amyotrophic lateral sclerosis patients with diffusion tensor tractography. 査読 国際誌

    Yusuke Fukui, Nozomi Hishikawa, Kota Sato, Yumiko Nakano, Ryuta Morihara, Jingwei Shang, Mami Takemoto, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    Neuroscience research   133   58 - 63   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The objective of this study was to determine alteration of corticospinal tract in patients with amyotrophic lateral sclerosis (ALS) using diffusion tensor tractograhy (DTT) focusing on the cervical spinal cord (C5) and transcranial magnetic stimulation (TMS). We recruited 38 ALS, 6 spinal and bulbar muscular atrophy (SBMA), 7 spastic paraplegia (SP) patients, and 8 age-matched normal controls, and then ALS were divided into two subgroups according to their clinical type: 28 ALS-limb and 10 ALS-bulbar. DTT was performed using the diffusion tensor image (DTI) track module to reconstruct two fiber tracts via C5. The fractional anisotropy (FA) values of ALS-total and ALS-limb patients were significantly reduced compared with normal controls, and SBMA patients. On the other hand, the mean diffusivity (MD) values were not significantly different among normal controls and the three disease groups. The rate of disease progression (ΔFRS-R) of ALS patients was significantly correlated with FA values and central motor conduction time (CMCT). In conclusion, the present study demonstrated a significant reduction of FA values in ALS patients, and the ΔFRS-R of ALS patients showed distinct regressions with FA values and CMCT, suggesting that this DTT analysis could be useful for detecting disease progression of ALS patients.

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  • Neuroprotective Effects of Tocovid Pretreatment in a Mouse Stroke Model. 査読 国際誌

    Yang Jiao, Jingwei Shang, Yasuyuki Ohta, Hongjing Yan, Xia Liu, Xianghong Li, Ryuta Morihara, Yumiko Nakano, Yusuke Fukui, Xiaowen Shi, Yong Huang, Tian Feng, Mami Takemoto, Kota Sato, Nozomi Hishikawa, Toru Yamashita, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   27 ( 8 )   2166 - 2174   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Tocovid is a new combination of tocotrienols and tocopherol, both of which are neuroprotective agents for preventing cerebral infarction in mice. However, the effects of tocovid on anti-inflammation in ischemic model remain elusive. In the present study, we assessed the effects of Tocovid pretreatment on anti-inflammatory effects after transient middle cerebral occlusion (tMCAO) in mice. MATERIALS AND METHODS: We evaluated the therapeutic and anti-inflammatory effects of tocovid pretreatment (200 mg/kg per day, for 1 month) on mice brain under 60 minutes of tMCAO. The expressive changes of inflammatory markers were observed after tMCAO in mice. RESULTS: Tocovid pretreatment greatly improved the mice neurobehaviors, reduced infarct volumes and decreased expressions of inflammatory markers such as tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1) and ionized calcium binding adapter molecule-1 (Iba-1), and improved the damage of neurovascular units including matrix metallopeptidase 9, IgG and collagen IV after tMCAO. CONCLUSIONS: Our present findings demonstrated that oral tocovid pretreatment showed obviously neuroprotective and at least in part by anti-inflammatory effects in ischemic mice brain.

    DOI: 10.1016/j.jstrokecerebrovasdis.2018.03.014

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  • Clinical predictors of Alzheimer's disease progression. 査読

    Nozomi Hishikawa, Yusuke Fukui, Mami Takemoto, Kota Sato, Jingwei Shang, Toru Yamashita, Yasuyuki Ohta, Koji Abe

    Geriatrics & gerontology international   18 ( 6 )   929 - 936   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIM: Rates of disease progression differ among patients with Alzheimer's disease (AD), but prognostic predictions remain a challenge. We carried out a clinic-based retrospective study to investigate the clinical factors for AD progression. METHODS: The 748 AD patients, who attended our hospital for >1 year and were given the Mini-Mental State Examination (MMSE) at least three times, were divided into three groups according to the annual change rate of MMSE score (G): Aggravater group (G < -2), Stabler group (-2 ≤ G ≤ 2) and Improver group (2 < G). We compared the three groups on cognitive, affective and activities of daily living functions, response to medication, clinical fluctuations, serum levels of metabolic factors, and neuroimaging data. RESULTS: We found no significant differences in age, sex, educational attainment or body mass index across the groups. The Aggravater group showed better baseline MMSE (P < 0.01) and Abe's behavioral and psychological symptoms of dementia (P < 0.01) scores than the Improver group, but its MMSE improvement after drug treatment was the worst among the three groups (P < 0.01 vs Stabler/Improver). Fluctuations in MMSE (P < 0.01), apathy scale (P < 0.05) and activities of daily living (P < 0.01) scores were smaller in the Improver group than in the Aggravater or Stabler groups. Serum docosahexaenoic acid levels tended to be lower (trend P < 0.05) and voxel-based specific regional analysis system for Alzheimer's disease Z-scores tended to be higher (trend P < 0.05) in the Improver group than in the Stabler or Aggravater groups. CONCLUSIONS: Initial responses to medication, fluctuations in cognitive, affective and activities of daily living functions, serum docosahexaenoic acid levels, and medial temporal atrophy are clinical factors related to AD prognosis. Geriatr Gerontol Int 2018; 18: 929-936.

    DOI: 10.1111/ggi.13286

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  • Different Associations of Plasma Biomarkers in Alzheimer's Disease, Mild Cognitive Impairment, Vascular Dementia, and Ischemic Stroke. 査読 国際誌

    Jingwei Shang, Toru Yamashita, Yusuke Fukui, Dongjing Song, Xianghong Li, Yun Zhai, Yumiko Nakano, Ryuta Morihara, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Journal of clinical neurology (Seoul, Korea)   14 ( 1 )   29 - 34   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND PURPOSE: Cognitive and cerebrovascular diseases are common in the elderly, but differences in the plasma levels and associations of plasma biomarkers in these diseases remain elusive. METHODS: The present study investigated differences in plasma fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], adiponectin, reptin, plasma markers of inflammation [high-sensitivity C-reactive protein (hsCRP) and serum amyloid A (serum AA)], and plasma lipids [high-density lipoprotein and low-density lipoprotein (LDL)] in patients with Alzheimer's disease (AD) (n=266), mild cognitive impairment (MCI) (n=44), vascular dementia (VaD) (n=33), and ischemic stroke (IS) (n=200) in comparison to normal controls (n=130). RESULTS: The serological data showed that lower EPA and DHA levels and higher reptin and LDL levels were associated with AD and IS, the reptin/adiponectin ratio was strongly associated with IS, the hsCRP level was more strongly associated with VaD and IS, and the serum AA level was associated with all three cognitive diseases and IS. CONCLUSIONS: This is the first report of differences in the expression levels of plasma biomarkers and peripheral arterial tonometry among AD, MCI, VaD, and IS patients and normal controls. These different associations indicate that diverse pathological mechanisms underlie these diseases.

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  • Different clinical effect of four antidementia drugs for Alzheimer's disease patients depending on white matter severity 査読

    Yusuke Fukui, Nozomi Hishikawa, Jin Ichinose, Kota Sato, Yumiko Nakano, Ryuta Morihara, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    GERIATRICS & GERONTOLOGY INTERNATIONAL   17 ( 11 )   1991 - 1999   2017年11月

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

    AimTo examine the clinical effect of four antidementia drugs (donepezil, galantamine, rivastigmine and memantine) in Alzheimer's disease patients who were divided into subgroups based on their periventricular hyperintensity (PVH) severity.
    MethodsA total of 551 Alzheimer's disease patients (201 men and 350 women) were divided into four subgroups based on their PVH severity (0-III). They received monotherapy for 12 months. We compared the clinical effects at the baseline, and at 3, 6 and 12 months after initiation.
    ResultsThe baseline age became higher with PVH grades, and the Mini-Mental State Examination and Hasegawa Dementia Scale-Revised showed a decrease that was dependent on white matter severity. Although the PVH 0 subgroup showed stable cognitive, affective and ADL functions until 12 months in all four drug groups, the PVH I subgroup showed an improved Apathy Scale from the baseline in response to memantine at 3 and 9 months (P &lt; 0.05), and galantamine at 9 months (P &lt; 0.01). In the PVH II subgroup, the Mini-Mental State Examination showed a significant improvement from the baseline in response to galantamine (P &lt; 0.05) at 9 months and Hasegawa Dementia Scale-Revised (P &lt; 0.05) at 3 months. In the PVH III subgroup, cognitive and affective functions were preserved in all four drug groups until 12 months, but activities of daily living deteriorated in the riverstigmine group at 6 and 12 months (P &lt; 0.05).
    ConclusionsThe present study shows that these four drugs showed sensitivity dependent on white matter severity that clinically affected cognitive, affective and activities of daily living functions. Geriatr Gerontol Int 2017; 17: 1991-1999.

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  • Comprehensive effects of galantamine and cilostazol combination therapy on patientswith Alzheimer's disease with asymptomatic lacunar infarction 査読

    Nozomi Hishikawa, Yusuke Fukui, Kota Sato, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    GERIATRICS & GERONTOLOGY INTERNATIONAL   17 ( 10 )   1384 - 1391   2017年10月

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

    Aim: The coexistence of Alzheimer's disease (AD) and cerebrovascular disease pathology increases age-dependently. WC comprehensively analyzed the clinical effects of galantamine or cilostazol monotherapy to the add-on combination therapy on three major factors of dementia, such as cognitive, affective and activities of daily living functions in AD patients with asymptomatic lacunar infarction.
    Methods: We divided 101 AD patients with asymptomatic lacunar infarction into two subgroups: group A (a = 61, first treated with galantamine and then cilostazol added) and group B (n=40, first treated with cilostazol and galantamine added). We compared the clinical effects before and after combination therapy of galantamine and cilostazol. (i.e. 3 months [MI before (-3 M), baseline (0 M), 3 and 6 M after the add-on combination).
    Results: Galantamine monotherapy increased cognitive Hasegawa dementia score-revised scores, which were further improved with add-on cilostazol. Cilostazol monotherapy also increased the cognitive tests, which were further improved with add-on galantamine. Add-on cilostazol significantly improved Geriatric Depression Scale and Abe's behavioral and psychological symptoms of dementia scores after galantamine monotherapy. Cilostazol monotherapy also significantly improved Geriatric Depression Scale scores, with further improvements in Geriatric Depression Scale, apathy scores and Abe's behavioral and psychological symptoms of dementia scores by add-on galantamine. Activities of daily living scores continuously improved with galantamine monotherapy and add-on cilostazol.
    Conclusions: The present study provides a clinical possibility that galantamine or cilostazol monotherapy and the combination therapy maintained or even improved cognitive, affective, and activities of daily living functions in AD with asymptomatic lacunar infarction.

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  • Neuroprotective Effects of a Novel Antioxidant Mixture Twendee X in Mouse Stroke Model 査読

    Momoko Kusaki, Yasuyuki Ohta, Haruhiko Inufusa, Toru Yamashita, Ryuta Morihara, Yumiko Nakano, Xia Liu, Jingwei Shang, Feng Tian, Yusuke Fukui, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Koji Abe

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES   26 ( 6 )   1191 - 1196   2017年6月

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

    Background: Oxidative stress and inflammation are important aggravating factors in acute ischemic stroke. Methods: In the present study, the neuroprotective effects of a novel antioxidant mixture Twendee X containing multiple antioxidative ingredients, such as coenzyme Q10, ascorbic acid, and cystine, were evaluated. After the pretreatment of a vehicle or Twendee X (20 mg/kg/d) for 14 days, mice were subjected to transient middle cerebral artery occlusion for 60 minutes and further treated with vehicle or Twendee X for 1 or 5 days. Results: Twendee X administration reduced the infarct size, and reduced oxidative stress markers such as 8-hydroxy-2'-deoxyguanosine,4-hydroxy-2-nonenal, and N-epsilon-(carboxymethyl) lysine (one of advanced glycation end products), as well as inflammatory markers such as ionized calcium binding adapter molecule-1, tumor necrosis factor-alpha, and monocyte chemotactic protein-1. Conclusions: In the present study, the neuroprotective effects of Twendee X were shown on transient middle cerebral artery occlusion mice via antioxidative and anti-inflammatory pathways, providing a potential of Twendee X as one preventive and therapeutic treatment. (C) 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

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  • Clinical features of incidental mild cognitive impairment and dementia in a population-based study 査読

    Nozomi Hishikawa, Yusuke Fukui, Kota Sato, Toru Yamashita, Yasuyuki Ohta, Koji Abe

    GERIATRICS & GERONTOLOGY INTERNATIONAL   17 ( 5 )   722 - 729   2017年5月

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

    Aim: The number of people with dementia is rapidly increasing as populations around the world age. It is important to grasp the characteristic features of mild cognitive impairment (MCI) for early detection and prevention of dementia.
    Methods: We examined 408 individuals recruited from a health checkup formetabolic syndrome, which comprised three groups: normal (n=325), MCI (n=55) and apparent cognitive decline (ACD; n=28). We compared cognitive/affective functions and exercise/hobby habits with assessments of vascular risk factors and results from computerized touch-panel tests.
    Results: Among the 408 individuals, 93.1% showed normal scores on the Mini-Mental State Examination, and 6.9% had ACD. Among the normal Mini-Mental State Examination participants, 14.5% had MCI (13.5% of all participants). The three groups of participants showed significant differences in age, education, systolic blood pressure, glycosylated hemoglobin and high-density lipoprotein cholesterol level. Even within the normal range, those in the MCI group showed significantly lower cognitive function than those in the normal group. Scores on the Geriatric Depression Scale were greater in the MCI group, and "day-night reversal" was worse in the ACD group. Scores on touch-panel screening tests were significantly worse in the MCI and ACD groups than in the normal group. Participants showed better cognitive and affective function if they exercised regularly or had hobbies.
    Conclusions: Incidental MCI and ACD had prevalences of 13.5% and 6.9%, respectively, in the population-based study. Participants with these conditions showed cognitive/affective decline and impairment on computerized touch-panel tests in relation to vascular risk factors and exercise/hobbies.

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  • ABERRANT DISTRIBUTIONS OF NUCLEAR PORE COMPLEX PROTEINS IN ALS MICE AND ALS PATIENTS 査読

    Jingwei Shang, Toru Yamashita, Yumiko Nakano, Ryuta Morihara, Xianghong Li, Tian Feng, Xia Liu, Yong Huang, Yusuke Fukui, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    NEUROSCIENCE   350   158 - 168   2017年5月

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

    Nuclear pore complexes (NPCs) play important roles in traffic of molecules between the nucleus and cytoplasm, aberrant distributions of components of NPCs were demonstrated in C9orf72 amyotrophic lateral sclerosis (C9-ALS) patients, but it is elusive whether such abnormities are also the case with other cause of ALS disease. In the present study, we investigated the spatiotemporal distributions of RanGAP1 and 4 representative nucleoporins (GP210, NUP205, NUP107 and NUP50) of NPCs in human Cu/Zn superoxide dismutase-1 mutation transgenic (SOD1-Tg) mice and sporadic ALS patients. Compared with wild type (WT), these proteins displayed age-dependent and progressive nuclear precipitations, and cytoplasmic aberrant expressions in motor neurons of lumbar cord in SOD1-Tg mice from 10 to 18 weeks (W). Double immunofluorescent analysis showed abnormal nuclear retention and apparent co-localizations of RanGAPI with NUP205 and NUP205 with NUP107, meanwhile, GP210 with NUP205 mainly co localized in the nuclear envelope (NE) of motor neurons. Furthermore, RanGAP1, GP210 and NUP50 showed similarly abnormal nuclear precipitations and cytoplasmic upregulations in SOD1-Tg mice and ALS patients, moreover, aberrant co-localizations of RanGAP1 with TDP-43 and NUP205 with TDP-43 were also observed in motor neurons. The present study indicated that the mislocalization of these proteins of NPCs may underlie the pathogenesis of ALS both in SOD1-Tg mice and human sporadic ALS patients, and these dysfunctions may be a fundamental pathway for ALS that is not specific only in C9-ALS but also in SOD1-ALS, which may be amenable to pharmacotherapeutic intervention. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

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  • Factors related to continuous and discontinuous attendance at memory clinics. 査読 国際誌

    N Hishikawa, Y Fukui, Y Nakano, R Morihara, M Takemoto, K Sato, T Yamashita, Y Ohta, K Abe

    European journal of neurology   24 ( 5 )   673 - 679   2017年5月

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    記述言語:英語  

    BACKGROUND AND PURPOSE: Few studies have examined why some patients with dementia stop attending medical consultations. We conducted a retrospective study to investigate factors associated with discontinuous clinic attendance. METHODS: Participants were 988 patients with dementia from university hospital (UH) clinics and affiliated local hospital (LH) clinics. We compared continuous and discontinuous attenders on cognitive and affective functions and activities of daily living (ADL), and also compared UH and LH patients (UH: continuous, n = 176; discontinuous, n = 207; LH: continuous, n = 418; discontinuous, n = 187). RESULTS: The total annual rate of discontinuation was 8.0%, and the mean period of attendance before discontinuation was 2.2 ± 2.4 years (UH, 2.8 ± 3.0; LH, 1.5 ± 1.3, P < 0.01). Scores for the Mini-Mental State Examination, Hasegawa Dementia Scale - Revised, Geriatric Depression Scale, apathy scale, Abe's behavioral and psychological symptoms of dementia (BPSD) score, and ADL were significantly worse in the discontinuous group than the continuous group for both UH and LH patients (P < 0.01). The best predictor of discontinuation was ADL decline (UH and LH) and Abe's BPSD score (UH). The most common reason for discontinuation was returning to the family doctor (39.1% for UH), and cessation of hospital attendance at their own discretion (35.3% for LH). CONCLUSIONS: We identified the main reasons for discontinuation of attendance as returning to the family doctor and cessation of hospital attendance at their own discretion. The best predictors of discontinuation were ADL decline and worsening BPSD. There were significant differences in discontinuation between UH and LH patients with dementia.

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  • Flow-metabolism uncoupling in the cervical spinal cord of ALS patients 査読

    Toru Yamashita, Tetsuhiro Hatakeyama, Kota Sato, Yusuke Fukui, Nozomi Hishikawa, Yasuyuki Ohta, Yoshihiro Nishiyama, Nobuyuki Kawai, Takashi Tamiya, Koji Abe

    NEUROLOGICAL SCIENCES   38 ( 4 )   659 - 665   2017年4月

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

    Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. In ALS, both glucose consumption and neuronal intensity reportedly decrease in the cerebral motor cortex when measured by positron emission tomography (PET). In this study, we evaluated cervical spinal glucose metabolism, blood flow, and neuronal intensity of 10 ALS patients with upper extremity (U/E) atrophy both with F-18-2-fluoro-2-deoxy-d-glucose (F-18-FDG) PET and C-11-flumazenil (C-11-FMZ) PET. On the ipsilateral side of C5 and T1 levels, F-18-FDG uptake increased significantly (*p &lt; 0.05), and was correlated with the rate of progression of the ALS FRS-R-U/E score (R = 0.645, *p = 0.041). Despite this hyperglucose metabolism, the C-11-FMZ PET study did not show a coupled increase of spinal blood flow even though neuronal intensity did not decrease. These results indicate a strong correlation between hyperglucose metabolism and ALS progression alongside the uncoupling of flow-metabolism. This mechanism, which could result in subsequent motor neuronal death, may be a potential therapeutic target for ALS.

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  • Cognitive and affective functions associated with insomnia: a population-based study 査読

    Nozomi Hishikawa, Yusuke Fukui, Kota Sato, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    NEUROLOGICAL RESEARCH   39 ( 4 )   331 - 336   2017年

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

    Objectives: The number of patients with insomnia is rapidly increasing as society ages. The influence of insomnia on cognitive, affective, and activities of daily living (ADL) functions has not been fully studied.Methods: Participants were 142 residents of a local super-aged community who underwent health check-ups provided by the local government. Participants completed cognitive, affective and ADL function tests including the MMSE. We divided participants into two subgroups based on Athens Insomnia Scale (AIS) scores (AIS3 and AIS4) and compared cognitive, affective, and ADL functions by sex and age.Results: Subjective insomnia (AIS4) was found in 36.2% of participants and was more frequent in females than males. No differences were found in cognitive function between the AIS subgroups. For both sexes, Geriatric Depression Scale scores were significantly higher in the AIS4 subgroup than the AIS3 subgroup. Apathy Scale scores were significantly higher in males in the AIS4 subgroup. Of the AIS subscales, sleepiness during the day' was significantly higher in females than males (**p&lt;0.01), especially in those aged 75years (**p&lt;0.01). This group of older females also showed a significantly lower Trail Making Test scores (*p&lt;0.05).Discussion: Insomnia was present in 36.2% of the population in a Japanese super-aged community. Those with insomnia showed more depressive symptoms (both sexes) and males showed more apathy. The most distinct characteristic of females aged 75years was a high frequency of daytime sleepiness, possibly related to a decline in attention and executive function.

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  • Differences between the behavioral and psychological symptoms of Alzheimer's disease and Parkinson's disease 査読

    Ryo Tokuchi, Nozomi Hishikawa, Kota Sato, Noriko Hatanaka, Yusuke Fukui, Mami Takemoto, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    JOURNAL OF THE NEUROLOGICAL SCIENCES   369   278 - 282   2016年10月

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

    Aim: We compared the behavioral and psychological symptoms of Alzheimer's disease (AD) and Parkinson's disease (PD) in order to determine the characteristic features of each disorder.
    Methods: For this retrospective cohort study, we compared the behavioral and psychological symptoms of 288 AD patients and 189 PD patients (mean age, 74.6 +/- 5.9 and 73.0 +/- 8.7 years respectively). Symptoms were evaluated using the geriatric depression scale (GDS), apathy scale (AS), and Abe's behavioral and psychological symptoms of dementia score (ABS).
    Results: AD patients had higher AS and ABS scores than PD patients. A gender-dependent comparison showed that ABS scores were worse in female AD patients than in female PD patients (p=0.001). A subscale analysis of ABS scores revealed that male AD patients were only significantly different from male PD patients in I item, whereas female AD patients were significantly different from female PD patients in 4 items. Among patients with mild cognitive decline, no differences in affective scores were observed. Alternatively, among patients with moderate cognitive decline, affective scores on all 3 scales were worse in PD patients than in AD patients.
    Conclusions: The present age-and gender-matched retrospective analysis identified greater behavioral and psychological disease severity in female AD patients relative to female PD patients, and greater affective severity in PD patients versus AD patients with a similar degree of cognitive decline. (C) 2016 Elsevier B.V. All rights reserved.

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  • Effects of Pretreatment with Warfarin or Rivaroxaban on Neurovascular Unit Dissociation after Tissue Plasminogen Activator Thrombolysis in Ischemic Rat Brain 査読

    Jingwei Shang, Toru Yamashita, Syoichiro Kono, Ryuta Morihara, Yumiko Nakano, Yusuke Fukui, Xianghong Li, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES   25 ( 8 )   1997 - 2003   2016年8月

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

    Background: Warfarin and rivaroxaban are highly effective in reducing stroke risk in patients with atrial fibrillation (AF). However, their effects on anticoagulation and neurovascular unit (NVU) change remain elusive. In this study, we assessed the risks and benefits of pre-treatment with warfarin or rivaroxaban after tissue-type plasminogen activator (tPA) thrombolysis in ischemic rat brain. Methods: Pretreatment with warfarin (.2 mg/kg/day), low dose rivaroxaban (60 mg/kg/day), high dose rivaroxaban (120 mg/kg/day) or vehicle was performed for 2 weeks, transient middle cerebral artery occlusion (tMCAO) was induced for 90 min, then followed by reperfusion with tPA. At 24 hours (h) after reperfusion, we observed the changes of matrix metalloproteinase-9 (MMP-9), tissue factor, caspase 3 and NVU dissociation. Results: Prothrombin time (PT) was significantly prolonged in the warfarin and rivaroxaban pretreated groups. MMP-9 expression greatly increased in the warfarin group, and this was reduced in the rivaroxaban groups compared with the vehicle group. Tissue factor expression remarkably decreased in the warfarin and rivaroxaban groups. The number of caspase 3-positive cells had no difference among all the groups. Marked dissociations between astrocyte foot processes and the basal lamina or pericytes were observed in the warfarin pretreated group, but such dissociations were improved in the rivaroxaban groups. Conclusions: Our present study shows that pre-treatment with rivaroxaban was noninferior to warfarin in the anticoagulation, but a lower risk of NVU dysfunction and dissociation after tPA treatment in rivaroxaban. This finding could partly explain the mechanism of reducing hemorrhagic complications by rivaroxaban in clinical studies.

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  • Peripheral arterial endothelial dysfunction of neurodegenerative diseases 査読

    Yusuke Fukui, Nozomi Hishikawa, Jingwei Shang, Kota Sato, Yumiko Nakano, Ryuta Morihara, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    JOURNAL OF THE NEUROLOGICAL SCIENCES   366   94 - 99   2016年7月

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

    This study evaluates endothelial functions of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and spinocerebellar ataxia (SCA).
    The reactive hyperemia index (RHI) of peripheral arterial tonometry and serological data were compared between age- and gender-matched normal controls (n = 302) and five disease groups (ALS; n = 75, PD; n = 180, PSP; n = 30, MSA; n = 35, SCA; n = 53). Correlation analyses were performed in ALS with functional rating scale-revised (FRS-R), and in PD with the Hehn-Yahr scale (H-Y) and a heart to mediastinum ratio using I-123-MIBG scintigraphy (MIBG).
    The RHI of ALS and PD, but not of PSP, MSA or SCA, were significantly lower than normal controls (p &lt; 0.01). ALS showed a negative correlation of RHI with serum triglycerides (TG) and immunoreactive insulin (IRI) levels, but not with disease severity (FRS-R) or rates of disease progression (Delta FRS-R). On the other hand, PD showed a negative correlation of RHI with a progressive disease severity (H-Y) and a positive correlation of RHI with early/delayed MIBG scintigraphy, but not with serological data.
    The present study demonstrated significant declines of peripheral arterial endothelial functions in ALS and PD. The RHI of ALS was more correlated with disease duration and serum parameters while the RHI of PD was more correlated with disease severity and MIBG, suggesting different mechanisms of endothelial dysfunction. (C) 2016 Elsevier B.V. All rights reserved.

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  • Age-dependent cognitive and affective differences in Alzheimer's and Parkinson's diseases in relation to MRI findings 査読

    Ryo Tokuchi, Nozomi Hishikawa, Kota Sato, Noriko Hatanaka, Yusuke Fukui, Mami Takemoto, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    JOURNAL OF THE NEUROLOGICAL SCIENCES   365   3 - 8   2016年6月

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

    Objective: To compare age-dependent changes in cognitive and affective functions related to white matter changes between patients with Alzheimer's disease (AD) and Parkinson's disease (PD).
    Methods: We retrospectively compared age-dependent cognitive and affective functions in 216 AD patients, 153 PD patients, and 103 healthy controls with cerebral white matter lesions (WMLs), periventricular hyperintensity (PVH), deep white matter hyperintensity (DWMH), micro-bleeds (MBs), and lacunar infarcts (LIs).
    Results: The average mini-mental state examination (MMSE) scores were 19.6 +/- 6.1 and 26.8 +/- 3.6 in AD and PD patients, respectively. Significant decreases were found in the MMSE score, Hasegawa's dementia scale-revised (HDS-R) score, frontal assessment battery score, and Abe's BPSD score (ABS) among the age-dependent AD subgroups and in the MMSE, HDS-R, Montreal cognitive assessment, geriatric depression scale, and ABS scores among the age-dependent PD subgroups; they were worse in AD patients. White matter changes were observed in &gt; 88% and &gt; 72% of patients with AD and PD, respectively. An age-dependent direct comparison of AD and PD showed significant differences in the PVH and DWMH grades, and numbers of MBs and LIs.
    Conclusion: WML-related cognitive and affective functions worsen with age in AD and PD patients; however, the abnormalities were more frequent and stronger in AD patients. (C) 2016 Elsevier B.V. All rights reserved.

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  • Characteristic features of cognitive, affective and daily living functions of late-elderly dementia 査読

    Nozomi Hishikawa, Yusuke Fukui, Kota Sato, Syoichiro Kono, Toru Yamashita, Yasuyuki Ohta, Kentaro Deguchi, Koji Abe

    GERIATRICS & GERONTOLOGY INTERNATIONAL   16 ( 4 )   458 - 465   2016年4月

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

    AimsThe world is rapidly aging, and is facing an increase of late-elderly dementia patients. It is important to investigate the characteristic features of late-elderly dementia in a super-aged country.
    MethodsWe examined 1554 patients with cognitive decline in Department of Neurology, Okayama University Hospital, Okayama, Japan, divided into three subgroups according to the age: young-elderly (age 64 years), middle-elderly (age 65-74 years) and late-elderly (age 75 years), and investigated the cognitive, affective and activities of daily living functions (ADL), especially in late-elderly patients compared with young-elderly and middle-elderly patients.
    ResultsAmong 1554 patients, Alzheimer's disease dominated at 62%, and age-dependently increased up to 69% in the late-elderly group. The total scores of four cognitive tests were significantly worse with aging for specific subscales of orientation, recall, visual retention, word fluency and so on. In contrast, total scores of the affective tests showed only an increase in the apathy scale in the late-elderly group. Each subgroup showed depressive/depression in 63.2-55.2%, and apathy in 44.2-54.8%. Furthermore, instrumental ADL items significantly deteriorated in the late-elderly group, which statistically correlated with Mini-Mental State Examination score.
    ConclusionsThese results show that the late-elderly group is characterized by significant cognitive declines, increasing apathy, and instrumental ADL decrease. The cognitive decline may be related to such affective and ADL declines. Geriatr Gerontol Int 2016; 16: 458-465.

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  • Cognitive and affective functions in Alzheimer's disease patients with metabolic syndrome. 査読 国際誌

    N Hishikawa, Y Fukui, K Sato, S Kono, T Yamashita, Y Ohta, K Deguchi, K Abe

    European journal of neurology   23 ( 2 )   339 - 45   2016年2月

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    記述言語:英語  

    BACKGROUND AND PURPOSE: The influence of metabolic syndrome (MetS) on cognitive and affective functions in patients with Alzheimer's disease (AD) was examined. METHODS: A total of 570 AD patients were divided into two subgroups depending on waist circumference (WC) (normal versus achieving Japanese diagnostic criteria of MetS). Afterwards, the AD control subgroup was defined as those normal WC patients with no vascular risk factors (VRFs). The AD with MetS (AD-MetS) subgroup was defined as the MetS WC group who had two or more VRFs to qualify as having MetS. Cognitive and affective functions, insulin resistance, vascular endothelial function and white matter changes between AD-MetS and AD controls were compared. RESULTS: Scores on the Mini-Mental State Examination, Hasegawa Dementia Score-Revised, Frontal Assessment Battery and Montreal Cognitive Assessment were worse in the AD-MetS group than in AD controls, but the difference was not significant. Some analyses were conducted twice, once including all patients and once including only late-elderly patients. Scores on the Geriatric Depression Scale were found to be significantly higher for AD-MetS than for AD controls (all ages, late-elderly), as were those for apathy (late-elderly). Furthermore, both the homeostasis model assessment of insulin resistance and reactive hyperemia index scores were significantly worse in AD-MetS than in AD controls, whilst white matter changes showed a tendency to be worse. CONCLUSIONS: Greater cognitive and affective decline occurs in patients with AD-MetS than in those without. Further, insulin resistance and vascular endothelial dysfunction are strongly correlated with AD-MetS before pathological white matter changes can be observed.

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  • Characteristic diffusion tensor tractography in multiple system atrophy with predominant cerebellar ataxia and cortical cerebellar atrophy 査読

    Yusuke Fukui, Nozomi Hishikawa, Kota Sato, Yumiko Nakano, Ryuta Morihara, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    JOURNAL OF NEUROLOGY   263 ( 1 )   61 - 67   2016年1月

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

    The objective of this study is to determine whether diffusion tensor imaging (DTI) tractography analysis is a potential method for differentiating cerebellar ataxia patients with multiple system atrophy with predominant cerebellar ataxia (MSA-C) and cortical cerebellar atrophy (CCA). Forty-one MSA-C patients (62.7 +/- A 8.1 years old, mean +/- A SD) and age- and gender-matched 15 CCA patients (63.0 +/- A 8.6 years old) were examined. Tractography was performed using the DTI track module provided in the MedINRIA version 1.9.4, and regions of interest were drawn manually to reconstruct an efferent fiber tract and two afferent fiber tracts via the cerebellum. Compared with CCA, MSA-C patients showed significant declines of fractional anisotropy (FA) values of afferent 1 and 2 (p &lt; 0.01, respectively) and a significant increase of the radial diffusivity (RD) value in afferent 1 (p &lt; 0.05). Receiver-operator characteristic curve analysis showed 85.7 % sensitivity and 75.0 % specificity of FA values in afferent 1 (cutoff value 0.476). Linear regressions showed strong correlations between FA value and disease duration in CCA patients (efferent 1, r = -0.466; afferent 2, r = -0.543; both p &lt; 0.05), and between the FA value and the ratio of the standardized scale for the assessment and rating of ataxia (SARA)/disease duration in MSA-C patients (afferent 1, r = -0.407; p &lt; 0.01). The present DTI tractography newly showed that the FA values of two afferent fiber tracts showed significant declines in MSA-C patients, and afferent 1 showed good diagnostic sensitivity and specificity. When combining the FA values of efferent 1 with disease duration, the present DTI tractography analysis could be useful for differentiating MSA-C and CCA patients.

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  • Strong Impact of Chronic Cerebral Hypoperfusion on Neurovascular Unit, Cerebrovascular Remodeling, and Neurovascular Trophic Coupling in Alzheimer's Disease Model Mouse 査読

    Jingwei Shang, Toru Yamashita, Yun Zhai, Yumiko Nakano, Ryuta Morihara, Yusuke Fukui, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    JOURNAL OF ALZHEIMERS DISEASE   52 ( 1 )   113 - 126   2016年

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

    Although chronic cerebral hypoperfusion (CCH) may affect Alzheimer's disease (AD) pathogenesis, the mechanism remains elusive. In the present study, we investigated the role of CCH on an AD mouse model in neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of galantamine. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral hypoperfusion. CCH exacerbated neuronal loss and decrease of alpha 7 subunit of nicotinic acetylcholine receptors (alpha 7-nAChRs) expression in hippocampus and thalamus at 12 months. Meanwhile, CCH greatly induced advanced glycation end products expression, and blood-brain barrier leakage through observing IgG and MMP9 expressions. Furthermore, a significant number of dramatic enlarged cerebral vessels with remodeling, BDNF/TrkB decreased in neurovascular trophic coupling. The present study demonstrated that CCH strongly enhanced primary AD pathology including neurodegeneration, neurovascular unit disruption, cerebrovascular remodeling and neurovascular trophic coupling damage in AD mice, and that galantamine treatment greatly ameliorated such neuropathologic abnormalities.

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  • Chronic Cerebral Hypoperfusion Accelerates Alzheimer's Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model 査読

    Yun Zhai, Toru Yamashita, Yumiko Nakano, Zhuoran Sun, Jingwei Shang, Tian Feng, Ryuta Morihara, Yusuke Fukui, Yasuyuki Ohta, Nozomi Hishikawa, Koji Abe

    JOURNAL OF ALZHEIMERS DISEASE   53 ( 3 )   893 - 905   2016年

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

    Recently, aging societies have been showing an increasingly strong relationship between Alzheimer's disease (AD) and chronic cerebral hypoperfusion (HP). In the present study, we created a new mouse model for AD with HP, and investigated its clinical and pathological characteristics. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral HP. In contrast to simple APP23 mice, cerebral HP exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-beta (A beta) burdens. Strong cerebrovascular inflammation and severe amyloid angiopathy with cerebrovascular remodeling were also observed in APP23 + HP mouse brains. An acetylcholinesterase inhibitor galantamine improved such clinical dysfunctions, retrieved above neuropathological characteristics, and enhanced nicotinic acetylcholine receptor (nAChR)-binding activity. The present study demonstrates that chronic cerebral HP enhanced cognitive/motor dysfunctions with parenchymal/cerebrovascular A beta accumulation and cerebrovascular remodeling. These neuropathological abnormalities were greatly ameliorated by galantamine treatment associated with nAChR-mediated neuroprotection by allosterically potentiating ligand action.

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  • Disruption of White Matter Integrity by Chronic Cerebral Hypoperfusion in Alzheimer's Disease Mouse Model 査読

    Yun Zhai, Toru Yamashita, Yumiko Nakano, Zhuoran Sun, Ryuta Morihara, Yusuke Fukui, Yasuyuki Ohta, Nozomi Hishikawa, Koji Abe

    JOURNAL OF ALZHEIMERS DISEASE   52 ( 4 )   1311 - 1319   2016年

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

    A rapidly progressing aging society has raised attention to white matter lesions in Alzheimer's disease. In the present study, we applied an AD plus cerebral hypoperfusion (HP) mouse model and investigated the alternation of key protein molecules in the nodal, paranodal, and intermodal sites in the white matter as well as the efficacy of galantamine. Cerebral HP was induced in APP23 mice by bilateral common carotid arteries stenosis with ameroid constrictors. Compared with the wild type and simple APP23 mice, APP23 + HP mice showed a progressive loss of MAG and NF186 from 6 to 12 months, broken misdistribution of MBP, and extended relocation of Na(v)1.6 and AnkG beyond the primary nodal region in the corpus callosum. Such abnormal neuropathological processes were retrieved with galantamine treatment. The present study demonstrated that cerebral HP strongly disrupted white matter integrity (WMI) at intermodal, paranodal, and Ranvier's nodal sites which may be associated with cognitive decline. Galantamine treatment significantly protected such WMI probably by allosterically potentiating ligand action.

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  • Differentiating progressive supranuclear palsy from Parkinson's disease by MRI-based dynamic cerebrospinal fluid flow. 査読 国際誌

    Yusuke Fukui, Nozomi Hishikawa, Kota Sato, Taijun Yunoki, Syoichiro Kono, Kosuke Matsuzono, Yumiko Nakano, Yasuyuki Ohta, Toru Yamashita, Kentaro Deguchi, Koji Abe

    Journal of the neurological sciences   357 ( 1-2 )   178 - 82   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: The purpose of this study was to clarify the difference between PSP and PD from the viewpoint of dynamic cerebrospinal fluid (CSF) flow focusing on the midbrain aqueduct. METHODS: Thirty-three PD patients (mean age 69.2±7.9) and 35 PSP patients (mean age 70.5±6.6) were included in this study. CSF flow was calculated by 15 images in an equidistant magnetic resonance imaging (MRI) sequence that was taken throughout a cardiac cycle. RESULTS: Absolute values of the velocity (time points of 2-6 and 12-15, *p<0.05), and the width of the CSF velocity (Vheight) (PSP, 5.1±2.3cm/s; PD, 6.0±1.6cm/s, p<0.05) effectively discriminated PSP from PD patients. On the other hand, conventional MRI measurements discriminated well the midbrain aqueduct area (Area) (PSP, 7.7±2.6mm(2); PD, 5.4±1.8mm(2), p<0.01). Two cutoff value lines (Vheight: 4.75, Area: 5.77) of the ROC curve analysis established two areas for discriminating PSP from PD. CONCLUSION: In the present dynamic CSF flow study, it was newly found that mean velocity of each time point and Vheight showed a more significant decline in PSP than in PD patients, providing a sensitive biomarker for differentiating them. The combination of Vheight and Area could further discriminate PSP from PD patients.

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  • Computerized Touch-panel Screening Tests for Detecting Mild Cognitive Impairment and Alzheimer's Disease 査読

    Yusuke Fukui, Toru Yamashita, Nozomi Hishikawa, Tomoko Kurata, Kota Sato, Yoshio Omote, Syoichiro Kono, Taijun Yunoki, Yuko Kawahara, Noriko Hatanaka, Ryo Tokuchi, Kentaro Deguchi, Koji Abe

    INTERNAL MEDICINE   54 ( 8 )   895 - 902   2015年

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

    Objective The increasing population of elderly people in Japan has accelerated the demand for a simple screening test to detect cognitive and affective declines in mild cognitive impairment (MCI) and the early stage of dementia.
    Methods We compared the cognitive and affective functions, activities of daily living (ADLs) and the results of four computerized touch-panel screening tests in 41 MCI subjects, 124 patients with Alzheimer's disease (AD) and 75 age-and gender-matched normal controls.
    Results All computerized touch-panel games were successfully used to discriminate the AD patients from the normal controls (** p&lt;0.01). Although there were no differences in the findings of the conventional cognitive assessments, the results of the flipping cards game were significantly different (** p&lt;0.01) between the normal controls (19.3 +/- 9.5 sec) and MCI subjects (30.9 +/- 18.4 sec). Three conventional affective assessments, the ADL score, Abe's behavioral and psychological symptoms of dementia (ABS) (** p&lt;0.01) and the apathy scale (AS) (* p&lt;0.05), could be used to discriminate the MCI subjects (ABS, 0.9 +/- 1.5; AS, 12.8 +/- 5.9) from the normal controls (ABS, 0.1 +/- 0.4; AS, 8.9 +/- 5.3).
    Conclusion In the present study, all four touch-panel screening tests could be employed to discriminate AD patients from normal controls, whereas only the flipping cards game was effective for distinguishing MCI subjects from normal controls. Therefore, this novel touch-panel screening test may be a more sensitive tool for detecting MCI subjects among elderly patients.

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  • Dynamic Cerebrospinal Fluid Flow on MRI in Cortical Cerebellar Atrophy and Multiple System Atrophy-cerebellar Type. 査読

    Yusuke Fukui, Nozomi Hishikawa, Kota Sato, Syoichiro Kono, Kosuke Matsuzono, Yumiko Nakano, Yasuyuki Ohta, Toru Yamashita, Kentaro Deguchi, Koji Abe

    Internal medicine (Tokyo, Japan)   54 ( 14 )   1717 - 23   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: The purpose of this study was to examine a new MRI technology, dynamic cerebrospinal fluid (CSF) flow, to examine sporadic cerebellar ataxia patients with cortical cerebellar atrophy (CCA) and multiple system atrophy-cerebellar type (MSA-C). METHODS: Nine CCA patients (3 men and 6 women; mean age: 64.2±6.9 years) and 31 MSA-C patients (13 men and 18 women; mean age: 62.7±6.8 years) were examined by a dynamic CSF flow analysis. All CSF flow data were evaluated by phase contrast-MRI using a 1.5T MRI scanner. The CSF flow was calculated by 15 images in the equidistant MRI sequence which was taken through a cardiac cycle. RESULTS: Compared with the CCA patients, the absolute values of the mean velocity of the MSA-C patients were significantly reduced at time points 5 (CCA, 0.24±0.14 cm/s; MSA-C, 0.13±0.11 cm/s; (*) p<0.05) and 13 (CCA, -0.60±0.37 cm/s; MSA-C, -0.31±0.17 cm/s; (**) p<0.01). Significant correlations in Spearman's rank correlation coefficient were also found in MSA-C patients between the disease duration and the difference between the maximum and minimum velocities (Vheight) (r=-0.429, (*) p<0.05), the minimum velocity of the CSF (Vmin) (r=0.486, (**) p<0.01) or the length of the minor axis of the pons (r=-0.529, (**) p<0.01). The linear regressions between the disease duration and Vheight or Vmin revealed a significant strong correlation only in the MSA-C patients. CONCLUSION: The present CSF flow study showed for the first time that Vheight and Vmin revealed good correlations with the disease duration in the MSA-C patients. Furthermore, the velocity of the prepontine CSF flow tended to decrease in the MSA-C patients compared with the CCA patients, suggesting that this particular CSF flow analysis may be a new surrogate marker for differentiating both types of cerebellar ataxia.

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  • Telmisartan Ameliorates Inflammatory Responses in SHR-SR after tMCAO 査読

    Kota Sato, Toru Yamashita, Tomoko Kurata, Yusuke Fukui, Nozomi Hishikawa, Kentaro Deguchi, Koji Abe

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES   23 ( 10 )   2511 - 2519   2014年11月

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

    Telmisartan, an angiotensin receptor blocker with high lipid solubility, also called metabo-sartan, not only reduces blood pressure (BP), but also ameliorates inflammation in the cerebral cortex and in adipose tissue. We examined the effects of telmisartan on inflammatory responses of monocyte chemotactic protein-1, tumor necrosis factor-a, and ionized calcium-binding adapter molecule 1 in the brain of spontaneously hypertensive rat stroke-resistant (SHR-SR) after transient middle cerebral artery occlusion (tMCAO). At 12 weeks of age, SHR-SR received tMCAO for 90 minutes and were divided into 3 groups, that is, the vehicle group, a low-dose telmisartan group (.3 mg/kg/day), and a high-dose telmisartan group (3 mg/kg/day). Immunohistological analysis was performed when rats became 6, 12 and 18 months old. Monocyte chemotactic protein-1, tumor necrosis factor-alpha, and ionized calcium-binding adapter molecule 1 cells (/mm(2)) immunoreactivities increased with age in the cerebral cortex and hippocampus of the vehicle group, suggesting strong and persistent inflammatory changes in SHR-SR after tMCAO up to 18 months of age. On the other hand, a low dose of telmisartan significantly reduced such inflammatory changes without lowering BP, whereas a high dose of telmisartan showed a few additional improvements, including the lowering of BP throughout 6-18 months of age. The present study suggests that persistent hypertension after tMCAO caused a long-lasting inflammatory response in the SHR-SR brain, and that even a low dose of telmisartan reduced continuous inflammation without lowering BP via its pleiotropic effects in the SHR-SR brain. A high dose of telmisartan had a few additional benefits, including lowering BP.

    DOI: 10.1016/j.jstrokecerebrovasdis.2014.02.019

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  • Long-term Amelioration of Telmisartan on Metabolic Syndrome-related Molecules in Stroke-resistant Spontaneously Hypertensive Rat after Transient Middle Cerebral Artery Occlusion 査読

    Kentaro Deguchi, Tomoko Kurata, Yusuke Fukui, Wentao Liu, Zhai Yun, Yoshio Omote, Kota Sato, Syoichiro Kono, Nozomi Hishikawa, Toru Yamashita, Koji Abe

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES   23 ( 10 )   2646 - 2653   2014年11月

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

    Telmisartan is expected to ameliorate not only hypertension, but also metabolic syndrome as a metabosartan. We examined the effects of telmisartan on metabolic syndrome-related molecules such as insulin receptor (IR), peroxisome proliferator-activated receptor gamma (PPAR-gamma), and angiotensin 2 type 1 receptor (AT1R) in stroke-resistant spontaneously hypertensive rat (SHR-SR) after transient middle cerebral artery occlusion (tMCAO), by administering telmisartan at either 0 (vehicle), .3 mg/kg/day (low dose), or 3 mg/kg/day (high dose), postoperatively, from 3 months of age and performed immunohistologic analysis at 6, 12, and 18 months of age. Compared with the vehicle group, the 2 telmisartan groups dose dependently decreased the number of IR-and AT1R-positive neurons in the cerebral cortex in the ipsilateral cerebral cortex from 6 to 18 months after tMCAO. On the other hand, the number of PPAR-gamma-positive neurons increased in a dose-dependent manner in the 2 telmisartan groups from 6 to 18 months. The present study suggests that telmisartan dose-dependently ameliorated metabolic syndrome-related changes in the poststroke brain of SHR-SR with a direct protective effect (low dose) and an additive benefit, an antihypertensive effect at a high dose, for long-term protection after tMCAO.

    DOI: 10.1016/j.jstrokecerebrovasdis.2014.06.012

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  • Strong Reduction of Low-Density Lipoprotein Receptor/Apolipoprotein E Expressions by Telmisartan in Cerebral Cortex and Hippocampus of Stroke Resistant Spontaneously Hypertensive Rats 査読

    Yun Zhai, Toru Yamashita, Tomoko Kurata, Yusuke Fukui, Kota Sato, Syoichiro Kono, Wentao Liu, Yoshio Omote, Nozomi Hishikawa, Kentaro Deguchi, Koji Abe

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES   23 ( 9 )   2350 - 2361   2014年10月

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

    Background: Telmisartan is a unique angiotensin II type 1 receptor blocker with a partial peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonistic property to exert not only antihypertensive effect but also antimetabolic syndrome effect. Methods: We examined the long-term effect of telmisartan on cholesterol transport-related proteins (low-density lipoprotein receptor [LDL-R]/apolipoprotein E [ApoE]) and microtubule-associated proteins 2 (MAP2) in the brains of stroke resistant spontaneously hypertensive rats (SHR-SRs), which were divided into 3 experiment groups including vehicle group (SHR/Ve), low-dose telmisartan group (SHR/Low, 3 mg/kg/day), and high-dose telmisartan group (SHR/High, 3 mg/kg/day). Results: The numbers of LDL-R-and immuno-ApoE-positive neurons increased in both cerebral cortex and hippocampus of SHR/Ve throughout 6, 12, and 18 months of age, compared with age-matched normotensive Wistar rats. On the other hand, telmisartan significantly reduced the numbers of LDL-R-and ApoE immuno-positive neurons in both cerebral cortex and hippocampus, with similar effectiveness in the SHR/Low group without blood pressure (BP) lowering to BP lowering (SHR/High). The decrease of MAP2-positive neuron in SHR/Ve was recovered by telmisartan in both cerebral cortex and hippocampus. Conclusions: These findings suggest that a long-term treatment with telmisartan directly improved neuronal lipid metabolism in the cerebral cortex and hippocampus of SHR-SR, mainly improving LDL-R and ApoE metabolism (SHR/Low) with a small additive benefit by BP lowering (SHR/High), which could provide a preventative approach in patients with hypertension at risk of Alzheimer disease.

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  • Protective Effect of Telmisartan Against Progressive Oxidative Brain Damage and Synuclein Phosphorylation in SHR-SR 査読

    Yusuke Fukui, Nozomi Hishikawa, Tomoko Kurata, Kota Sato, Toru Yamashita, Kentaro Deguchi, Koji Abe

    CEREBROVASCULAR DISEASES   38   84 - 84   2014年9月

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    記述言語:英語   出版者・発行元:KARGER  

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  • Protective Effect of Telmisartan Against Progressive Oxidative Brain Damage and Synuclein Phosphorylation in Stroke-resistant Spontaneously Hypertensive Rats 査読

    Yusuke Fukui, Toru Yamashita, Tomoko Kurata, Kota Sato, Violeta Lukic, Nozomi Hishikawa, Kentaro Deguchi, Koji Abe

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES   23 ( 6 )   1545 - 1553   2014年7月

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

    Previously, we reported that reactive oxygen species and signaling molecules of angiotensin II produced lipid peroxides, degenerated proteins, and injured DNA after cerebral ischemia in normotensive Wistar rats. Here, we investigated the long-term effect of the angiotensin II type I receptor blocker telmisartan on oxidative stress and hyperphosphorylated alpha-synuclein accumulation in stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 3 months, SHR-SR were divided into 3 treatment groups: SHR-SR vehicle (SHR/Ve), SHR-SR low-dose telmisartan (.3 mg/kg/day) (SHR/low), and SHR-SR high-dose telmisartan (3 mg/kg/day) (SHR/high). Immunohistologic analyses were conducted in these groups and Wistar rats at the age of 6, 12, and 18 months. The SHR/Ve group demonstrated more progressive increase in advanced glycation end product (AGE)-, 4-hydroxy-2-nonenal (4-HNE)-, and phosphorylated alpha-synuclein (pSyn)-positive cells in the cerebral cortex and hippocampus compared with the Wistar group at 18 months. These expressions were reduced in the SHR/low group even without lowering blood pressure (BP), and expressions were dramatically suppressed in the SHR/high group with lowering of BP. These data suggest that persistent hypertension in SHR-SR strongly potentiate the markers of oxidative damage (AGEs and 4-HNE) and abnormal accumulation of pSyn, which were greatly suppressed by telmisartan in a dose-dependent manner without and with lowering of BP. (C) 2014 by National Stroke Association

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  • Telmisartan reduces progressive oxidative stress and phosphorylated α-synuclein accumulation in stroke-resistant spontaneously hypertensive rats after transient middle cerebral artery occlusion. 査読

    Sato K, Yamashita T, Kurata T, Lukic V, Fukui Y, Hishikawa N, Deguchi K, Abe K

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   23 ( 6 )   1554 - 1563   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • 臨床研究教育のための臨床研究部講座開設の試み

    片島 るみ, 近藤 秀治, 渡部 有加, 福井 裕介, 前田 和寿

    国立病院機構四国こどもとおとなの医療センター医学雑誌   7 ( 1 )   1 - 4   2020年8月

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    記述言語:日本語   出版者・発行元:(独)国立病院機構四国こどもとおとなの医療センター  

    当院では、臨床研究教育としてe-ラーニングシステム(eAPRIN)を用いているが、臨床研究を初めて行うコメディカルに対してわかりやすくて実践的な教育の提供を目的として、2018年から臨床研究部講座を開始した。本講座では、Research Questionの設定、臨床研究計画の作成から論文投稿までの各過程において、臨床研究を実践する上で必要な基本の考え方および知識を講義する。2018年5月から2019年2月までに全11回を開催し、受講者対象に講座に関するアンケート調査を行った。臨床研究教育受講経験なし、臨床研究実施経験なしのコメディカルはいずれも本講座受講者の約半数を占めていた。本講座の内容が理解できたと回答した者は約8割、1回30分という講義時間は約9割が適当との回答を得た。本調査により、受講者の本講座に対する要望が明らかになり、本講座が受講者にとって有益であったことが示唆された。(著者抄録)

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  • ALS患者頚髄では糖代謝と血流のuncouplingが起きている

    山下徹, 畠山哲宗, 佐藤恒太, 中野由美子, 森原隆太, 商敬偉, 福井祐介, 菱川望, 太田康之, 西山佳宏, 河井信行, 田宮隆, 阿部康二

    日本脳神経CI学会総会プログラム・抄録集(Web)   43rd ( 1 )   182 - 182   2020年

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    記述言語:日本語   出版者・発行元:日本脳循環代謝学会  

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  • 腎性低尿酸血症患者における尿酸トランスポーター遺伝子の解析

    片島るみ, 渡部有加, 福井裕介, 森谷眞紀, 近藤秀治, 近藤秀治, 前田和寿

    日本小児科学会雑誌   124 ( 8 )   1290 - 1290   2020年

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    記述言語:日本語   出版者・発行元:(公社)日本小児科学会  

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    Dementia Japan   32 ( 3 )   438 - 438   2018年9月

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  • 大脳白質病変を伴うアルツハイマー病患者における抗認知症薬の臨床的効果

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  • 一般住民健診における不眠症と認知・情動機能障害の特徴

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    Dementia Japan   31 ( 4 )   618 - 618   2017年10月

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  • 大脳白質病変を考慮したアルツハイマー病の治療薬の選択

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    日本老年医学会雑誌   54 ( 4 )   625 - 625   2017年10月

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    記述言語:日本語   出版者・発行元:(一社)日本老年医学会  

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  • 検診患者における認知機能障害の有病率とその特徴について

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    記述言語:日本語   出版者・発行元:(一社)日本老年医学会  

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  • アルツハイマー病患者におけるメタボリック症候群の影響

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    記述言語:日本語   出版者・発行元:(一社)日本認知症ケア学会  

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  • メタボリック症候群を伴うアルツハイマー病の認知機能と情動機能の特徴

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  • PROTECTIVE EFFECT OF TELMISARTAN AGAINST PROGRESSIVE OXIDATIVE BRAIN DAMAGE AND SYNUCLEIN PHOSPHORYLATION IN STROKE-RESISTANT SPONTANEOUSLY HYPERTENSIVE RATS

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  • 後期高齢者認知症の臨床的特徴について

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  • 軽度認知機能障害の知的機能・情動機能の特徴

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    日本老年医学会雑誌   52 ( 4 )   451 - 451   2015年10月

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    記述言語:日本語   出版者・発行元:(一社)日本老年医学会  

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  • 後期高齢者の認知機能、情動機能、ADLの特徴についての検討

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    日本老年医学会雑誌   52 ( 4 )   451 - 451   2015年10月

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    記述言語:日本語   出版者・発行元:(一社)日本老年医学会  

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  • 高血圧ラット中大脳動脈閉塞再灌流モデルにおけるαシヌクレインの蓄積とテルミサルタンの効果について

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    神経治療学   32 ( 5 )   833 - 833   2015年9月

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    記述言語:日本語   出版者・発行元:(一社)日本神経治療学会  

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  • 後期高齢者における認知症の認知・情動機能、ADLの特徴

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    Dementia Japan   29 ( 3 )   411 - 411   2015年9月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • タッチパネル式検査の軽度認知機能障害とアルツハイマー病における有用性の検討

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    Dementia Japan   29 ( 3 )   404 - 404   2015年9月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • 高血圧ラットにおけるテルミサルタンの酸化ストレスとαシヌクレインに対する効果

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    Dementia Japan   29 ( 3 )   379 - 379   2015年9月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • 軽度認知障害からコンバートあるいはリバートする要因の検討

    徳地 亮, 菱川 望, 佐藤 恒太, 福井 裕介, 太田 康之, 出口 健太郎, 山下 徹, 阿部 康二

    日本老年医学会雑誌   52 ( Suppl. )   104 - 104   2015年5月

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    記述言語:日本語   出版者・発行元:(一社)日本老年医学会  

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  • 当院の認知症外来における後期高齢者の認知・情動機能、ADLの特徴についての検討

    菱川 望, 福井 裕介, 太田 康之, 出口 健太郎, 山下 徹, 阿部 康二

    日本認知症ケア学会誌   14 ( 1 )   187 - 187   2015年4月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症ケア学会  

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  • 側頭葉内側萎縮と大脳白質病変の併存がアルツハイマー病患者の認知機能と情動機能に及ぼす影響

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    脳循環代謝   26 ( 1 )   214 - 214   2014年11月

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    記述言語:日本語   出版者・発行元:日本脳循環代謝学会  

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  • 後期高齢者におけるうつと認知症の関連

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    脳循環代謝   26 ( 1 )   163 - 163   2014年11月

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  • 頭痛とてんかん・うつの脳循環代謝 後期高齢者におけるうつと認知症の関連

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    脳循環代謝   26 ( 1 )   146 - 146   2014年11月

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  • 軽度認知障害とアルツハイマー病におけるタッチパネル式スクリーニング検査の有用性

    福井 裕介, 菱川 望, 山下 徹, 佐藤 恒太, 河野 祥一郎, 柚木 太淳, 河原 由子, 幡中 典子, 出口 健太郎, 阿部 康二

    Dementia Japan   28 ( 4 )   516 - 516   2014年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • MCIのコンバートあるいはリバートに影響する要因の検討

    徳地 亮, 菱川 望, 佐藤 恒太, 幡中 典子, 武本 麻美, 福井 裕介, 出口 健太郎, 山下 徹, 阿部 康二

    Dementia Japan   28 ( 4 )   519 - 519   2014年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • 地域住民健診受診者におけるタッチパネル式簡易認知症スクリーニング検査の有用性

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    Anti-aging Science   5 ( 3 )   228 - 228   2013年12月

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

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▼全件表示

共同研究・競争的資金等の研究

  • 慢性脳低血流がアルツハイマー病に及ぼす影響と抗酸化機能食品による保護的効果の検討

    研究課題/領域番号:20K19666  2020年04月 - 2022年03月

    日本学術振興会  科学研究費助成事業 若手研究  若手研究

    福井 裕介

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

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  • 高血圧による認知機能障害とインスリンシグナルの相関性についての解明

    研究課題/領域番号:19K21507  2018年08月 - 2020年03月

    日本学術振興会  科学研究費助成事業 研究活動スタート支援  研究活動スタート支援

    福井 裕介

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    配分額:2990000円 ( 直接経費:2300000円 、 間接経費:690000円 )

    糖尿病でかつ高血圧を示す生理的2型糖尿病モデルマウスは、6ヶ月齢以降で海馬依存的記憶学習能の低下を呈する時、海馬インスリンシグナル受容体基質1(IRS1)の特定セリン残基のリン酸化が随伴する事が所属研究室から報告されていたが、この海馬IRS1の変化が他種の記憶学習能の低下にも関与するのかについては明らかでは無かった。
    2型糖尿病と同様に、1型糖尿病によっても記憶学習能の障害が誘導される事が知られているため、今回、ストレプトゾトシン誘導性インスリン欠損糖尿病モデル(STZ)マウスを作成し、海馬IRS1の変化について解析を行った。その結果、STZマウスは海馬依存的記憶学習能の低下は観察されなかったが、海馬と前脳に関与する記憶学習能が有意に低下する事が判った。しかしながら、この時、海馬IRS1セリンのリン酸化の変化は見られなかった。
    他方、加齢に伴う代謝機能の低下と同様に観察される記憶学習能の低下には、2型糖尿病と同様に、海馬IRS1の特定セリンのリン酸化が連動する事を突き止めた。これらの結果から、1型糖尿病に起因する記憶学習能障害は、海馬IRS1とは独立して誘導され、一方で、加齢に伴う生理的な記憶学習能低下には海馬IRS1のセリン残基の活性化が関与する事が示唆された。海馬IRS1の特定セリンのリン酸化は、1型糖尿病以外の記憶学習能異常のマーカー候補となる可能性が考えられる。

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  • アルツハイマー病への移行機構における脳代謝調節経路の役割

    研究課題/領域番号:17H02188  2017年04月 - 2020年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    田口 明子, 福井 裕介, 田之頭 大輔, 王 蔚

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    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

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